@article{%a1:%Y_240,

title = {Effect of MRJF4 on C6 Glioma Cells Proliferation and Migration.},

author = {Pacella S and Fiorito J and Cacciatore I and di Giacomo V and Patruno A and Rapino M and Di Stefano A and Marinelli L and Fornasari E and Cataldi A and Prezzavento O and Marrazzo A},

url = {http://www.eurekaselect.com/145013/article},

doi = {10.2174/1871524916666160823122712 },

year  = {2017},

date = {2017-02-15},

journal = {Central nervous system agents in medicinal chemistry},

volume = {17},

number = {2},

pages = {129-134},

abstract = {BACKGROUND: MRJF4, a novel haloperidol metabolite II prodrug, was obtained through the esterification of the secondary hydroxyl group of haloperidol metabolite II with 4-phenylbutyric acid. The activities of (+/-)-MRJF4 and its two enantiomers [(+)-MRJF4 and (-)-MRJF4] as tumor specific inducers of pro-apoptotic genes were evaluated on malignant C6 glioma cells. In particular, changes in Nf-kB signaling pathway, activity of nitric oxide synthases (NOS), metalloproteinases (MMPs), and membrane adhesion proteins were investigated. RESULTS: IkBα reduced phosphorylation and iNOS lowered activity could be correlated with the previously demonstrated decreased proliferation and tumor progression of C6 cells upon 24 h of treatment with all the three compounds. Integrin beta1 decreased expression, at the same experimental time, seems to support lower C6 cells migrative capability and the consequent reduced invasiveness of these cells upon treatment with (+/-)-MRJF4 and its enantiomers. CONCLUSIONS: These results suggest that this multi-target prodrug and its two enantiomers might be a valuable clinical tool for the treatment of metastatic glioblastoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_241,

title = {Autofluorescence Spectroscopy for Monitoring Metabolism in Animal Cells and Tissues.},

author = {Croce AC and Bottiroli G},

url = {https://link.springer.com/protocol/10.1007%2F978-1-4939-6788-9_2},

doi = {10.1007/978-1-4939-6788-9_2},

year  = {2017},

date = {2017-02-15},

journal = {Methods in molecular biology - Histochemistry of Single Molecules Methods and Protocols},

volume = {1560},

pages = {15-43},

abstract = {Excitation of biological substrates with light at a suitable wavelength can give rise to a light emission in the ultraviolet (UV)-visible, near-infrared (IR) spectral range, called autofluorescence (AF). This is a widespread phenomenon, ascribable to the general presence of biomolecules acting as endogenous fluorophores (EFs) in the organisms of the whole life kingdom. In cytochemistry and histochemistry, AF is often an unwanted signal enhancing the background and affecting in particular the detection of low signals or rare positive labeling spots of exogenous markers. Conversely, AF is increasingly considered as a powerful diagnostic tool because of its role as an intrinsic biomarker directly dependent on the nature, amount, and microenvironment of the EFs, in a strict relationship with metabolic processes and structural organization of cells and tissues. As a consequence, AF carries multiple information that can be decrypted by a proper analysis of the overall emission signal, allowing the characterization and monitoring of cell metabolism in situ, in real time and in the absence of perturbation from exogenous markers. In the animal kingdom, AF studies at the cellular level take advantage of the essential presence of NAD(P)H and flavins, primarily acting as coenzymes at multiple steps of common metabolic pathways for energy production, reductive biosynthesis and antioxidant defense. Additional EFs such as vitamin A, porphyrins, lipofuscins, proteins, and neuromediators can be detected in different kinds of cells and bulk tissues, and can be exploited as photophysical biomarkers of specific normal or altered morphofunctional properties, from the retinoid storage in the liver to aging processes, metabolic disorders or cell transformation processes. The AF phenomenon involves all living system, and literature reports numerous investigations and diagnostic applications of AF, taking advantage of continuously developing self-assembled or commercial instrumentation and measuring procedures, making almost impossible to provide their comprehensive description. Therefore a brief summary of the history of AF observations and of the development of measuring systems is provided, along with a description of the most common EFs and their metabolic significance. From our direct experience, examples of AF imaging and microspectrofluorometric procedures performed under a single excitation in the near-UV range for cell and tissue metabolism studies are then reported.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_210,

title = {Express or Repress? The Transcriptional Dilemma of Damaged Chromatin.},

author = {Capozzo I and Iannelli F and Francia S and {d'Adda di Fagagna F}},

url = {http://onlinelibrary.wiley.com/doi/10.1111/febs.14048/abstract},

doi = {10.1111/febs.14048},

year  = {2017},

date = {2017-02-15},

journal = {FEBS journal},

volume = {284},

number = {14},

pages = {2133-2147},

abstract = {The fine modulation of transcriptional activity around DNA lesions is essential to carefully regulate the crosstalk between transcription, the DNA damage response, and DNA repair, particularly when the lesion occurs next to, or within, actively transcribed genes. Recently, several studies have been carried out to investigate how DNA lesions have an impact on local transcription, but the emerging model remains incomplete. Transcription of genes around damaged DNA is actively down-regulated by the DNA damage response through different mechanisms, which appear specific to the chromatin context, the type of DNA damage or its complexity. Intriguingly, emerging evidence also indicates that transcription of non-coding RNAs (ncRNAs) is induced at sites of DNA damage, producing small ncRNAs that are, in turn, required for a full DDR activation. We discuss here these recent findings, highlighting the major unresolved questions in the field, and propose ways to reconcile these apparently contradictory observations. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_186,

title = {DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs.},

author = {Rossiello F and Aguado J and Sepe S and Iannelli F and Nguyen Q and Pitchiaya S and Carninci P and {d'Adda di Fagagna F}},

url = {https://www.nature.com/articles/ncomms13980},

doi = {10.1038/ncomms13980},

year  = {2017},

date = {2017-02-11},

journal = {Nature Communications},

volume = {8},

pages = {13980},

abstract = {The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_235,

title = {Cytokine expression profile and blood parameter evaluation of patients undergoing cardiac surgery.},

author = {De Iuliis V and Dadorante V and Marino A and Griffo I and Pennelli A and Breda V and Robuffo I and Ursi S and Martinotti S and Caputi S and Toniato E},

url = {https://www.biolifesas.org/biolife/category/journals/journal-of-biological-regulators-and-homeostatic-agents/},

