383 results on '"Massimo Santoro"'
Search Results
2. What do we know about the role of lncRNAs in multiple sclerosis?
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Viviana Nociti and Massimo Santoro
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antisense lncrnas ,enhancer lncrnas ,epigenetics ,immune system ,intergenic lncrna ,intronic lncrna ,multiple sclerosis ,sense lncrnas ,single nucleotide polymorphisms ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system of unknown aetiology although well-defined evidence supports an autoimmune pathogenesis. So far, the exact mechanisms leading to autoimmune diseases are still only partially understood. We know that genetic, epigenetic, molecular, and cellular factors resulting in pathogenic inflammatory responses are certainly involved. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that play an important role in both innate and acquired immunity, so there is great interest in lncRNAs involved in autoimmune diseases. The research on multiple sclerosis has been enriched with many studies on the molecular role of lncRNAs in the pathogenesis of the disease and their potential application as diagnostic and prognostic biomarkers. In particular, many multiple sclerosis fields of research are based on the identification of lncRNAs as possible biomarkers able to predict the onset of the disease, its activity degree, its progression phase and the response to disease-modifying drugs. Last but not least, studies on lncRNAs can provide a new molecular target for new therapies, missing, so far, a cure for multiple sclerosis. While our knowledge on the role of lncRNA in multiple sclerosis has recently improved, further studies are required to better understand the specific role of lncRNAs in this neurological disease. In this review, we present the most recent studies on molecular characterization of lncRNAs in multiple sclerosis disorder discussing their clinical relevance as biomarkers for diagnosis and treatments.
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- 2021
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3. Resveratrol corrects aberrant splicing of RYR1 pre-mRNA and Ca2+ signal in myotonic dystrophy type 1 myotubes
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Massimo Santoro, Roberto Piacentini, Alessia Perna, Eugenia Pisano, Anna Severino, Anna Modoni, Claudio Grassi, and Gabriella Silvestri
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alternative splicing ,calcium homeostasis ,cug-bp1 ,foci ,mbnl1 ,myotonic dystrophy type 1 ,myotubes ,resveratrol ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Myotonic dystrophy type 1 (DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1 (RYR1), sarcoplasmatic/endoplasmatic Ca2+-ATPase (SERCA) and α1S subunit of voltage-gated Ca2+ channels (Cav1.1) is related to Ca2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol (RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy (rs9879/14) on May 20, 2014.
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- 2020
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4. Emission Factors of CO2 and Airborne Pollutants and Toxicological Potency of Biofuels for Airplane Transport: A Preliminary Assessment
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Maurizio Gualtieri, Massimo Berico, Maria Giuseppa Grollino, Giuseppe Cremona, Teresa La Torretta, Antonella Malaguti, Ettore Petralia, Milena Stracquadanio, Massimo Santoro, Barbara Benassi, Antonio Piersanti, Andrea Chiappa, Manuele Bernabei, and Gabriele Zanini
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biofuels ,emission factors ,in vitro exposure ,hazard assessment ,human exposure ,aviation ,Chemical technology ,TP1-1185 - Abstract
Aviation is one of the sectors affecting climate change, and concerns have been raised over the increase in the number of flights all over the world. To reduce the climate impact, efforts have been dedicated to introducing biofuel blends as alternatives to fossil fuels. Here, we report environmentally relevant data on the emission factors of biofuel/fossil fuel blends (from 13 to 17% v/v). Moreover, in vitro direct exposure of human bronchial epithelial cells to the emissions was studied to determine their potential intrinsic hazard and to outline relevant lung doses. The results show that the tested biofuel blends do not reduce the emissions of particles and other chemical species compared to the fossil fuel. The blends do reduce the elemental carbon (less than 40%) and total volatile organic compounds (less than 30%) compared to fossil fuel emissions. The toxicological outcomes show an increase in oxidative cellular response after only 40 min of exposure, with biofuels causing a lower response compared to fossil fuels, and lung-deposited doses show differences among the fuels tested. The data reported provide evidence of the possibility to reduce the climate impact of the aviation sector and contribute to the risk assessment of biofuels for aviation.
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- 2022
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5. Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an 'Out-Brain Origin' of the Disease From a Family Study
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Sara Petrillo, Massimo Santoro, Piergiorgio La Rosa, Alessia Perna, Maria Giovanna Gallo, Enrico Silvio Bertini, Gabriella Silvestri, and Fiorella Piemonte
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Friedreich ataxia ,oxidative stress ,neurodegenerative disease ,Nrf2 ,glutathione ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.
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- 2021
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6. Methylation analysis of HOXA10 regulatory elements in patients with endometriosis
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Pietro G. Signorile, Anna Severino, Massimo Santoro, Maria Spyrou, Rosa Viceconte, and Alfonso Baldi
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Endometriosis ,HOXA10 gene promoter ,DNA methylation analysis ,CpG islands ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Objective The pathogenesis of endometriosis is still mysterious, being retrograde menstruation and coelomic metaplasia the most accepted hypotheses. Recently, it has been proposed that endometriosis is caused by fine-tuning alterations of the female genital system development during the foetal life and that in utero exposition to endocrine disruptors can be one of the factors causing the disease, possibly acting on the methylation status of the genome. In this study, we have evaluated the methylation status of HOXA10 gene regulation regions in a cohort of 22 endometriosis patients respect to a control group of 6 healthy women. Results The methylation study was carried out on three CpG islands, previously described hypermethylated in the endometrium of endometriosis patients and include 22 CpG sites, 21 CpG sites and 10 CpG sites, respectively identified through the online platform MethPrimer. The analysis did not find significant differences between patients with endometriosis and healthy control individuals. These results confirm previous studies on genome wide methylation analysis in endometriosis patients. Therefore, other epigenetically altered genes should be considered more related to the pathogenesis of endometriosis.
