Showing papers by "University of Milano-Bicocca published in 2012"

Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation

Abstract: The DNA-damage response (DDR) arrests cell-cycle progression until damage is removed. DNA-damage-induced cellular senescence is associated with persistent DDR. The molecular bases that distinguish transient from persistent DDR are unknown. Here we show that a large fraction of exogenously induced persistent DDR markers is associated with telomeric DNA in cultured cells and mammalian tissues. In yeast, a chromosomal DNA double-strand break next to a telomeric sequence resists repair and impairs DNA ligase 4 recruitment. In mammalian cells, ectopic localization of telomeric factor TRF2 next to a double-strand break induces persistent DNA damage and DDR. Linear, but not circular, telomeric DNA or scrambled DNA induces a prolonged checkpoint in normal cells. In terminally differentiated tissues of old primates, DDR markers accumulate at telomeres that are not critically short. We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.

Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4

Abstract: Ingestion of wheat, barley, or rye triggers small intestinal inflammation in patients with celiac disease. Specifically, the storage proteins of these cereals (gluten) elicit an adaptive Th1-mediated immune response in individuals carrying HLA-DQ2 or HLA-DQ8 as major genetic predisposition. This well-defined role of adaptive immunity contrasts with an illdefined component of innate immunity in celiac disease. We identify the -amylase/trypsin inhibitors (ATIs) CM3 and 0.19, pest resistance molecules in wheat, as strong activators of innate immune responses in monocytes, macrophages, and dendritic cells. ATIs engage the TLR4–MD2–CD14 complex and lead to up-regulation of maturation markers and elicit release of proinflammatory cytokines in cells from celiac and nonceliac patients and in celiac patients’ biopsies. Mice deficient in TLR4 or TLR4 signaling are protected from intestinal and systemic immune responses upon oral challenge with ATIs. These findings define cereal ATIs as novel contributors to celiac disease. Moreover, ATIs may fuel inflammation and immune reactions in other intestinal and nonintestinal immune disorders.

Theoretical predictions for charm and bottom production at the LHC

Abstract: We present predictions for a variety of single-inclusive observables that stem from the production of charm and bottom quark pairs at the 7 TeV LHC. They are obtained within the FONLL semi-analytical framework, and with two "Monte Carlo + NLO" approaches, MC@NLO and POWHEG. Results are given for final states and acceptance cuts that are as close as possible to those used by experimental collaborations and, where feasible, are compared to LHC data.

Low-frequency gravitational-wave science with eLISA/NGO

Abstract: We review the expected science performance of the New Gravitational-Wave Observatory (NGO, a.k.a. eLISA), a mission under study by the European Space Agency for launch in the early 2020s. eLISA will survey the low-frequency gravitational-wave sky (from 0.1 mHz to 1 Hz), detecting and characterizing a broad variety of systems and events throughout the Universe, including the coalescences of massive black holes brought together by galaxy mergers; the inspirals of stellar-mass black holes and compact stars into central galactic black holes; several millions of ultra-compact binaries, both detached and mass transferring, in the Galaxy; and possibly unforeseen sources such as the relic gravitational-wave radiation from the early Universe. eLISA's high signal-to-noise measurements will provide new insight into the structure and history of the Universe, and they will test general relativity in its strong-field dynamical regime.

Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy

Abstract: Exosomes are endosome-derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2-overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity of the humanized antibody Trastuzumab and the dual tyrosine kinase inhibitor (TKI) Lapatinib anti-HER2 biodrugs. We show that exosomes released by the HER2-overexpressing tumor cell lines SKBR3 and BT474 express a full-length HER2 molecule that is also activated, although to a lesser extent than in the originating cells. Release of these exosomes was significantly modulated by the growth factors EGF and heregulin, two of the known HER2 receptor-activating ligands and naturally present in the surrounding tumor microenvironment. Exosomes secreted either in HER2-positive tumor cell-conditioned supernatants or in breast cancer patients' serum bound to Trastuzumab. Functional assays revealed that both xenogeneic and autologous HER2-positive nanovesicles, but not HER2-negative ones, inhibited Trastuzumab activity on SKBR3 cell proliferation. By contrast, Lapatinib activity on SKBR3 cell proliferation was unaffected by the presence of autologous exosomes. Together, these findings point to the role of HER2-positive exosomes in modulating sensitivity to Trastuzumab, and, consequently, to HER2-driven tumor aggressiveness.

Low power, non-coherent sensitized photon up-conversion: modelling and perspectives.