year  = {2017},

date = {2017-02-09},

journal = {Journal of biological regulators and homeostatic agents},

volume = {31},

number = {4},

pages = {1109-1113},

abstract = {Cardiac surgery is accompanied by an important immune response that is poorly understood. This inflammatory response is caused by several stimuli: surgical trauma, cardiopulmonary bypass apparatus, aortic-cross clamping, reperfusion injury and hypothermia. The aim of the present study is to investigate the cytokine level profile involved in the inflammatory pathway of patients undergoing cardiac surgery. One hundred and two patients undergoing elective cardiac surgery utilizing cardiopulmonary bypass (CPB) apparatus were enrolled in the study. In the hematological and biochemical profiles investigated, we observed a significant increase of WBC and blood glucose concentration and a strong decrease of RBC, HB, HCT and PLT 24 h post-surgery compared to baseline and immediately after surgery groups. Furthermore, we found a modulation of cytokine levels mostly for IL-10 and an increase of IL-6, detected at 6 h post-surgery, IL-8 at 6 and 24 h, and TNFalfa only at 24 h post-surgery. In conclusion, these findings evidence a time course profile on cytokine levels and a balance between pro- and anti-inflammatory cytokine activation during and after cardiac surgery. In fact, IL-6 and IL-10, a pro- and an anti-inflammatory cytokine, respectively, increased immediately after surgery. The plasma level of TNF-alfa could be inhibited by the high concentration of IL-10 up to 6 h post-surgery. An IL-10 reduction at baseline level, after 24 h post-surgery, could explain a rise of TNF-alfa plasma concentration. On the other hand, considering the dual role of IL-6 on inflammation acting both as an activator of inflammatory cascade or an anti-inflammatory agent, the increased IL-6 levels 24 h after surgery could be related to the negative feedback action on TNFalfa activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_237,

title = {Association of a history of childhood-onset obesity and dieting with eating disorders.},

author = {Cena H and Stanford FC and Ochner L and Fonte ML and Biino G and De Giuseppe R and Taveras E and Misra M},

url = {http://www.tandfonline.com/doi/abs/10.1080/10640266.2017.1279905?journalCode=uedi20},

doi = {10.1080/10640266.2017.1279905},

year  = {2017},

date = {2017-02-09},

journal = {Eating disorders },

volume = {25},

number = {3},

pages = {216-229},

abstract = {This was a retrospective, observational chart review conducted on a convenience sample of 537 outpatients, aged 16-60 years, referred to an Italian Dietetic and Nutrition University Center. The study aimed to look at the association between a history of childhood obesity and dieting behaviors with development of eating disorders (EDs) at a later age. Subjects with a history of EDs (n = 118), assessed using both self-report and health records, were compared with those with no EDs (n = 419), who were attending the clinic mainly for primary prevention of metabolic and cardiovascular risk. Logistic regression analysis was performed to assess the association of childhood-onset obesity with development of an ED at a later age. Childhood-onset obesity, gender, maternal history of eating disorders, and dieting were associated with a positive history of EDs at a later age (p < .05). It is important to raise professional awareness of early symptoms of EDs in children with a history of obesity and treat them accordingly.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_209,

title = {Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma.},

author = {Musumeci F and Fallacara AL and Brullo C and Grossi G and Botta L and Calandro P and Chiariello M and Kissova M and Crespan E and Maga G and Schenone S},

url = {http://www.sciencedirect.com/science/article/pii/S0223523416310418},

doi = {dx.doi.org/10.1016/j.ejmech.2016.12.036},

year  = {2017},

date = {2017-02-05},

journal = {European journal of medicinal chemistry},

volume = {127},

pages = {369-378},

abstract = {In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50 value of 7.1 microM.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_213,

title = {Genetic evidence for a worldwide chaotic dispersion pattern of the arbovirus vector, Aedes albopictus.},

author = {Manni M and Guglielmino CR and Scolari F and Vega-Rúa A and Failloux AB and Somboon P and Lisa A and Savini G and Bonizzoni M and Gomulski LM and Malacrida AR and Gasperi G},

url = {http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0005332},

doi = {dx.doi.org/10.1371/journal.pntd.0005332},

year  = {2017},

date = {2017-01-30},

journal = {PLoS neglected tropical diseases},

volume = {11},

number = {1},

pages = {e0005332},

abstract = {BACKGROUND: Invasive species represent a global concern for their rapid spread and the possibility of infectious disease transmission. This is the case of the global invader Aedes albopictus, the Asian tiger mosquito. This species is a vector of medically important arboviruses, notably chikungunya (CHIKV), dengue (DENV) and Zika (ZIKV). The reconstruction of the complex colonization pattern of this mosquito has great potential for mitigating its spread and, consequently, disease risks.

METHODOLOGY/PRINCIPAL FINDINGS: Classical population genetics analyses and Approximate Bayesian Computation (ABC) approaches were combined to disentangle the demographic history of Aedes albopictus populations from representative countries in the Southeast Asian native range and in the recent and more recently colonized areas. In Southeast Asia, the low differentiation and the high co-ancestry values identified among China, Thailand and Japan indicate that, in the native range, these populations maintain high genetic connectivity, revealing their ancestral common origin. China appears to be the oldest population. Outside Southeast Asia, the invasion process in La Réunion, America and the Mediterranean Basin is primarily supported by a chaotic propagule distribution, which cooperates in maintaining a relatively high genetic diversity within the adventive populations. CONCLUSIONS/SIGNIFICANCE:

From our data, it appears that independent and also trans-continental introductions of Ae. albopictus may have facilitated the rapid establishment of adventive populations through admixture of unrelated genomes. As a consequence, a great amount of intra-population variability has been detected, and it is likely that this variability may extend to the genetic mechanisms controlling vector competence. Thus, in the context of the invasion process of this mosquito, it is possible that both population ancestry and admixture contribute to create the conditions for the efficient transmission of arboviruses and for outbreak establishment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_195,

title = {EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression.},

author = {Pradella D and Naro C and Sette C and Ghigna C},

url = {https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-016-0579-2},

doi = {10.1186/s12943-016-0579-2},

year  = {2017},

date = {2017-01-30},

journal = {Molecular cancer},

volume = {16},

number = {1},

pages = {8},

abstract = {Epithelial-to-mesenchymal transition (EMT) is associated with metastasis formation as well as with generation and maintenance of cancer stem cells. In this way, EMT contributes to tumor invasion, heterogeneity and chemoresistance. Morphological and functional changes involved in these processes require robust reprogramming of gene expression, which is only partially accomplished at the transcriptional level. Alternative splicing is another essential layer of gene expression regulation that expands the cell proteome. This step in post-transcriptional regulation of gene expression tightly controls cell identity between epithelial and mesenchymal states and during stem cell differentiation. Importantly, dysregulation of splicing factor function and cancer-specific splicing isoform expression frequently occurs in human tumors, suggesting the importance of alternative splicing regulation for cancer biology.In this review, we briefly discuss the role of EMT programs in development, stem cell differentiation and cancer progression. Next, we focus on selected examples of key factors involved in EMT and stem cell differentiation that are regulated post-transcriptionally through alternative splicing mechanisms. Lastly, we describe relevant oncogenic splice-variants that directly orchestrate cancer stem cell biology and tumor EMT, which may be envisioned as novel targets for therapeutic intervention.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_197,