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- 2018
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7. Nano-Sampling and Reporter Tools to Study Metabolic Regulation in Zebrafish
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Thomas Dickmeis, Yi Feng, Maria Caterina Mione, Nikolay Ninov, Massimo Santoro, Herman P. Spaink, and Philipp Gut
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zebrafish ,metabolomics ,fluorescent reporter ,nano sampling ,nano scaling ,live imaging ,Biology (General) ,QH301-705.5 - Abstract
In the past years, evidence has emerged that hallmarks of human metabolic disorders can be recapitulated in zebrafish using genetic, pharmacological or dietary interventions. An advantage of modeling metabolic diseases in zebrafish compared to other “lower organisms” is the presence of a vertebrate body plan providing the possibility to study the tissue-intrinsic processes preceding the loss of metabolic homeostasis. While the small size of zebrafish is advantageous in many aspects, it also has shortcomings such as the difficulty to obtain sufficient amounts for biochemical analyses in response to metabolic challenges. A workshop at the European Zebrafish Principal Investigator meeting in Trento, Italy, was dedicated to discuss the advantages and disadvantages of zebrafish to study metabolic disorders. This perspective article by the participants highlights strategies to achieve improved tissue-resolution for read-outs using “nano-sampling” approaches for metabolomics as well as live imaging of zebrafish expressing fluorescent reporter tools that inform on cellular or subcellular metabolic processes. We provide several examples, including the use of reporter tools to study the heterogeneity of pancreatic beta-cells within their tissue environment. While limitations exist, we believe that with the advent of new technologies and more labs developing methods that can be applied to minimal amounts of tissue or single cells, zebrafish will further increase their utility to study energy metabolism.
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- 2019
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8. Correction: BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression.
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Viviana Nociti, Massimo Santoro, Davide Quaranta, Francesco Antonio Losavio, Chiara De Fino, Rocco Giordano, Nicole Piera Palomba, Paolo Maria Rossini, Franca Rosa Guerini, Mario Clerici, Domenico Caputo, and Massimiliano Mirabella
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0206140.].
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- 2019
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9. Serotonin Levels and Cognitive Recovery in Patients with Subacute Stroke after Rehabilitation Treatment
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Mariacristina Siotto, Marco Germanotta, Massimo Santoro, Valeria Cipollini, Giulia Guardati, Dionysia Papadopoulou, Elisa Bray, Alessia Mastrorosa, and Irene Aprile
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post-stroke depression ,post-stroke cognitive impairment ,serotonin ,5-HT ,stroke ,rehabilitation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Post-stroke depression and cognitive impairment are common conditions affecting patients after stroke. Serotonin is a neurotransmitter involved in modulating, among others, mood, cognition, learning, and memory. Sub-optimal serotonin activity may be in part responsible for cognitive deficits seen in depression. In this pilot study serotonin levels were evaluated in 29 patients with sub-acute stroke before and after a rehabilitation treatment (consisting of a program of upper limb robotic rehabilitation in addition to conventional physical therapy treatment). We employed the Back Depression Inventory scale to evaluate symptoms of depression, and specific tools to evaluate cognitive functions. We found a significant reduction of the serotonin levels after rehabilitation in the whole group (T0: 85.9 ± 92.4 ng/mL; T1: 61.9 ± 58.4 ng/mL; p = 0.0018), as well as in the subgroup of patients untreated with Selective Serotonin Reuptake Inhibitors (SRRI), (mean serotonin at T0: 154.0 ± 102.3 ng/mL; mean serotonin at T1: 92.9. ± 68.7 ng/mL at T1; p = 0.005). We also found a correlation with cognitive assessment: in particular, the change from baseline of the serotonin (ΔSerotonin) was correlated with the changes from baseline of the Rey’s Figure (ΔROCF) (r = 0.535; p < 0.05), the Tower of London (ΔToL) (subscore point: r = 0.621; p < 0.005; subscore time: r = −0.619; p < 0.005) meaning that a serotonin levels decrease is associated with a worsening of cognitive functions. Considering patients treated and untreated with SSRIs separately, in patients treated with SSRIs (n = 16) we found only a positive correlation between ∆Serotonin and ∆ToL (subscore point: r= 0.587; p = 0.045), whereas in patients untreated with SSRIs (n = 13) we found a positive correlations between ΔSerotonin and ΔROCF (r = 0.700; p = 0.036), ∆Stroop (subscore time: r = 0.750; p = 0.020) and ∆Tol (subscore point: r = 0.740; p = 0.023) and a negative correlation between ΔSerotonin and ∆Tol (subscore time: r= −0.833; p = 0.005). These results suggest that variation of serotonin levels should be monitored in patients during a rehabilitation program, not only for their relationship with depression symptoms, but also for the correlation with cognitive performance.
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- 2021
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10. NCOA4 Deficiency Impairs Systemic Iron Homeostasis
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Roberto Bellelli, Giorgia Federico, Alessandro Matte’, David Colecchia, Achille Iolascon, Mario Chiariello, Massimo Santoro, Lucia De Franceschi, and Francesca Carlomagno
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iron ,hypochromic anemia ,NCOA4 ,ferritin ,autophagy ,Biology (General) ,QH301-705.5 - Abstract
The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2–3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239–614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.