Abstract: In the last few years, non-coherent sensitized photon up-conversion (SUC) in multi-component systems has been developed to achieve significantly high quantum yields for various chromophore combinations at low excitation powers, spanning from the ultraviolet (UV) to near infrared (NIR) spectrum This promising photon energy management technique became indeed suitable for wide applications in lighting technology and especially in photovoltaics, being able to recover the sub-bandgap photons lost by current devices A full and general description of the SUC photophysics will be presented, with the analysis of the parameter affecting the photon conversion quantum yield and the quantities which define the optimal working range of any SUC system, namely the threshold and saturation excitation intensity It will be shown how these quantities depend on intrinsic photophysical properties of the moieties involved and on the SUC solid host matrix The model proposed represents a powerful tool for evaluation of a newly proposed system, and its reliability will be discussed in respect to an optimized system with SUC yield of 026 ± 002 The results obtained will outline the research guidelines which must be pursued to optimize the SUC efficiency for its perspective technological applications

Comparison of different approaches to define the applicability domain of QSAR models.

Abstract: One of the OECD principles for model validation requires defining the Applicability Domain (AD) for the QSAR models. This is important since the reliable predictions are generally limited to query chemicals structurally similar to the training compounds used to build the model. Therefore, characterization of interpolation space is significant in defining the AD and in this study some existing descriptor-based approaches performing this task are discussed and compared by implementing them on existing validated datasets from the literature. Algorithms adopted by different approaches allow defining the interpolation space in several ways, while defined thresholds contribute significantly to the extrapolations. For each dataset and approach implemented for this study, the comparison analysis was carried out by considering the model statistics and relative position of test set with respect to the training space.

Recombinant Protein Production in Yeasts

Abstract: Recombinant protein production is a multibillion-dollar market. The development of a new product begins with the choice of a production host. While one single perfect host for every protein does not exist, several expression systems ranging from bacterial hosts to mammalian cells have been established. Among them, yeast cell factories combine the advantages of being single cells, such as fast growth and easy genetic manipulation, as well as eukaryotic features including a secretory pathway leading to correct protein processing and post-translational modifications. In this respect, especially the engineering of yeast glycosylation to produce glycoproteins of human-like glycan structures is of great interest. Additionally, different attempts of cellular engineering as well as the design of different production processes that are leading to improved productivities are presented. With the advent of cheaper next-generation sequencing techniques, systems biotechnology approaches focusing on genome scale analyses will advance and accelerate yeast cell factories and thus recombinant protein production processes in the near future. In this review we summarize advantages and limitations of the main and most promising yeast hosts, including Saccharomyces cerevisiae, Pichia pastoris, and Hansenula polymorpha as those presently used in large scale production of heterologous proteins.

Strongly Fluorescent Quaternary Cu-In-Zn-S Nanocrystals Prepared from Cu1-xInS2 Nanocrystals by Partial Cation Exchange

Abstract: We report a high-yield, low cost synthesis route to colloidal Cu1-xInS2 nanocrystals with a tunable amount of Cu vacancies in the crystal lattice These are then converted into quaternary Cu–In–Zn–S (CIZS) nanocrystals by partial exchange of Cu+ and In3+ cations with Zn2+ cations The photoluminescence quantum yield of these CIZS nanocrystals could be tuned up to a record 80%, depending on the amount of copper vacancies

The trisomy 18 syndrome

Abstract: The trisomy 18 syndrome, also known as Edwards syndrome, is a common chromosomal disorder due to the presence of an extra chromosome 18, either full, mosaic trisomy, or partial trisomy 18q. The condition is the second most common autosomal trisomy syndrome after trisomy 21. The live born prevalence is estimated as 1/6,000-1/8,000, but the overall prevalence is higher (1/2500-1/2600) due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis. The prevalence of trisomy 18 rises with the increasing maternal age. The recurrence risk for a family with a child with full trisomy 18 is about 1%. Currently most cases of trisomy 18 are prenatally diagnosed, based on screening by maternal age, maternal serum marker screening, or detection of sonographic abnormalities (e.g., increased nuchal translucency thickness, growth retardation, choroid plexus cyst, overlapping of fingers, and congenital heart defects ). The recognizable syndrome pattern consists of major and minor anomalies, prenatal and postnatal growth deficiency, an increased risk of neonatal and infant mortality, and marked psychomotor and cognitive disability. Typical minor anomalies include characteristic craniofacial features, clenched fist with overriding fingers, small fingernails, underdeveloped thumbs, and short sternum. The presence of major malformations is common, and the most frequent are heart and kidney anomalies. Feeding problems occur consistently and may require enteral nutrition. Despite the well known infant mortality, approximately 50% of babies with trisomy 18 live longer than 1 week and about 5-10% of children beyond the first year. The major causes of death include central apnea, cardiac failure due to cardiac malformations, respiratory insufficiency due to hypoventilation, aspiration, or upper airway obstruction and, likely, the combination of these and other factors (including decisions regarding aggressive care). Upper airway obstruction is likely more common than previously realized and should be investigated when full care is opted by the family and medical team. The complexity and the severity of the clinical presentation at birth and the high neonatal and infant mortality make the perinatal and neonatal management of babies with trisomy 18 particularly challenging, controversial, and unique among multiple congenital anomaly syndromes. Health supervision should be diligent, especially in the first 12 months of life, and can require multiple pediatric and specialist evaluations.

Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study

Abstract: Summary Background Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin–Frankfurt–Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL. Methods Patients aged 1–18 years recruited to national trials of front-line treatment for ALL were eligible if they had t(9;22)(q34;q11). Patients with abnormal renal or hepatic function, or an active systemic infection, were ineligible. Patients were enrolled by ten study groups between 2004 and 2009, and were classified as good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned by a web-based system with permuted blocks (size four) to receive post-induction imatinib with chemotherapy or chemotherapy only in a 1:1 ratio, while all poor-risk patients received post-induction imatinib with chemotherapy. Patients were stratified by study group. The chemotherapy regimen was modelled on a Berlin–Frankfurt–Munster high-risk backbone; all received four post-induction blocks of chemotherapy after which they became eligible for stem-cell transplantation. The primary endpoints were disease-free survival at 4 years in the good-risk group and event-free survival at 4 years in the poor-risk group, analysed by intention to treat and a secondary analysis of patients as treated. The trial is registered with EudraCT (2004-001647-30) and ClinicalTrials.gov, number NCT00287105. Findings Between Jan 1, 2004, and Dec 31, 2009, we screened 229 patients and enrolled 178: 108 were good risk and 70 poor risk. 46 good-risk patients were assigned to receive imatinib and 44 to receive no imatinib. Median follow-up was 3·1 years (IQR 2·0–4·6). 4-year disease-free survival was 72·9% (95% CI 56·1–84·1) in the good-risk, imatinib group versus 61·7% (45·0–74·7) in the good-risk, no imatinib group (p=0·24). The hazard ratio (HR) for failure, adjusted for minimal residual disease, was 0·63 (0·28–1·41; p=0·26). The as-treated analysis showed 4-year disease-free survival was 75·2% (61·0–84·9) for good-risk patients receiving imatinib and 55·9% (36·1–71·7) for those who did not receive imatinib (p=0·06). 4-year event-free survival for poor-risk patients was 53·5% (40·4–65·0). Serious adverse events were much the same in the good-risk groups, with infections caused by myelosuppression the most common. 16 patients in the good-risk imatinib group versus ten in the good-risk, no imatinib group (p=0·64), and 24 in the poor-risk group, had a serious adverse event. Interpretation Our results suggests that imatinib in conjunction with intensive chemotherapy is well tolerated and might be beneficial for treatment of children with Philadelphia-chromosome-positive ALL. Funding Projet Hospitalier de Recherche Clinique-Cancer (France), Fondazione Tettamanti-De Marchi and Associazione Italiana per la Ricerca sul Cancro (Italy), Novartis Germany, Cancer Research UK, Leukaemia Lymphoma Research, and Central Manchester University Hospitals Foundation Trust.

The effect of nanoparticle uptake on cellular behavior: disrupting or enabling functions?

Abstract: Nanoparticles (NPs) are materials with overall dimensions in the nanoscale range. They have unique physicochemical properties, and have emerged as important players in current research in modern medicine. In the last few decades, several types of NPs and microparticles have been synthesized and proposed for use as contrast agents for diagnostics and imaging and for drug delivery; for example, in cancer therapy. Yet specific targeting that will improve their delivery still represents an unsolved challenge. The mechanism by which NPs enter the cell has important implications not only for their fate but also for their impact on biological systems. Several papers in the literature discuss the potential risks related to NP exposure, and more recently the concept that even sublethal doses of NPs may elicit a cell response has been proposed. In this review, we intend to present an overall view of cell mechanisms that may be perturbed by cell-NP interaction. Published data, in fact, emphasize that NPs should no longer be viewed only as simple carriers for biomedical applications, but that they can also play an active role in mediating biological effects.