title = {Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.},

author = {Masetti R and Bertuccio SN and Astolfi A and Chiarini F and Lonetti A and Indio V and De Luca M and Bandini J and Serravalle S and Franzoni M and Pigazzi M and Martelli AM and Basso G and Locatelli F and Pession A},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251306/},

doi = {10.1186/s13045-017-0396-0},

year  = {2017},

date = {2017-01-21},

journal = {Journal of hematology & oncology },

volume = {10},

number = {1},

pages = {26},

abstract = {BACKGROUND: CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. METHODS: We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. RESULTS: As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. CONCLUSIONS: Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_306,

title = {TGF-beta1 differentially modulates the collagen VI alpha5 and alpha6 chains in human tendon cultures.},

author = {Sabatelli P and Sardone F and Traina F and Merlini L and Santi S and Wagener R and Faldini C},

url = {https://www.biolifesas.org/biolife/jbrha-2/},

year  = {2016},

date = {2016-12-02},

journal = {Journal of Biological Regulators and Homeostatic Agents},

volume = {30},

number = {4},

pages = {107-113},

abstract = {Collagen VI is a microfibrillar collagen with a potential regulatory role in tendon repair mechanism. We studied the expression of collagen VI alpha5 and alpha6 chains in normal human tendon fibroblast cultures, both under basal condition and in response to TGF-beta1, a potent regulator of tendon healing. Under basal condition, we found that the alpha5 chain was expressed, although to a lesser extent with respect to the alpha3 chain; in contrast, the alpha6 chain was absent. The treatment with TGFbeta1 induced an opposite effect on the expression of the alpha5 and alpha6 chains; in fact, while the alpha5 chain was dramatically reduced, the alpha6 chain was induced and released in the culture medium. These data indicate that collagen VI alpha5 and alpha6 chains are differentially involved in tendon matrix homeostasis. The alpha6 chain may represent a new potential biomarker for monitoring TGFbeta1-related events in tendon, as healing and fibrotic scar formation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_274,

title = {Potential therapeutic effects of the mtor inhibitors for preventing ageing and progeria-related disorders.},

author = {Evangelisti C and Cenni V and Lattanzi G},

url = {http://onlinelibrary.wiley.com/doi/10.1111/bcp.12928/abstract;jsessionid=34B2DFDBFC206F2806B33262A44B1552.f03t02},

doi = {10.1111/bcp.12928},

year  = {2016},

date = {2016-11-30},

journal = {British Journal of Clinical Pharmacology (Literature Review)},

volume = {82},

number = {5},

pages = {1229-1244},

abstract = {The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, such signaling pathway has come to the attention of the scientific community due to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends life-span in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome that recapitulates most of the traits of physiological ageing, the Hutchinson-Gilford Progeria (HGPS). The promising perspectives raised by those results warrant a better understanding of mTOR signaling and of potential applications of mTOR inhibitors to counteract ageing-associated diseases and increase longevity. This review is focused on these issues. This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_243,

title = {Predictive value of microparticle-associated tissue factor activity for permeability glycoprotein-mediated multidrug resistance in cancer.},

author = {Angelini A and Miscia S and Centurione MA and Di Pietro R and Centurione L},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103930/},

doi = {10.3892/ol.2016.5105},

year  = {2016},

date = {2016-11-29},

journal = {Oncology Letters},

volume = {12},

number = {5},

pages = {3273-3277},

abstract = {Multidrug resistance (MDR) protein 1, which is also known as permeability glycoprotein (Pgp), and tissue factor (TF) are recurrently overexpressed on the surface of cancer cells, likely in response to stimuli such as chemotherapy. Microparticles (MPs) released from cancer cells into the bloodstream express tumour markers on their surface that may be useful as predictive biomarkers for evaluating disease progression. The present study measured the level of TF/factor VII (FVII)-dependent coagulation of MPs isolated from the plasma of cancer patients with various tumours, who were undergoing chemotherapy. Furthermore, Pgp expression on the surface of MPs was evaluated by immunohistochemistry. A total of 50 cancer patients, as well as 10 healthy volunteers, were enrolled in the present study. MP-associated TF/FVII-dependent coagulation pathways were evaluated as the effect of an anti-FVII antibody on the time to thrombin generation, as compared with controls treated with saline. The significantly lengthened times of coagulation [obtained in 20/50 samples (36.5 ± 16%) after treatment with anti-FVIIa when compared with controls] suggest the presence of TF activity is associated with circulating MPs. Furthermore, the 20 MP/TF-positive samples were associated with Pgp overexpression on their surface. Conversely, in the remaining samples (n=30), treatment with the anti-FVIIa antibody did not significantly lengthen the time to clotting (<10%), and Pgp overexpression was not detected. In addition, in the control samples from healthy individuals, Pgp expression at the plasma membrane and clotting in the presence of the anti-FVII antibody were not observed, indicating the absence of MPs. The present study demonstrated that MPs in the blood of cancer patients promoted fibrin generation via TF/FVII-dependent pathways, thus suggesting that the evaluation of MP-TF activity may have a predictive value for Pgp-mediated MDR in various cancer types. Although further studies are required, the measurement of plasma MP-associated TF activity as a predictive biomarker may provide novel therapeutic perspectives to improve the prognosis and effectiveness of anti-cancer drugs in patients who are at a high-risk of Pgp-mediated MDR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_275,

title = {Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies.},

author = {Evangelisti C and Evangelisti C and Buontempo F and Lonetti A and Orsini E and Chiarini F and Barata JT and Pyne S and Pyne NJ and Martelli AM},

editor = {Ardizzoni A},

doi = {10.1038/leu.2016.208},

year  = {2016},

date = {2016-11-17},

journal = {Leukemia},

volume = {30},

number = {11},

pages = {2142-2151},

abstract = {Sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P), are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on determination of the cell fate by contributing to either cell survival or death. While ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis, and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of hematological cancers.Leukemia accepted article preview online, 27 July 2016. doi:10.1038/leu.2016.208.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_272,

title = {Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line.},

author = {El-Moghazy SM and George RF and Osman EE and Elbatrawy AA and Kissova M and Colombo A and Crespan E and Maga G},

url = {http://www.sciencedirect.com/science/article/pii/S0223523416305827},

doi = {10.1016/j.ejmech.2016.07.034},

year  = {2016},

date = {2016-11-10},

journal = {European Journal of Medicinal Chemistry},

volume = {123},

pages = {1-13},

abstract = {Some novel 6-substituted pyrazolo[3,4-d]pyrimidines 4, 5, 6a-d, 7a-c, 8 and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines 9a-c, 10a-c, 11, 12a,b, 13a-c and 14 were synthesized and characterized by spectral and elemental analyses. They were screened for their biological activity in vitro against Abl and Src kinases. Compounds 7a and 7b revealed the highest activity against both wild and mutant Abl kinases as well as the Src kinase and the leukemia K-562 cell line. They can be considered as new hits for further structural optimization to obtain better activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_245,