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- 2016
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11. Total Serum Calcium and Recovery after Rehabilitation in Patients with Stroke
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Mariacristina Siotto, Marco Germanotta, Massimo Santoro, Chiara Di Blasi, Claudia Loreti, Simona Mastropaolo, and Irene Aprile
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calcium ,stroke ,rehabilitation ,nutrition ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Calcium deficiency is frequently observed in stroke survivors, but no data exist concerning the relationship between calcium and rehabilitation outcome in patients with stroke. Therefore, we examined in a group of subacute stroke patients if changes in the Barthel Index after a rehabilitation treatment were associated with blood parameters related to calcium status. We retrospectively explored serum calcium status (total calcium, ionized calcium), serum total protein status, and serum albumin percentage in 30 subacute stroke patients admitted to our rehabilitation center. Patients underwent a 6-week rehabilitation treatment (each session lasting 45 min, 2 sessions/day, 6 days/week). Overall, 26.7% of patients had total calcium levels below the reference range, whereas 100% of patients had ionized calcium in the reference range. Total protein and albumin were below the reference range in about 77% and 67% of patients, respectively. We found that only total calcium was correlated with the change from baseline of the Barthel Index (BI) (rho = 0.466, p = 0.009). A multiple linear regression model confirmed that in our sample the total calcium significantly predicted the change from baseline of the Barthel Index (F5, 24 = 4.074, p = 0.008, adj. R2 = 0.346). This study suggests a possible connection between serum calcium status and total protein status of stroke patients undergoing rehabilitation treatment and rehabilitation outcomes. Further investigations are necessary to confirm the importance of testing serum calcium status of patients at admission in a rehabilitation unit for an eventual supplementation or a dietary personalized program.
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- 2020
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12. Identification of Aberrantly-Expressed Long Non-Coding RNAs in Osteoblastic Cells from Osteoporotic Patients
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Federica Centofanti, Massimo Santoro, Mario Marini, Virginia Veronica Visconti, Anna Maria Rinaldi, Monica Celi, Giovanna D’Arcangelo, Giuseppe Novelli, Augusto Orlandi, Virginia Tancredi, Umberto Tarantino, and Annalisa Botta
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osteoporosis ,epigenetics ,long non-coding rnas ,inflammation ,bone homeostasis ,osteoblast ,Biology (General) ,QH301-705.5 - Abstract
Osteoporosis (OP) is a multifactorial disease influenced by genetic, epigenetic, and environmental factors. One of the main causes of the bone homeostasis alteration is inflammation resulting in excessive bone resorption. Long non-coding RNAs (lncRNAs), have a crucial role in regulating many important biological processes in bone, including inflammation. We designed our study to identify lncRNAs misregulated in osteoblast primary cultures derived from OP patients (n = 4), and controls (CTRs, n = 4) with the aim of predicting possible RNA and/or protein targets implicated in this multifactorial disease. We focused on 84 lncRNAs regulating the expression of pro-inflammatory and anti-inflammatory genes and miRNAs. In silico analysis was utilized to predict the interaction of lncRNAs with miRNAs, mRNAs, and proteins targets. Six lncRNAs were significantly down-regulated in OP patients compared to controls: CEP83-AS1, RP11-84C13.1, CTC-487M23.5, GAS5, NCBP2-AS2, and SDCBP2-AS1. Bioinformatic analyses identified HDCA2, PTX3, and FGF2 proteins as downstream targets of CTC-487M23.5, GAS5, and RP11-84C13.1 lncRNAs mediated by the interaction with miRNAs implicated in OP pathogenesis, including miR-21-5p. Altogether, these data open a new regulatory mechanism of gene expression in bone homeostasis and could direct the development of future therapeutic approaches.
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- 2020
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13. Vitamin D and Rehabilitation after Stroke: Status of Art
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Mariacristina Siotto, Massimo Santoro, and Irene Aprile
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vitamin d ,stroke ,rehabilitation ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Stroke is the first cause of disability in the population and post-stroke patients admitted to rehabilitation units often present a malnutrition status which can influence nutritional indices and then vitamin levels. Vitamin D deficiency seems implicated beyond stroke severity and stroke risk, and also affects post-stroke recovery. Some studies on vitamin D levels and outcome in stroke patients are available but very few data on vitamin D levels and outcome after rehabilitation treatment are reported. This literature review shows the possible relationship between vitamin D deficiency and recovery in post-stroke patients undergoing rehabilitation treatment. Moreover, because several studies have reported that single nucleotide polymorphisms and promoter methylation in genes are involved in vitamin D metabolism and might affect circulating vitamin D levels, these aspects are evaluated in the current paper. From the studies evaluated in this review, it emerges that vitamin D deficiency could not only have an important role in the recovery of patients undergoing rehabilitation after a stroke, but that genetic and epigenetic factors related to vitamin D levels could have a crucial role on the rehabilitation outcome of patients after stroke. Therefore, further studies are necessary on stroke patients undergoing rehabilitation treatment, including: (a) the measurement of the 25(OH) vitamin D serum concentrations at admission and post rehabilitation treatment; (b) the identification of the presence/absence of CYP2R1, CYP27B1, CYP24A1 and VDR polymorphisms, and (c) analysis of the methylation levels of these genes pre- and post-rehabilitation treatment.
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- 2020
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14. BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression.
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Viviana Nociti, Massimo Santoro, Davide Quaranta, Francesco Antonio Losavio, Chiara De Fino, Rocco Giordano, Nicole Piera Palomba, Paolo Maria Rossini, Franca Rosa Guerini, Mario Clerici, Domenico Caputo, and Massimiliano Mirabella
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Medicine ,Science - Abstract
INTRODUCTION:Brain-Derived Neurotrophic Factor (BDNF) and its most common polymorphism Val66Met are known to have a role in Multiple Sclerosis (MS) pathogenesis. Evidence is accumulating that there is an involvement of DNA methylation in the regulation of BDNF expression. The aim of this study was to assess in blood samples of MS patients the correlation between the methylation status of the CpG site near BDNF-Val66Met polymorphism and the severity of the disease. METHODS:We recruited 209 MS patients that were genotyped for the BDNF Val66Met polymorphism. For each patient we quantitatively measured the methylation level of cytosine included in the exonic CpG site that can be created or abolished by the Val66Met BDNF polymorphism. Furthermore, we analyzed the clinical history of each patient and determined the time elapsed since the onset of the disease and an EDSS score of 6.0. RESULTS:The genetic analysis identified 122 (58.4%) subjects carrying the Val/Val genotype, 81 (38.8%) with Val/Met genotype, and 6 (2.8%) carrying the Met/Met genotype. When the endpoint of an EDSS score of 6 was taken into account by means of a survival analysis, 52 failures (i.e., reaching an EDSS score of 6) were reported. When the sample was stratified according to the percentage of the BDNF methylation, subjects falling below the median (median methylation = 81%) were at higher risk of failure (IRD = 0.016; 95%CI = 0.0050-0.0279; p = 0.004). CONCLUSIONS:In patients with a high disease progression the hypomethylation of the BDNF gene could increase the secretion of the protective neurotrophin, so epigenetic modifications could be the organism response to limit a brain functional reserve loss. Our study suggests that the percentage of methylation of the BDNF gene could be used as a prognostic factor for disease progression toward a high disability in MS patient.