MINLO: multi-scale improved NLO

Abstract: In the present work we consider the assignment of the factorization and renormalization scales in hadron collider processes with associated jet production, at next-to-leading order (NLO) in perturbation theory. We propose a simple, definite prescription to this end, including Sudakov form factors to consistently account for the distinct kinematic scales occuring in such collisions. The scheme yields results that are accurate at NLO and, for a large class of observables, it resums to all orders the large logarithms that arise from kinematic configurations involving disparate scales. In practical terms the method is most simply understood as an NLO extension of the matrix element reweighting procedure employed in tree level matrix element-parton shower merging algorithms. By way of a proof-of-concept, we apply the method to Higgs and Z boson production in association with up to two jets.

Cancer Risk Associated with Use of Metformin and Sulfonylurea in Type 2 Diabetes: A Meta-Analysis

Abstract: Objective. Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue.

Short- and Long-Term Blood Pressure Variability Present and Future

Abstract: It has long been known that blood pressure (BP) is characterized by an array of spontaneous variations.1 That is, BP values vary markedly within the 24 hours because of day-night changes but also because of differences among hours, minutes, and even adjacent beats. They also show variations over more prolonged periods because of differences among days, months, and seasons,2 also with a trend for systolic BP to increase over the years and for diastolic BP to display an age-related biphasic change.3 This article summarizes current knowledge on short-term (within the 24 hours) and long-term BP variability. Mention will be made of the following: (1) factors responsible for BP variations and mechanisms through which they occur; (2) the relationship of BP variability with BP mean values in absence and during antihypertensive treatment; and (3) the prognostic significance of BP variability. Current limitations of the studies on BP variability will be also discussed to emphasize what future studies should address. ### Factors and Mechanisms A large body of evidence shows that, over the 24 hours, BP undergoes marked variations in response to physical activity, sleep, and emotional stimuli of various nature and duration, thereby documenting the profound involvement of behavioral influences on BP variability. However, spontaneous BP variations also occur independently on behavior. For example, throughout the day and night, BP oscillates regularly at different frequencies, presumably because of influences originating within the brain.4 Furthermore, BP varies more or less regularly in response to the mechanical forces generated by ventilation and also shows irregular nonbehaviorally and nonmechanically related changes with a possible origin from humoral influences and even local vasomotor phenomena. Finally, BP variations are opposed throughout the 24 hours by the baroreflex, which makes the magnitude of 24-hour BP variability in a given individual the net effect of pro-oscillatory and antioscillatory …

Supersymmetry on Curved Spaces and Holography

Abstract: We study superconformal and supersymmetric theories on Euclidean four- and threemanifolds with a view toward holographic applications. Preserved supersymmetry for asymptotically locally AdS solutions implies the existence of a (charged) “conformal Killing spinor” on the boundary. We study the geometry behind the existence of such spinors. We show in particular that, in dimension four, they exist on any complex manifold. This implies that a superconformal theory has at least one supercharge on any such space, if we allow for a background field (in general complex) for the R-symmetry. We also show that this is actually true for any supersymmetric theory with an R-symmetry. We also analyze the three-dimensional case and provide examples of supersymmetric theories on Sasaki spaces.

Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies.

Abstract: Left-ventricular hypertrophy (LVH) is a cardinal manifestation of hypertensive organ damage associated with an increased cardiovascular (CV) risk. We reviewed recent literature on the prevalence of LVH, as assessed by echocardiography, in order to offer an updated information on the magnitude of subclinical alterations in LV structure in contemporary human hypertension. A MEDLINE search using key words 'left ventricular hypertrophy', 'hypertension', 'echocardiography' and 'cardiac organ damage' was performed in order to identify relevant papers. Full articles published in English language in the last decade, (1 January 2000-1 December 2010), reporting studies in adult or elderly individuals, were considered. A total of 30 studies, including 37,700 untreated and treated patients (80.3% Caucasian, 52.4% men, 9.6% diabetics, 2.6% with CV disease) were considered. LVH was defined by 23 criteria; its prevalence ranged from 36% (conservative criteria) to 41% (less conservative criteria) in the pooled population. LVH prevalence was not different between women and men (range 37.9-46.2 versus 36.0-43.5%, respectively). Eccentric LVH was more frequent than concentric hypertrophy (range 20.3-23.0 versus 14.8-15.8, respectively, P<0.05); concentric phenotype was found in a consistent fraction (20%) of both genders. Despite the improved management of hypertension in the last two decades, LVH remains a highly frequent biomarker of cardiac damage in the hypertensive population. Our analysis calls for a more aggressive treatment of hypertension and related CV risk factors leading to LVH.

Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012

Abstract: AIMS: To update epidemiological data on alcohol and breast cancer, with special emphasis on light alcohol consumption, and to review mechanisms of alcohol mediated mammary carcinogenesis. METHODS: For epidemiological data, in November 2011 we performed a literature search in various bibliographic databases, and we conducted a meta-analysis of data on light alcohol drinking. Relevant mechanistic studies were also reviewed to November 2011. RESULTS: A significant increase of the order of 4% in the risk of breast cancer is already present at intakes of up to one alcoholic drink/day. Heavy alcohol consumption, defined as three or more drinks/day, is associated with an increased risk by 40-50%. This translates into up to 5% of breast cancers attributable to alcohol in northern Europe and North America for a total of approximately 50,000 alcohol-attributable cases of breast cancer worldwide. Up to 1-2% of breast cancers in Europe and North America are attributable to light drinking alone, given its larger prevalence in most female populations when compared with heavy drinking. Alcohol increases estrogen levels, and estrogens may exert its carcinogenic effect on breast tissue either via the ER or directly. Other mechanisms may include acetaldehyde, oxidative stress, epigenetic changes due to a disturbed methyl transfer and decreased retinoic acid concentrations associated with an altered cell cycle. CONCLUSIONS: Women should not exceed one drink/day, and women at elevated risk for breast cancer should avoid alcohol or consume alcohol occasionally only.

Cultural adaptation of the difficulties in emotion regulation scale: reliability and validity of an Italian version.

Abstract: Objective The aim of this study was to evaluate the reliability and validity of an Italian version of the Difficulties in Emotion Regulation Scale (DERS; Gratz & Roemer, 2004). Method Three studies were completed. First, factorial structure, internal consistency, and concurrent validity of our Italian version of the DERS were examined with a sample of 323 students (77% female; mean age 25.6). Second, test-retest analyses were completed using a different sample of 61 students (80% female; mean age 24.7). Third, the scores produced by a small clinical sample of participants (N = 38; mean age = 24.2) affected by anorexia, binge eating disorder, or bulimia were compared to those of an age-matched, nonclinical female sample (N = 38; mean age = 24.7). Results The factorial structure replicated quite well the six-factor structure proposed by Gratz and Roemer. The internal consistency and test-retest reliability were adequate and comparable to previous findings. The validity was good, as indicated by both the concurrent validity analysis and the clinical-nonclinical sample comparison. Conclusions These studies provide further support for the multidimensional model of emotion regulation postulated by Gratz and Roemer and strengthen the rationale for cross-cultural utilization of the DERS. © 2012 Wiley Periodicals, Inc. J. Clin. Psychol. 00:1-20, 2012.

You want to give a good impression? Be honest! Moral traits dominate group impression formation

Abstract: Research has shown that warmth and competence are core dimensions on which perceivers judge others and that warmth has a primary role at various phases of impression formation. Three studies explored whether the two components of warmth (i.e., sociability and morality) have distinct roles in predicting the global impression of social groups. In Study 1 (N= 105) and Study 2 (N= 112), participants read an immigration scenario depicting an unfamiliar social group in terms of high (vs. low) morality, sociability, and competence. In both studies, participants were asked to report their global impression of the group. Results showed that global evaluations were better predicted by morality than by sociability or competence-trait ascriptions. Study 3 (N= 86) further showed that the effect of moral traits on group global evaluations was mediated by the perception of threat. The importance of these findings for the impression-formation process is discussed.

Sympathetic regulation of vascular function in health and disease.

Abstract: The sympathetic nervous system (SNS) is known to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular system. In the past decades increasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels. Evidence from experimental studies indicates that the SNS is critically influenced, at the central and also at the peripheral level, by the most relevant factors regulating vascular function, such as nitric oxide (NO), reactive oxygen species (ROS), endothelin (ET), the renin-angiotensin system. Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SNS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute increase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects. However, direct evidence of a cause-effect relationship from human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. On the other hand, large artery stiffness can interfere with autonomic regulation by impairing carotid baroreflex sensitivity.