title = {Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage.},

author = {Aredia F and Czaplinski S and Fulda S and Scovassi AI},

url = {https://bmccancer.biomedcentral.com/articles/10.1186/s12885-016-2878-9},

doi = {10.1186/s12885-016-2878-9},

year  = {2016},

date = {2016-11-05},

journal = {BMC Cancer},

volume = {16},

number = {1},

pages = {851},

abstract = {BACKGROUND: NH exchangers (NHEs) play a crucial role in regulating intra/extracellular pH, which is altered in cancer cells, and are therefore suitable targets to alter cancer cell metabolism in order to inhibit cell survival and proliferation. Among NHE inhibitors, amiloride family members are commonly used in clinical practice as diuretics; we focused on the amiloride HMA, reporting a net cytotoxic effect on a panel of human cancer cell lines; now we aim to provide new insights into the molecular events leading to cell death by HMA. METHODS:Colon cancer cell lines were treated with HMA and analysed with: morphological and cellular assays for cell viability and death, and autophagy; biochemical approaches to evaluate mitochondrial function and ROS production; in situ detection of DNA damage; molecular tools to silence crucial autophagy/necroptosis factors. RESULTS: HMA affects cellular morphology, alters mitochondrial structure and function, causes an increase in ROS, which is detrimental to DNA integrity, stimulates poly(ADP-ribose) synthesis, activates RIPK3-dependent death and triggers autophagy, which is unable to rescue cell survival. These features are hot points of an intricate network of processes, including necroptosis and autophagy, regulating the homeostasis between survival and death. CONCLUSION: Our results allow the identification of multiple events leading to cell death in cancer cells treated with HMA. The here-defined intricate network activated by HMA could be instrumental to selectively target the key players of each pathway in the attempt to improve the global response to HMA. Our data could be the starting point for developing a newly designed targeted therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_294,

title = {Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway.},

author = {Lonetti A and Cappellini A and Bertaina A and Locatelli F and Pession A and Buontempo F and Evangelisti C and Evangelisti C and Orsini E and Zambonin L and Neri LM and Martelli AM and Chiarini F},

url = {https://jhoonline.biomedcentral.com/articles/10.1186/s13045-016-0344-4},

doi = {10.1186/s13045-016-0344-4},

year  = {2016},

date = {2016-10-24},

journal = {Journal Of Hematology & Oncology },

volume = {9},

number = {1},

pages = {114},

abstract = {BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_285,

title = {Production of Small Noncoding RNAs from the flamenco Locus Is Regulated by the gypsy Retrotransposon of Drosophila melanogaster.},

author = {Guida V and Cernilogar FM and Filograna A and De Gregorio R and Ishizu H and Siomi MC and Schotta G and Bellenchi GC and Andrenacci D},

url = {http://www.genetics.org/content/204/2/631.long},

doi = {10.1534/genetics.116.187922},

year  = {2016},

date = {2016-10-12},

journal = {Genetics},

volume = {204},

number = {2},

pages = {631-644},

abstract = {Protective mechanisms based on RNA silencing directed against the propagation of transposable elements are highly conserved in eukaryotes. The control of transposable elements is mediated by small noncoding RNAs, which derive from transposon-rich heterochromatic regions that function as small RNA-generating loci. These clusters are transcribed and the precursor transcripts are processed to generate Piwi-interacting RNAs (piRNAs) and endogenous small interfering RNAs (endo-siRNAs), which silence transposable elements in gonads and somatic tissues. The flamenco locus is a Drosophila melanogaster small RNA cluster that controls gypsy and other transposable elements, and has played an important role in understanding how small noncoding RNAs repress transposable elements. In this study, we describe a cosuppression mechanism triggered by new euchromatic gypsy insertions in genetic backgrounds carrying flamenco alleles defective in gypsy suppression. We found that the silencing of gypsy is accompanied by the silencing of other transposons regulated by flamenco, and of specific flamenco sequences from which small RNAs against gypsy originate. This cosuppression mechanism seems to depend on a post-transcriptional regulation that involves both endo-siRNA and piRNA pathways and is associated with the occurrence of developmental defects. In conclusion, we propose that new gypsy euchromatic insertions trigger a post-transcriptional silencing of gypsy sense and antisense sequences, which modifies the flamenco activity. This cosuppression mechanism interferes with some developmental processes, presumably by influencing the expression of specific genes. Copyright 2016 by the Genetics Society of America.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_257,

title = {Low-Coherence Reflectometry for Refractive Index Measurements of Cells in Micro-Capillaries.},

author = {Carpignano F and Rigamonti G and Mazzini G and Merlo S},

url = {http://www.mdpi.com/1424-8220/16/10/1670},

doi = {10.3390/s16101670},

year  = {2016},

date = {2016-10-11},

journal = {Sensors},

volume = {16},

number = {10},

pages = {E1670},

abstract = {The refractive index of cells provides insights into their composition, organization and function. Moreover, a good knowledge of the cell refractive index would allow an improvement of optical cytometric and diagnostic systems. Although interferometric techniques undoubtedly represent a good solution for quantifying optical path variation, obtaining the refractive index of a population of cells non-invasively remains challenging because of the variability in the geometrical thickness of the sample. In this paper, we demonstrate the use of infrared low-coherence reflectometry for non-invasively quantifying the average refractive index of cell populations gently confined in rectangular glass micro-capillaries. A suspension of human red blood cells in plasma is tested as a reference. As a use example, we apply this technique to estimate the average refractive index of cell populations belonging to epithelial and hematological families.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_269,

title = {Human periodontal ligament stem cells cultured onto cortico-cancellous scaffold drive bone regenerative process.},

author = {Diomede F and Zini N and Gatta V and Fulle S and Merciaro I and D'Aurora M and La Rovere RM and Traini T and Pizzicannella J and Ballerini P and Caputi S and Piattelli A and Trubiani O},