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- 2018
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15. Evaluation of AZD1446 as a Therapeutic in DYT1 Dystonia
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Chelsea N. Zimmerman, Karen L. Eskow Jaunarajs, Maria Meringolo, Francesca R. Rizzo, Massimo Santoro, David G. Standaert, and Antonio Pisani
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AZD1446 ,nicotine ,DYT1 ,dystonia ,cholinergic interneurons ,dopamine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
DYT1 dystonia is an early-onset, hyperkinetic movement disorder caused by a deletion in the gene TOR1A, which encodes the protein torsinA. Several lines of evidence show that in animal models of DTY1 dystonia, there is impaired basal dopamine (DA) release and enhanced acetylcholine tone. Clinically, anticholinergic drugs are the most effective pharmacological treatment for DYT1 dystonia, but the currently used agents are non-selective muscarinic antagonists and associated with side effects. We used a DYT1 ∆GAG knock-in mouse model (DYT1 KI) to investigate whether nicotine and/or a non-desensitizing nicotinic agonist, AZD1446, would increase DA output in DYT1 dystonia. Using in vivo microdialysis, we found that DYT1 KI mice showed significantly increased DA output and greater sensitivity to nicotine compared to wild type (WT) littermate controls. In contrast, neither systemic injection (0.25–0.75 mg/kg) or intrastriatal infusion (30 μM–1 mM) of AZD1446 had a significant effect on DA efflux in WT or DYT1 KI mice. In vitro, we found that AZD1446 had no effect on the membrane properties of striatal spiny projection neurons (SPNs) and did not alter the spontaneous firing of ChI interneurons in either WT or DYT1 KI mice. We did observe that the firing frequency of dopaminergic neurons was significantly increased by AZD1446 (10 μM), an effect blocked by dihydro-beta-erythroidine (DHβE 3 μM), but the effect was similar in WT and DYT1 KI mice. Our results support the view that DYT1 models are associated with abnormal striatal cholinergic transmission, and that the DYT1 KI animals have enhanced sensitivity to nicotine. We found little effect of AZD1446 in this model, suggesting that other approaches to nicotinic modulation should be explored.
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- 2017
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16. RET Recognition of GDNF-GFRα1 Ligand by a Composite Binding Site Promotes Membrane-Proximal Self-Association
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Kerry M. Goodman, Svend Kjær, Fabienne Beuron, Phillip P. Knowles, Agata Nawrotek, Emily M. Burns, Andrew G. Purkiss, Roger George, Massimo Santoro, Edward P. Morris, and Neil Q. McDonald
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Biology (General) ,QH301-705.5 - Abstract
The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RETECD), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RETECD envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RETECD cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.
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- 2014
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17. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.
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Marialuisa Moccia, Qingsong Liu, Teresa Guida, Giorgia Federico, Annalisa Brescia, Zheng Zhao, Hwan Geun Choi, Xianming Deng, Li Tan, Jinhua Wang, Marc Billaud, Nathanael S Gray, Francesca Carlomagno, and Massimo Santoro
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Medicine ,Science - Abstract
Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.
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- 2015
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18. Introduction
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Massimo Santoro
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Italian Planning ,Italy ,Environmental Planning ,Development Control ,Development Plans ,Strategic Plans ,Strategic Environmental Assessment ,Heritage Management ,Aesthetics of cities. City planning and beautifying ,NA9000-9428 - Abstract
Introduction
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- 2014
19. XB130 mediates cancer cell proliferation and survival through multiple signaling events downstream of Akt.
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Atsushi Shiozaki, Grace Shen-Tu, Xiaohui Bai, Daisuke Iitaka, Valentina De Falco, Massimo Santoro, Shaf Keshavjee, and Mingyao Liu
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Medicine ,Science - Abstract
XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G(1)-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking-down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3β, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells.
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- 2012
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20. SOD3 decreases ischemic injury derived apoptosis through phosphorylation of Erk1/2, Akt, and FoxO3a.
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Lilja E Laatikainen, Mariarosaria Incoronato, Maria Domenica Castellone, Juha P Laurila, Massimo Santoro, and Mikko O Laukkanen
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Medicine ,Science - Abstract
BackgroundExtracellular superoxide dismutase (SOD3), which dismutates superoxide anion to hydrogen peroxide, has been shown to reduce the free radical stress derived apoptosis in tissue injuries. Since both superoxide anion and hydrogen peroxide have a marked impact on signal transduction pathways and could potentially explain a number of apoptosis and survival -related phenomena in different pathological conditions, we clarified the impact of SOD3 on Akt and Erk1/2 cell survival pathways in rat hind limb injury model.Methodology and principal findingsBased on our data, the hind limb ischemic rats treated with virally delivered sod3 have milder injury and less apoptosis than control animals that could be due to parallel activation of pro-proliferative and anti-apoptotic Erk1/2 and Akt pathways. The common downstream factor of both signaling pathways, the apoptosis related forkhead box protein O3a (FoxO3a), was phosphorylated and translocated to the cytoplasm in sod3 treated tissues and cell line. Additionally, we obtained increased mRNA production of elk-1, ets-1, and microRNA 21 (miR-21), whereas synthesis of bim mRNA was decreased in sod3 overexpressing tissues. We further showed that overexpression of sod3 modulated redox related gene expression by downregulating nox2 and inos when compared to injured control animals.Conclusions and significanceThe study shows the complexity of SOD3-derived effects on tissue injury recovery that are not limited to the reduction of superoxide anion caused cellular stress but highlights the impact of SOD3 related signal transduction on tissue functions and suggests an important role for SOD3 in attenuating cell stress effects in different pathological conditions.
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- 2011
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21. Knock-down of cathepsin D affects the retinal pigment epithelium, impairs swim-bladder ontogenesis and causes premature death in zebrafish.
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Carlo Follo, Matteo Ozzano, Vera Mugoni, Roberta Castino, Massimo Santoro, and Ciro Isidoro
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Medicine ,Science - Abstract
The lysosomal aspartic protease Cathepsin D (CD) is ubiquitously expressed in eukaryotic organisms. CD activity is essential to accomplish the acid-dependent extensive or partial proteolysis of protein substrates within endosomal and lysosomal compartments therein delivered via endocytosis, phagocytosis or autophagocytosis. CD may also act at physiological pH on small-size substrates in the cytosol and in the extracellular milieu. Mouse and fruit fly CD knock-out models have highlighted the multi-pathophysiological roles of CD in tissue homeostasis and organ development. Here we report the first phenotypic description of the lack of CD expression during zebrafish (Danio rerio) development obtained by morpholino-mediated knock-down of CD mRNA. Since the un-fertilized eggs were shown to be supplied with maternal CD mRNA, only a morpholino targeting a sequence containing the starting ATG codon was effective. The main phenotypic alterations produced by CD knock-down in zebrafish were: 1. abnormal development of the eye and of retinal pigment epithelium; 2. absence of the swim-bladder; 3. skin hyper-pigmentation; 4. reduced growth and premature death. Rescue experiments confirmed the involvement of CD in the developmental processes leading to these phenotypic alterations. Our findings add to the list of CD functions in organ development and patho-physiology in vertebrates.
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- 2011
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22. Supplementary Tables 1-3 from Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases
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Massimo Santoro, Samuel A. Wells, Jeffrey F. Moley, J. Silvio Gutkind, Liqiang Xi, Mark Raffeld, Rebecca D. Chernock, Paolo Salerno, Alfredo A. Molinolo, and Anna Tamburrino
- Abstract
PDF file - 138K, Table S1. Characteristics of 53 MTC (hereditary or sporadic) cases for which the RAS/MEK/ERK and PI3K/AKT/mTOR pathways were studied; Table S2. Study of MTC samples for RET and RAS mutation status and for immunoreactivity for pS6, pAKT and Perk; Table S3. Antibodies used for immunohistochemistry
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- 2023
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23. Data from Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases
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Massimo Santoro, Samuel A. Wells, Jeffrey F. Moley, J. Silvio Gutkind, Liqiang Xi, Mark Raffeld, Rebecca D. Chernock, Paolo Salerno, Alfredo A. Molinolo, and Anna Tamburrino
- Abstract
Purpose: Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease.Experimental Design: We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade.Results: Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells.Conclusion: The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC. Clin Cancer Res; 18(13); 3532–40. ©2012 AACR.
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- 2023
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24. Supplementary Figure 1 from Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases
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Massimo Santoro, Samuel A. Wells, Jeffrey F. Moley, J. Silvio Gutkind, Liqiang Xi, Mark Raffeld, Rebecca D. Chernock, Paolo Salerno, Alfredo A. Molinolo, and Anna Tamburrino
- Abstract
PDF file - 87K, Figure S1: Both MZ-CRC-1 and TT MTC cells were treated with either rapamycin (rap; 50 nM, 24 hr), Rad001 (rad; 50 nM, 24 hr), vandetanib (vand;1,000 nM, 24 hr) or vehicle. Proteins were extracted and pS6 and pAKT phosphorylation measured by immunoblot in compound and mock treated cells. Total AKT and S6 were used for normalization
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- 2023
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25. Supplementary Table 3 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Table 3 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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26. Supplementary Figure 1 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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Alfredo Fusco, Massimo Santoro, Giancarlo Troncone, Silvana Sacchetti, Vincenza Leone, Giovanna Maria Pierantoni, Maria Russo, Antonino Iaccarino, Floriana Forzati, Angelo Ferraro, Mimma Bianco, Maria Teresa Berlingieri, Antonella Federico, and Pierlorenzo Pallante
- Abstract
Supplementary Figure 1 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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- 2023
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27. Supplementary Figure 4 from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
- Abstract
PDF file - 141K, RET-PTC triggers CD44-ICD and CD44-CTF production
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- 2023
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28. Supplementary Figure 3 from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
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PDF file- 142K, The RET-PTC-RAS-BRAF cascade triggers CD44 cleavage
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- 2023
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29. Supplementary Figure 1 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Figure 1 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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30. Supplementary Figure 2 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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Alfredo Fusco, Massimo Santoro, Giancarlo Troncone, Silvana Sacchetti, Vincenza Leone, Giovanna Maria Pierantoni, Maria Russo, Antonino Iaccarino, Floriana Forzati, Angelo Ferraro, Mimma Bianco, Maria Teresa Berlingieri, Antonella Federico, and Pierlorenzo Pallante
- Abstract
Supplementary Figure 2 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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- 2023
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31. Supplementary Table 4 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Table 4 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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32. Supplementary Table 5 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Table 5 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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33. Supplementary Figure 1 from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
- Abstract
PDF file - 102K, PKA and MEK inhibition blunts CD44-ICD mediated CREB phosphorylation
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- 2023