url = {https://www.ecmjournal.org/papers/vol032/vol032a12.php},

year  = {2016},

date = {2016-09-16},

journal = {European Cells & Materials},

volume = {32},

pages = {181-201},

abstract = {The purpose of this work was to test, in vitro and in vivo, a new tissue-engineered construct constituted by porcine cortico-cancellous scaffold (Osteobiol Dual Block) (DB) and xeno-free ex vivo culture of human Periodontal Ligament Stem Cells (hPDLSCs). hPDLSCs cultured in xeno-free media formulation preserved the stem cells' morphological features, the expression of stemness and pluripotency markers, and their ability to differentiate into mesenchymal lineage. Transmission electron microscopy analysis suggested that after one week of culture, both noninduced and osteogenic differentiation induced cells joined and grew on DB secreting extracellular matrix (ECM) that in osteogenic induced samples was hierarchically assembled in fibrils. Quantitative RT-PCR (qRT-PCR) showed the upregulation of key genes involved in the bone differentiation pathway in both differentiated and undifferentiated hPDLSCs cultured with DB (hPDLSCs/DB). Functional studies revealed a significant increased response of calcium transients in the presence of DB, both in undifferentiated and differentiated cells stimulated with calcitonin and parathormone, suggesting that the biomaterial could drive the osteogenic differentiation process of hPDLSCs. These data were confirmed by the increase of gene expression of L-type voltage-dependent Ca2+ (VDCCL), subunits α1C and α2D1 in undifferentiated cells in the presence of DB. In vivo implantation of the hPDLSCs/DB living construct in the mouse calvaria evidenced a precocious osteointegration and vascularisation process. Our results suggest consideration of DB as a biocompatible, osteoinductive and osteoconductive biomaterial, making it a promising tool to regulate cell activities in biological environments and for a potential use in the development of new custom-made tissue engineering.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_260,

title = {Evaluation of eating habits and lifestyle in patients with obesity before and after bariatric surgery: a single Italian center experience.},

author = {Cena H and De Giuseppe R and Biino G and Persico F and Ciliberto A and Giovanelli A and Stanford FC},

url = {http://www.sciencedirect.com/science/article/pii/S0167488915002931},

doi = {10.1186/s40064-016-3133-1},

year  = {2016},

date = {2016-09-01},

journal = {Springerplus},

volume = {5},

number = {1},

pages = {1467},

abstract = {"The study evaluated and compared the eating habits and lifestyle of patients with moderate to severe obesity who have undergone Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG). METHODS: Food frequency (FF), food habits (FH), physical activity and life style (PA) as well as smoking habits (SH) were analyzed in 50 RYGB (25 M; aged: 24-64) and 50 SG patients (25 M; aged: 22-63) by means of a validated questionnaire, before (T0) and 6 months (T1) post bariatric surgery. A score for each section (FF, FH, PA, SH) was calculated. RESULTS: ANOVA analysis (age/sex adjusted): FF and FH scores improved at T1 (RYGB and SG: p < 0.001); PA score improved but not significantly; SH score did not change at T1 neither in RYGB nor in SG. Mixed models: FF and PA scores did not correlate with age, gender, weight, BMI, neither in RYGB nor in SG; FH score was negatively correlated both with weight (RYGB: p = 0.002) and BMI (SG: p = 0.003); SH score was positively correlated with age, in SG (p = 0.002); the correlation was stronger in females than in males (p = 0.004). CONCLUSIONS: Although dietary habits improved, patients did not change their physical activity level or their smoking habits. Patients should receive adequate lifestyle counseling to ensure the maximal benefit from bariatric surgery.

"},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_242,

title = {NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex.},

author = {Adamowicz M and Vermezovic J and {d'Adda di Fagagna F}},

url = {http://www.sciencedirect.com/science/article/pii/S2211124716309561},

doi = {10.1016/j.celrep.2016.07.038},

year  = {2016},

date = {2016-08-23},

journal = {Cell Reports},

volume = {16},

number = {8},

pages = {2068-2076},

abstract = {The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding. Lack of FOXO3a binding to ATM leads to the loss of KAT5/Tip60 association with ATM. Moreover, expression of NOTCH1 or depletion of ATM impairs the formation of the FOXO3a-KAT5/Tip60 protein complex. Finally, we show that pharmacological induction of FOXO3a nuclear localization sensitizes NOTCH1-driven cancers to DNA-damage-induced cell death.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_256,

title = {The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence.},

author = {Burla R and Carcuro M and Torre ML and Fratini F and Crescenzi M and D'Apice MR and Spitalieri P and Raffa GD and Astrologo L and Lattanzi G and Cundari E and Raimondo D and Biroccio A and Gatti M and Saggio I},

url = {http://rsob.royalsocietypublishing.org/content/6/8/160103.long},

doi = {10.1098/rsob.160103},

year  = {2016},

date = {2016-08-12},

journal = {Open Biology},

volume = {6},

number = {8},

pages = {160103},

abstract = {AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP-depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_313,

title = {PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis.},

author = {Terzaghi L and Tessaro I and Raucci F and Merico V and Mazzini G and Garagna S and Zuccotti M and Franciosi F and Lodde V},

url = {http://www.tandfonline.com/doi/abs/10.1080/15384101.2016.1192731?journalCode=kccy20},

doi = {10.1080/15384101.2016.1192731},

year  = {2016},

date = {2016-08-02},

journal = {Cell Cycle},

volume = {15},

number = {15},

pages = {2019-2032},

abstract = {Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in both oocyte and ovarian somatic cells, where it is found in multiple cellular sub-compartments including the mitotic spindle apparatus. Strikingly, PGRMC1 localization in the maturing bovine oocytes mirrors its localization in mitotic cells, suggesting a possible common action in mitosis and meiosis. To test the hypothesis that altering PGRMC1 activity leads to similar defects in mitosis and meiosis, PGRMC1 function was perturbed in cultured bovine granulosa cells (bGC) and maturing oocytes and the effect on mitotic and meiotic progression assessed. RNA interference-mediated PGRMC1 silencing in bGC significantly reduced cell proliferation, with a concomitant increase in the percentage of cells arrested at G2/M phase, which is consistent with an arrested or prolonged M-phase. This observation was confirmed by time-lapse imaging that revealed defects in late karyokinesis. In agreement with a role during late mitotic events, a direct interaction between PGRMC1 and Aurora Kinase B (AURKB) was observed in the central spindle at of dividing cells. Similarly, treatment with the PGRMC1 inhibitor AG205 or PGRMC1 silencing in the oocyte impaired completion of meiosis I. Specifically the ability of the oocyte to extrude the first polar body was significantly impaired while meiotic figures aberration and chromatin scattering within the ooplasm increased. Finally, analysis of PGRMC1 and AURKB localization in AG205-treated oocytes confirmed an altered localization of both proteins when meiotic errors occur. The present findings demonstrate that PGRMC1 participates in late events of both mammalian mitosis and oocyte meiosis, consistent with PGRMC's localization at the mid-zone and mid-body of the mitotic and meiotic spindle.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_287,

title = {RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress.},

author = {Kanu N and Zhang T and Burrell RA and Chakraborty A and Cronshaw J and Costa CD and Grönroos E and Pemberton HN and Anderton E and Gonzalez L and Sabbioneda S and Ulrich HD and Swanton C and Behrens A},