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34. Supplementary Figure 2 from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
- Abstract
PDF file - 175K, CD44-ICD-CREB complex in human PTC cell lines
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- 2023
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35. Supplementary Methods from Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Giuliana Salvatore, Francesca Carlomagno, Horst Zitzelsberger, Paolo Salerno, and Tito Claudio Nappi
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Supplementary Methods from Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
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- 2023
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36. Supplementary Table 1 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Table 1 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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37. Supplementary Figure 5 from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
- Abstract
PDF file - 78K, CD44-ICD expression in human thyroid cancer cell lines
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- 2023
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38. Supplementary Methods and Figure Legends 1-2 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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Alfredo Fusco, Massimo Santoro, Giancarlo Troncone, Silvana Sacchetti, Vincenza Leone, Giovanna Maria Pierantoni, Maria Russo, Antonino Iaccarino, Floriana Forzati, Angelo Ferraro, Mimma Bianco, Maria Teresa Berlingieri, Antonella Federico, and Pierlorenzo Pallante
- Abstract
Supplementary Methods and Figure Legends 1-2 from Loss of the CBX7 Gene Expression Correlates with a Highly Malignant Phenotype in Thyroid Cancer
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- 2023
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39. Supplementary Table 2 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Supplementary Table 2 from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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- 2023
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40. Supplementary Figure 1 from Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Giuliana Salvatore, Francesca Carlomagno, Horst Zitzelsberger, Paolo Salerno, and Tito Claudio Nappi
- Abstract
Supplementary Figure 1 from Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
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- 2023
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41. Data from A Cell Proliferation and Chromosomal Instability Signature in Anaplastic Thyroid Carcinoma
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Massimo Santoro, Michael L. Bittner, Alfredo Fusco, Rosa Marina Melillo, Anna Maria Cirafici, Maria Domenica Castellone, Fulvio Basolo, Paolo Miccoli, Clara Ugolini, Corrado Garbi, Yuan Jiang, Paolo Salerno, Tito Claudio Nappi, and Giuliana Salvatore
- Abstract
Here, we show that the anaplastic thyroid carcinoma (ATC) features the up-regulation of a set of genes involved in the control of cell cycle progression and chromosome segregation. This phenotype differentiates ATC from normal tissue and from well-differentiated papillary thyroid carcinoma. Transcriptional promoters of the ATC up-regulated genes are characterized by a modular organization featuring binding sites for E2F and NF-Y transcription factors and cell cycle–dependent element (CDE)/cell cycle gene homology region (CHR) cis-regulatory elements. Two protein kinases involved in cell cycle regulation, namely, Polo-like kinase 1 (PLK1) and T cell tyrosine kinase (TTK), are part of the gene set that is up-regulated in ATC. Adoptive overexpression of p53, p21 (CIP1/WAF1), and E2F4 down-regulated transcription from the PLK1 and TTK promoters in ATC cells, suggesting that these genes might be under the negative control of tumor suppressors of the p53 and pRB families. ATC, but not normal thyroid, cells depended on PLK1 for survival. RNAi-mediated PLK1 knockdown caused cell cycle arrest associated with 4N DNA content and massive mitotic cell death. Thus, thyroid cell anaplastic transformation is accompanied by the overexpression of a cell proliferation/genetic instability-related gene cluster that includes PLK1 kinase, which is a potential molecular target for ATC treatment. [Cancer Res 2007;67(21):10148–57]
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- 2023
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42. Supplementary Methods from CD44 Proteolysis Increases CREB Phosphorylation and Sustains Proliferation of Thyroid Cancer Cells
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Massimo Santoro, Serge N. Manié, Mouhannad Malek, Maria Domenica Castellone, Simona Ventre, Anna Tamburrino, and Valentina De Falco
- Abstract
PDF file - 117K
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- 2023
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43. Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose
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Lingtian Zhang, Marialuisa Moccia, David C. Briggs, Jaideep B. Bharate, Naga Rajiv Lakkaniga, Phillip Knowles, Wei Yan, Phuc Tran, Anupreet Kharbanda, Xiuqi Wang, Yuet-Kin Leung, Brendan Frett, Massimo Santoro, Neil Q. McDonald, Francesca Carlomagno, Hong-yu Li, Zhang, Lingtian, Moccia, Marialuisa, Briggs, David C, Bharate, Jaideep B, Lakkaniga, Naga Rajiv, Knowles, Phillip, Yan, Wei, Tran, Phuc, Kharbanda, Anupreet, Wang, Xiuqi, Leung, Yuet-Kin, Frett, Brendan, Santoro, Massimo, Mcdonald, Neil Q, Carlomagno, Francesca, and Li, Hong-Yu
- Subjects
Wound Healing ,Lung Neoplasms ,Proto-Oncogene Proteins c-ret ,Adenocarcinoma of Lung ,Apoptosis ,Structure-Activity Relationship ,Pyrimidines ,Mutation ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Molecular Medicine ,Protein Kinase Inhibitors ,Cell Proliferation - Abstract
Mutations of the rearranged during transfection (RET) kinase are frequently reported in cancer, which make it as an attractive therapeutic target. Herein, we discovered a series of N-trisubstituted pyrimidine derivatives as potent inhibitors for both wild-type (wt) RET and RETV804M, which is a resistant mutant for several FDA-approved inhibitors. The X-ray structure of a representative inhibitor with RET revealed that the compound binds in a unique pose that bifurcates beneath the P-loop and confirmed the compound as a type I inhibitor. Through the structure-activity relationship (SAR) study, compound 20 was identified as a lead compound, showing potent inhibition of both RET and RETV804M. Additionally, compound 20 displayed potent antiproliferative activity of CCDC6-RET-driven LC-2/ad cells. Analysis of RET phosphorylation indicated that biological activity was mediated by RET inhibition. Collectively, N-trisubstituted pyrimidine derivatives could serve as scaffolds for the discovery and development of potent inhibitors of type I RET and its gatekeeper mutant for the treatment of RET-driven cancers.
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- 2022
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44. A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells
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Brian G. Coon, Sushma Timalsina, Matteo Astone, Zhen W. Zhuang, Jennifer Fang, Jinah Han, Jurgen Themen, Minhwan Chung, Young Joo Yang-Klingler, Mukesh Jain, Karen K. Hirschi, Ai Yamamato, Louis-Eric Trudeau, Massimo Santoro, and Martin A. Schwartz
- Subjects
Inflammation ,Kruppel-Like Transcription Factors ,Endothelial Cells ,MAP Kinase Kinase Kinase 3 ,Cell Biology ,MAP Kinase Kinase 5 ,MAP Kinase Kinase Kinase 2 ,Stress ,Mechanical ,Atherosclerosis ,CRISPR-Cas Systems ,Calcium Signaling ,Humans ,Mitogen-Activated Protein Kinase 7 ,Reactive Oxygen Species ,Mitochondria ,Stress, Mechanical - Abstract
Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3–MEK5–ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK–MEK5–ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.
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- 2022
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45. Oxidative Stress Status in Post Stroke Patients: Sex Differences
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Mariacristina Siotto, Marco Germanotta, Massimo Santoro, Raffaella Canali, Simona Pascali, Sabina Insalaco, Valeria Cipollini, Dionysia Papadopoulou, Erika Antonacci, and Irene Aprile
- Subjects
Health Information Management ,Leadership and Management ,Health Policy ,oxidative stress ,antioxidant defense ,Oxidative Status Index (OSI) ,hydroperoxides ,stroke ,rehabilitation ,Health Informatics - Abstract
After a cerebral stroke insult, there is an overproduction of Reactive Oxygen Species (ROS), which overcome the antioxidant defenses, causing further tissues damage. The status of oxidative stress in stroke patients over time, particularly in those undergoing rehabilitation treatments, has been poorly investigated. We analyzed the oxidative stress status in 61 subacute stroke patients (33 females and 28 males) admitted to our rehabilitation center by measuring, in serum: hydroperoxides levels (d-ROMs), antioxidant activity (BAP test), and the relative antioxidant capacity (OSI index). We also analyzed patients for glucose levels and lipid profile. In addition, we analyzed the correlation between oxidative stress status biomarkers and motor deficits, disability, and pain. Almost all patients showed high or very high levels of d-ROMs, while BAP levels were apparently in the reference range of normality. Females had lower BAP values (females: 2478 ± 379; males: 2765 ± 590; p = 0.034) and lower OSI index (females: 5.7 ± 1.9; males: 6.8 ± 1.9; p = 0.043). Moreover, in the male group, the correlation with motor impairment and disability showed a worsened motor performance when oxidative stress is higher. Female group, on the other hand, had an unexpected different trend of correlation, probably due to an unbalanced systemic oxidative stress. Further research is needed to see if sex differences in oxidative stress status in subacute stroke patients persist after rehabilitation.
- Published
- 2022
46. Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia
- Author
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Vittorio Riso, Piergiorgio La Rosa, Massimo Santoro, Gabriella Silvestri, Pietro Chiurazzi, Fiorella Piemonte, Salvatore Rossi, Maria Grazia Pomponi, Tommaso Nicoletti, Sara Petrillo, Alessia Perna, and Anna Modoni
- Subjects
Adult ,Male ,0301 basic medicine ,Proband ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Ataxia ,Friedreich’s ataxia ,Locus (genetics) ,FXN intronic array ,Settore MED/03 - GENETICA MEDICA ,Compound heterozygosity ,Polymerase Chain Reaction ,Molecular testing ,Epigenesis, Genetic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Trinucleotide Repeats ,Iron-Binding Proteins ,Leukocytes ,Genetics ,medicine ,Humans ,Allele ,Gene ,Alleles ,Genetics (clinical) ,Family Health ,biology ,Frataxin ,FXN methylation ,Sequence Analysis, DNA ,DNA Methylation ,Fibroblasts ,Human genetics ,Pedigree ,Phenotype ,030104 developmental biology ,Friedreich Ataxia ,biology.protein ,Female ,medicine.symptom ,frataxin ,molecular testing ,030217 neurology & neurosurgery ,Microsatellite Repeats - Abstract
Friedreich’s ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at the FXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here we describe a family whose proband was affected by late-onset Friedreich’s ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband’s unaffected sister, as well as their healthy mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66–67 repeat mimicking a GAA expansion at the LR-PCR that was the cause of the wrong initial diagnosis of pre-symptomatic LOFA. Extensive studies in tissues from all the family members, including LR-PCR, assessment of methylation status of FXN locus, MboII restriction analysis and direct sequencing of LR-PCR products, analysis of FXN mRNA, and frataxin protein expression, support the virtual lack of pathogenicity of the rare (GAAGGA)66–67 repeat, also providing significant data about the modulation of epigenetic modifications at the FXN locus. Overall, this report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.
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- 2020
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47. Correction to: Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas
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Monica Fedele, Sabrina Battista, Lawrence Kenyon, Gustavo Baldassarre, Vincenzo Fidanza, Andres J. P. Klein-Szanto, A. F. Parlow, Rosa Visone, Giovanna M. Pierantoni, Eric Outwater, Massimo Santoro, Carlo M. Croce, and Alfredo Fusco
- Subjects
Cancer Research ,Genetics ,Molecular Biology - Published
- 2022
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48. Pathogenesis of Thyroid Cancer
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Massimo Santoro, Barbara Jarzab, Jolanta Krajewska, and Dagmara Rusinek
- Abstract
Thyroid cancers (TCs) include a wide spectrum of cancer types, from indolent papillary microcarcinomas, through well-differentiated TCs to aggressive and treatment-refractory poorly and undifferentiated TCs. TC, mostly papillary microcarcinoma, features one of the most rapid incidence increases compared to other malignant neoplasms. This phenomenon is mainly explained by a widespread use of diagnostic tools (neck ultrasound, fine needle aspiration biopsy). However, it is possibly also a consequence of the impact of environmental and genetic factors. This chapter summarizes the current knowledge concerning environmental and in particular molecular factors related to TC pathogenesis. The use of high throughput methods showed a wide spectrum of genetic and epigenetic alterations as well as their associations in TC. Notwithstanding our better understanding of the molecular pathology of TC, numerous questions still remain open.