url = {http://www.nature.com/onc/journal/v35/n30/full/onc2015427a.html},

doi = {10.1038/onc.2015.427},

year  = {2016},

date = {2016-07-28},

journal = {35},

volume = {30},

number = {4009-4019},

abstract = {The DNA replication machinery invariably encounters obstacles that slow replication fork progression, and threaten to prevent complete replication and faithful segregation of sister chromatids. The resulting replication stress activates ATR, the major kinase involved in resolving impaired DNA replication. In addition, replication stress also activates the related kinase ATM, which is required to prevent mitotic segregation errors. However, the molecular mechanism of ATM activation by replication stress is not defined. Here, we show that monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA), a marker of stalled replication forks, interacts with the ATM cofactor ATMIN via WRN-interacting protein 1 (WRNIP1). ATMIN, WRNIP1 and RAD18, the E3 ligase responsible for PCNA monoubiquitination, are specifically required for ATM signalling and 53BP1 focus formation induced by replication stress, not ionising radiation. Thus, WRNIP1 connects PCNA monoubiquitination with ATMIN/ATM to activate ATM signalling in response to replication stress and contribute to the maintenance of genomic stability.Oncogene advance online publication, 9 November 2015; doi:10.1038/onc.2015.427.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_315,

title = {Multimodal transfer of MDR by exosomes in human osteosarcoma},

author = {Torreggiani E and Roncuzzi L and Perut F and Zini N and Baldini N},

url = {https://www.spandidos-publications.com/ijo/49/1/189},

doi = {10.3892/ijo.2016.3509},

year  = {2016},

date = {2016-07-19},

journal = {International Journal of Oncology},

volume = {49},

number = {1},

pages = {189-196},

abstract = {Exosomes are extracellular vesicles released by both normal and tumour cells which are involved in a new intercellular communication pathway by delivering cargo (e.g., proteins, microRNAs, mRNAs) to recipient cells. Tumour-derived exosomes have been shown to play critical roles in different stages of tumour growth and progression. In this study, we investigated the potential role of exosomes to transfer the multidrug resistance (MDR) phenotype in human osteosarcoma cells. Exosomes were isolated by differential centrifugation of culture media from multidrug resistant human osteosarcoma MG-63DXR30 (Exo/DXR) and MG-63 parental cells (Exo/S). Exosome purity was examined by transmission electron microscopy and confirmed by immunoblot analysis for the expression of specific exosomal markers. Our data showed that exosomes derived from doxorubicin-resistant osteosarcoma cells could be taken up into secondary cells and induce a doxorubicin-resistant phenotype. The incubation of osteosarcoma cells with Exo/DXR decreased the sensitivity of parental cells to doxorubicin, while exposure with Exo/S was ineffective. In addition, we demonstrated that Exo/DXR expressed higher levels of MDR-1 mRNA and P-glycoprotein compared to Exo/S (p=0.03). Interestingly, both MDR-1 mRNA and P-gp increased in MG-63 cells after incubation with Exo/DXR, suggesting this as the main mechanism of exosome-mediated transfer of drug resistance. Our findings suggest that multidrug resistant osteosarcoma cells are able to spread their ability to resist the effects of doxorubicin treatment on sensitive cells by transferring exosomes carrying MDR-1 mRNA and its product P-glycoprotein.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_271,

title = {Assessing Cell Cycle Independent Function of the CDK Inhibitor p21(CDKN1A) in DNA Repair.},

author = {Dutto I and Tillhon M and Prosperi E},

url = {https://link.springer.com/protocol/10.1007%2F978-1-4939-2926-9_11},

doi = {10.1007/978-1-4939-2926-9_11},

year  = {2016},

date = {2016-06-09},

journal = {Methods in Molecular Biology - Cyclin-Dependent Kinase (CDK) Inhibitors},

volume = {1336},

pages = {123-139},

abstract = {The cyclin-dependent kinase (CDK) inhibitor p21(CDKN1A) is a small protein that is able to regulate many important cell functions, often independently of its activity of CDK inhibitor. In addition to cell cycle, this protein regulates cell transcription, apoptosis, cell motility, and DNA repair. In particular, p21 may participate in different DNA repair processes, like the nucleotide excision repair (NER), base excision repair (BER), and double-strand breaks (DSB) repair, because of its ability to interact with DNA repair proteins, such as proliferating cell nuclear antigen (PCNA), a master regulator of many DNA transactions. Although this role has been debated for a long time, the influence of p21 in DNA repair has been now established. However, it remain to be clarified how this role is coupled to proteasomal degradation that has been shown to occur after DNA damage. This chapter describes procedures to study p21 protein recruitment to localized DNA damage sites in the cell nucleus. In particular, we describe a technique based on local irrradiation with UV light through a polycarbonate filter with micropores; an in situ lysis procedure to detect chromatin-bound proteins by immunofluorescence; a cell fractionation procedure to study chromatin association of p21 by Western blot analysis, and p21 protein-protein interactions by an immunoprecipitation assay.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_303,

title = {Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells},

author = {Pascucci B and D'Errico M and Romagnoli A and De Nuccio C and Savino M and Pietraforte D and Lanzafame M and Calcagnile AS and Fortini P and Baccarini S and Orioli D and Degan P and Visentin S and Stefanini M and Isidoro C and Fimia GM and Dogliotti E},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=9913&pubmed-linkout=1},

doi = {10.18632/oncotarget.9913},

year  = {2016},

date = {2016-06-07},

journal = {Oncotarget},

volume = {8},

number = {61},

pages = {102852-102867},

abstract = {The ERCC8/CSA gene encodes a WD-40 repeat protein (CSA) that is part of a E3-ubiquitin ligase/COP9 signalosome complex. When mutated, CSA causes the Cockayne Syndrome group A (CS-A), a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. CS-A cells features include ROS hyperproduction, accumulation of oxidative genome damage, mitochondrial dysfunction and increased apoptosis that may contribute to the neurodegenerative process. In this study, we show that CSA localizes to mitochondria and specifically interacts with the mitochondrial fission protein dynamin-related protein (DRP1) that is hyperactivated when CSA is defective. Increased fission is not counterbalanced by increased mitophagy in CS-A cells thus leading to accumulation of fragmented mitochondria. However, when mitochondria are challenged with the mitochondrial toxin carbonyl cyanide m-chloro phenyl hydrazine, CS-A fibroblasts undergo mitophagy as efficiently as normal fibroblasts, suggesting that this process remains targetable to get rid of damaged mitochondria. Indeed, when basal mitophagy was potentiated by overexpressing Parkin in CSA deficient cells, a significant rescue of the dysfunctional mitochondrial phenotype was observed. Importantly, Parkin overexpression not only reactivates basal mitophagy, but plays also an anti-apoptotic role by significantly reducing the translocation of Bax at mitochondria in CS-A cells. These findings provide new mechanistic insights into the role of CSA in mitochondrial maintenance and might open new perspectives for therapeutic approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_301,

title = {Ultrastructural regenerating features of nasal mucosa following microdebrider-assisted turbinoplasty are related to clinical recovery.},

author = {Neri G and Cazzato F and Mastronardi V and Pugliese M and Centurione MA and Di Pietro R and Centurione L},

url = {http://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0931-8},

doi = {10.1186/s12967-016-0931-8.},

year  = {2016},

date = {2016-06-02},

journal = {Journal of Translational Medicine},

volume = {14},

number = {1},

pages = {164},

abstract = {turbinoplasty},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_297,

title = {Specific inductive potential of a novel nanocomposite biomimetic biomaterial for osteochondral tissue regeneration},

author = {Manferdini C and Cavallo C and Grigolo B and Fiorini M and Nicoletti A and Gabusi E and Zini N and Pressato D and Facchini A and Lisignoli G},

url = {http://onlinelibrary.wiley.com/doi/10.1002/term.1723/abstract;jsessionid=0358FE4D72F098C66724266255F4F49A.f02t04},

year  = {2016},

date = {2016-05-27},

journal = {Journal of Tissue Engineering and Regenerative Medicine},

volume = {10},

pages = {374-391},

abstract = {Osteochondral lesions require treatment to restore the biology and functionality of the joint. A novel nanostructured biomimetic gradient scaffold was developed to mimic the biochemical and biophysical properties of the different layers of native osteochondral structure. The present results show that the scaffold presents important physicochemical characteristics and can support the growth and differentiation of mesenchymal stromal cells (h-MSCs), which adhere and penetrate into the cartilaginous and bony layers. H-MSCs grown in chondrogenic or osteogenic medium decreased their proliferation during days 14-52 on both scaffold layers and in medium without inducing factors used as controls. Both chondrogenic and osteogenic differentiation of h-MSCs occurred from day 28 and were increased on day 52, but not in the control medium. Safranin O staining and collagen type II and proteoglycans immunostaining confirmed that chondrogenic differentiation was specifically induced only in the cartilaginous layer. Conversely, von Kossa staining, osteocalcin and osteopontin immunostaining confirmed that osteogenic differentiation occurred on both layers. This study shows the specific potential of each layer of the biomimetic scaffold to induce chondrogenic or osteogenic differentiation of h-MSCs. These processes depended mainly on the media used but not the biomaterial itself, suggesting that the local milieu is fundamental for guiding cell differentiation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_254,

title = {Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.},

author = {Brai A and Fazi R and Tintori C and Zamperini C and Bugli F and Sanguinetti M and Stigliano E and Este' J and Badia R and Franco S and Martinez MA and Martinez JP and Meyerhans A and Saladini F and Zazzi M and Garbelli A and Maga G and Botta M},

url = {http://www.pnas.org/content/113/19/5388.long},

doi = {10.1073/pnas.1522987113},

year  = {2016},

date = {2016-05-10},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {113},

number = {9},

pages = {5388-5393},

abstract = {Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_284,

title = {External validation of the MetS score, a prediction tool for metabolic syndrome.},

author = {Graziano F and Grassi M and Bonati MT and Zanchetti A and Biino G},

url = {http://www.sciencedirect.com/science/article/pii/S093947531500263X},

doi = {10.1016/j.numecd.2015.12.014},

year  = {2016},

date = {2016-04-29},

journal = {Nutrition, Metabolism, and Cardiovascular Diseases : Nmcd. Letter To Editor},

volume = {26},

number = {4},

pages = {359-360},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_249,

title = {Experimental measurements and mathematical modeling of biological noise arising from transcriptional and translational regulation of basic synthetic gene circuits.},

author = {Bandiera L and Pasini A and Pasotti L and Zucca S and Mazzini G and Magni P and Giordano E and Furini S},

url = {http://www.sciencedirect.com/science/article/pii/S0022519316000941},

doi = {10.1016/j.jtbi.2016.02.004},

year  = {2016},

date = {2016-04-21},

journal = {Journal of Theoretical Biology},

volume = {395},

pages = {153-160},

abstract = {The small number of molecules, unevenly distributed within an isogenic cell population, makes gene expression a noisy process, and strategies have evolved to deal with this variability in protein concentration and to limit its impact on cellular behaviors. As translational efficiency has a major impact on biological noise, a possible strategy to control noise is to regulate gene expression processes at the post-transcriptional level. In this study, fluctuations in the concentration of a green fluorescent protein were compared, at the single cell level, upon transformation of an isogenic bacterial cell population with synthetic gene circuits implementing either a transcriptional or a post-transcriptional control of gene expression. Experimental measurements showed that protein variability is lower under post-transcriptional control, when the same average protein concentrations are compared. This effect is well reproduced by stochastic simulations, supporting the hypothesis that noise reduction is due to the control mechanism acting on the efficiency of translation. Similar strategies are likely to play a role in noise reduction in natural systems and to be useful for controlling noise in synthetic biology applications. Copyright 2016 Elsevier Ltd. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_319,

title = {A comprehensive strategy for the analysis of acoustic compressibility and optical deformability on single cells.},

author = {Yang T and Bragheri F and Nava G and Chiodi I and Mondello C and Osellame R and Berg-Sørensen K and Cristiani I and Minzioni P},

url = {http://www.nature.com/articles/srep23946},

doi = {10.1038/srep23946},

year  = {2016},

date = {2016-04-20},

journal = {Scientific Reports},

volume = {6},

pages = {23946},

abstract = {We realized an integrated microfluidic chip that allows measuring both optical deformability and acoustic compressibility on single cells, by optical stretching and acoustophoresis experiments respectively. Additionally, we propose a measurement protocol that allows evaluating the experimental apparatus parameters before performing the cell-characterization experiments, including a non-destructive method to characterize the optical force distribution inside the microchannel. The chip was used to study important cell-mechanics parameters in two human breast cancer cell lines, MCF7 and MDA-MB231. Results indicate that MDA-MB231 has both higher acoustic compressibility and higher optical deformability than MCF7, but statistical analysis shows that optical deformability and acoustic compressibility are not correlated parameters. This result suggests the possibility to use them to analyze the response of different cellular structures. We also demonstrate that it is possible to perform both measurements on a single cell, and that the order of the two experiments does not affect the retrieved values.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_289,

title = {Non‑invasive prostate cancer detection by measuring miRNA variants (isomiRs) in urine extracellular vesicles.},

author = {Koppers-Lalic D and Hackenberg M and Menezes R and Misovic B and Wachalska M and Geldof A and Zini N and Reijke T and Wurdinger T and Vis A and Moorselaar JV and Pegtel M and Bijnsdorp I},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=8124&pubmed-linkout=1},