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- 2021
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49. Association Study of SLC6A4 (5-HTTLPR) Polymorphism and Its Promoter Methylation with Rehabilitation Outcome in Patients with Subacute Stroke
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Mariacristina Siotto, Irene Aprile, Massimo Santoro, Dionysia Papadopoulou, Marco Germanotta, and Alessia Mastrorosa
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Male ,0301 basic medicine ,medicine.medical_specialty ,5-HTTLPR polymorphism ,Genotyping Techniques ,QH426-470 ,Gastroenterology ,Article ,SLC6A4 ,Epigenesis, Genetic ,rehabilitation ,03 medical and health sciences ,0302 clinical medicine ,Polymorphism (computer science) ,Internal medicine ,Genotype ,Genetics ,medicine ,Humans ,Allele ,Promoter Regions, Genetic ,Stroke ,Genetics (clinical) ,Serotonin transporter ,Aged ,Aged, 80 and over ,Serotonin Plasma Membrane Transport Proteins ,Polymorphism, Genetic ,biology ,business.industry ,Stroke Rehabilitation ,Promoter ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,stroke ,Treatment Outcome ,030104 developmental biology ,CpG site ,biology.protein ,CpG Islands ,Female ,methylation ,business ,030217 neurology & neurosurgery - Abstract
Recently it has been suggested that serotonin transporter (SLC6A4) and its 5HTTLPR polymorphism could be involved in post stroke recovery. Here, we characterized the methylation profile of two different CpG islands within the SLC6A4 promoter region in the whole blood of 50 patients with subacute stroke before and after a six-week rehabilitation treatment. These patients were genotyped for 5HTTLPR polymorphism identifying patients on the basis of short (S) and L (L) alleles: 17 patients LL, 22 patients LS and 11 patients SS. At baseline, all CpG sites for both CpG islands displayed a heterogeneous methylation percentage that were not influenced by the different genotypes. After rehabilitation, we found a significant variation in the methylation levels (increase/decrease) in the specific CpG sites of both CpG islands. The statistical analysis showed a significant relationship between the LL, LS and SS alleles and the outcome of the rehabilitation intervention (χ2 (2,50) = 6.395, p = 0.041). Specifically, we found a significant difference between patients with or without a favorable outcome in the LL (11.1% with a favorable outcome) and in the SS (54.4% with a favorable outcome) groups. Our data suggest that 5-HTTLPR polymorphisms and SLC6A4 promoter methylation may be employed as a non-invasive biological marker of recovery in patients with stroke undergoing rehabilitation.
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- 2021
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50. Circulating long non-coding RNA signature in knee osteoarthritis patients with postoperative pain one-year after total knee replacement
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Massimiliano Valeriani, Kristian Kjær Petersen, Rocco Giordano, Lars Arendt-Nielsen, Ole Simonsen, Massimo Santoro, Costanza Pazzaglia, Giordano, R., Petersen, K. K., Santoro, M., Pazzaglia, C., Simonsen, O., Valeriani, M., and Arendt-Nielsen, L.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Visual analogue scale ,Replacement ,Osteoarthritis ,Gastroenterology ,knee osteoarthritis ,Arthroplasty ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Knee ,pain ,Postoperative ,Arthroplasty, Replacement, Knee ,Pain Measurement ,MALAT1 ,Pain, Postoperative ,long non-coding RNA ,business.industry ,circulating pain biomarker ,Myeloid zinc finger 1 ,Osteoarthritis, Knee ,medicine.disease ,Fold change ,030104 developmental biology ,Anesthesiology and Pain Medicine ,Neuropathic pain ,RNA ,Adenocarcinoma ,Long Noncoding ,RNA, Long Noncoding ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Objectives The incidence of chronic postoperative pain after total knee replacement (TKR) is approx. 20%, and hence preoperative risk factors are important to identify. Recent studies have indicated that preoperative inflammatory markers might hold prognostic information for the development of chronic postoperative pain. Long non-coding RNA (lncRNA) regulates the expression of genes related to e.g. inflammatory processes. The current study aimed to investigate the preoperative lncRNA signature as possible preoperative predictive markers for chronic postoperative pain following TKR. Methods Serum samples, collected preoperatively from 20 knee osteoarthritis (KOA) patients, were analyzed for 84 validated circulatory lncRNA. Pain intensity was assessed using a visual analog scale (VAS) before and one-year after TKR. Differences for the lncRNA expression were analyzed between patients with chronic postoperative pain (VAS≥3) and those with a normal postoperative recovery (VAS Results LncRNA Myeloid Zinc Finger 1 Antisense RNA 1 (MZF1-AS1) (fold change −3.99; p-value: 0.038) (shown to be involved neuropathic pain) Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) (fold change −3.39; p-value: 0.044) (shown to be involved neuropathic pain); Patched 1 pseudogene (LOC100287846) (fold change −6.99; p-value: 0.029) (unknown in pain) were down-regulated preoperatively in the group with chronic postoperative pain compared to the group normal postoperative pain recovery. Conclusions These findings suggest, that TKR patients with chronic postoperative pain present preoperative downregulations of three specific lncRNA detectable at the systemic level. The presented study might give new insights into the complexity of chronic postoperative pain development and show how non-coding RNA plays a role in the underlying molecular mechanisms of pain.
- Published
- 2021
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