doi = {10.18632/oncotarget.8124},

year  = {2016},

date = {2016-04-19},

journal = {Oncotarget},

volume = {7},

number = {16},

pages = {22566-22578},

abstract = {In many cancer types, the expression and function of ~22 nucleotide-long microRNAs (miRNA) is deregulated. Mature miRNAs can be stably detected in extracellular vesicles (EVs) in biofluids, therefore they are considered to have great potential as biomarkers. In the present study, we investigated whether miRNAs have a distinct expression pattern in urine-EVs of prostate cancer (PCa) patients compared to control males. By next generation sequencing, we determined the miRNA expression in a discovery cohort of 4 control men and 9 PCa patients. miRNAs were validated by using a stemloop RT-PCR in an independent cohort of 74 patients (26 control and 48 PCa-patients). Whereas standard mapping protocols identified > 10 PCa associated miRNAs in urinary EVs, miR-21, miR-375 and miR-204 failed to robustly discriminate for disease in a validation study with RT-PCR-detection of mature miRNA sequences. In contrast, we observed that miRNA isoforms (isomiRs) with 3' end modifications were highly discriminatory between samples from control men and PCa patients. Highly differentially expressed isomiRs of miR-21, miR-204 and miR-375 were subsequently validated in an independent group of 74 patients. Receiver-operating characteristic analysis was performed to evaluate the diagnostic performance of three isomiRs, resulting in a 72.9% sensitivity with a high (88%) specificity and an area under the curve (AUC) of 0.866. In comparison, prostate specific antigen had an AUC of 0.707 and measuring the mature form of these miRNAs yielded a lower 70.8% sensitivity and 72% specificity (AUC 0.766). We propose that isomiRs may carry discriminatory information which is useful to generate stronger biomarkers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_290,

title = {GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.},

author = {Kuschal C and Botta E and Orioli D and Digiovanna JJ and Seneca S and Keymolen K and Tamura D and Heller E and Khan SG and Caligiuri G and Lanzafame M and Nardo T and Ricotti R and Peverali FA and Stephens R and Zhao Y and Lehmann AR and Baranello L and Levens D and Kraemer KH and Stefanini M},

url = {http://www.sciencedirect.com/science/article/pii/S0002929716000598},

doi = {10.1016/j.ajhg.2016.02.008},

year  = {2016},

date = {2016-04-16},

journal = {American Journal of Human Genetics},

volume = {98},

number = {4},

pages = {627-642},

abstract = {The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEbeta). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEalpha and TFIIEbeta) as well as decreased phosphorylation of TFIIEalpha in cells from both children. Interestingly, decreased phosphorylation of TFIIEalpha was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. Copyright  2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_279,

title = {Solution and Solid-State Analysis of Binding of 13-Substituted Berberine Analogues to Human Telomeric G-quadruplexes.},

author = {Ferraroni M and Bazzicalupi C and Papi F and Fiorillo G and Guamán-Ortiz LM and Nocentini A and Scovassi AI and Lombardi P and Gratteri P},

url = {http://onlinelibrary.wiley.com/doi/10.1002/asia.201600116/abstract;jsessionid=41A7EB754351C529E5530508A971084B.f04t01},

doi = {10.1002/asia.201600116},

year  = {2016},

date = {2016-04-05},

journal = {Chemistry, an Asian Journal},

volume = {11},

number = {7},

pages = {1107-1115},

abstract = {he interaction between 13-phenylalkyl and 13-diphenylalkyl berberine derivatives (NAX) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X-ray diffraction result for the NAX053-Tel12 adduct, showing the ligand which interacts via π-stacking, sandwiched at the interface of two symmetry-related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π-stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose-dependent manner. 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_277,

title = {Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.},

author = {Fan Q and Verhoeven VJ and Wojciechowski R and Barathi VA and Hysi PG and Guggenheim JA and Höhn R and Vitart V and Khawaja AP and Yamashiro K and Hosseini SM and {et aò} and Biino G and Vaccargiu S and Fossarello M and Fleck B and Yazar S and Tideman JW and Tedja M and Deangelis MM and Morrison M and Farrer L and Zhou X and Chen W and Mizuki N and Meguro A and Makela KM},

url = {http://www.nature.com/ncomms/2016/160329/ncomms11008/full/ncomms11008.html},

doi = {10.1038/ncomms11008},

year  = {2016},

date = {2016-03-29},

journal = {Nature Communications},

volume = {7},

pages = {11008},

abstract = {Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_252,

title = {Snail levels control the migration mechanism of mesenchymal tumor cells.},

author = {Belgiovine C and Chiesa G and Chiodi I and Frapolli R and Bonezzi K and Taraboletti G and D'Incalci M and Mondello C},

url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907273/},

doi = {10.3892/ol.2016.4642},

year  = {2016},

date = {2016-03-16},

journal = {Oncology Letters},

volume = {12},

number = {1},

pages = {767-771},

abstract = {Cancer cells use two major types of movement: Mesenchymal, which is typical of cells of mesenchymal origin and depends on matrix metalloproteinase (MMP) activity, and amoeboid, which is characteristic of cells with a rounded shape and relies on the activity of Rho-associated kinase (ROCK). The present authors previously demonstrated that, during neoplastic transformation, telomerase-immortalized human fibroblasts (cen3tel cells) acquired a ROCK-dependent/MMP independent mechanism of invasion, mediated by the downregulation of the ROCK cellular inhibitor Round (Rnd)3/RhoE. In the present study, cen3tel transformation was also demonstrated to be paralleled by downregulation of Snail, a major determinant of the mesenchymal movement. To test whether Snail levels could determine the type of movement adopted by mesenchymal tumor cells, Snail was ectopically expressed in tumorigenic cells. It was observed that ectopic Snail did not increase the levels of typical mesenchymal markers, but induced cells to adopt an MMP-dependent mechanism of invasion. In cells expressing ectopic Snail, invasion became sensitive to the MMP inhibitor Ro 28-2653 and insensitive to the ROCK inhibitor Y27632, suggesting that, once induced by Snail, the mesenchymal movement prevails over the amoeboid one. Snail-expressing cells had a more aggressive behavior in vivo, and exhibited increased tumor growth rate and metastatic ability. These results confirm the high plasticity of cancer cells, which can adopt different types of movement in response to changes in the expression of specific genes. Furthermore, the present findings indicate that Rnd3 and Snail are possible regulators of the type of invasion mechanism adopted by mesenchymal tumor cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_261,

title = {Telomere and telomerase stability in human diseases and cancer.},

author = {Chiodi I and Mondello C},

year  = {2016},

date = {2016-03-11},

journal = {Frontiers In  Bioscience},

volume = {21},

pages = {203-224},

abstract = {Telomeres are the nucleoprotein structures at the end of linear eukaryotic chromosomes required for genome stability. Telomerase is the specialized enzyme deputed to their elongation. Maintenance of a proper telomere structure, an accurate regulation of telomerase biogenesis and activity, as well as a correct telomere-telomerase interaction and a faithful telomeric DNA replication are all processes that a cell has to precisely control to safeguard its functionality. Here, we review key factors that play a role in the development of these processes and their relationship with human health.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}