Height as a potential indicator of early life events predicting Parkinson's disease: a case-control study.

Aim of this study was to investigate the relationship between height in young adult age and Parkinson's disease (PD) risk. We included 266 persons affected by idiopathic PD. Patients were matched by age and sex to 266 controls by a random selection from the municipality of residence. We collected information about height preceding PD from official documents where these characteristics referred to young adult age (nearly 30 years). We compared height in cases and controls by calculating differences in mean distribution and by χ2 analyses. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression models. Mean height was significantly lower in persons affected by PD compared to controls (P = 0.03). Difference was significant only in men (P = 0.001). Logistic regression models showed an inverse association between height and PD (OR 0.35; CI 0.16, 0.79; P < 0.01 comparing individuals in the highest percentiles of height with those in the lowest). Our results indicate an association between height and PD in men. Considering that dopamine sensitivity in the hypothalamic-pituitary axis is related to adult height, our findings suggest a relationship between PD and factors modulating somatic growth early in life

Keratin 7 expression as an early marker of reflux-related columnar mucosa without intestinal metaplasia in the esophagus

BACKGROUND: The role of Barrett esophagus in carcinogenesis is widely accepted, but the significance of esophageal columnar mucosa without histological intestinal metaplasia, known as columnar-lined esophagus, is debated. MATERIAL/METHODS: We studied 128 patients free of Helicobacter pylori with reflux-related symptoms and columnar mucosa in the esophagus at endoscopy, 106 patients with Barrett esophagus (referred to as the Barrett group) and 22 patients without intestinal metaplasia (columnar group). Samples from 20 subjects free of H. pylori were used as controls. Immunostaining for keratin 7 (KRT7), keratin 20 (KRT20), caudal type homeobox 2 (CDX2), mucin 2, oligomeric mucus/gel-forming (MUC2), and tumor protein p53 (TP53) was assessed. RESULTS: Samples taken 1 cm above the gastroesophageal junction showed KRT7 staining in all cases in the Barrett and columnar groups and none in the control group. Immunostaining for TP53 was absent in the control group, and more frequent in the columnar group (7, 31.8%) compared with the Barrett group (14, 13.2%, P=0.033). In the columnar group, low grade dysplasia and TP53 expression was seen in 7 of 22 biopsy specimens (31.8%) at baseline and in 4 additional specimens after 2 years, for a total of 11 specimens (50.0%). CONCLUSIONS: The expression of KRT7 might help to explain the pathological, reflux-related nature of columnar-lined esophagus, as aberrant expression in a very early stage of the multistep Barrett esophagus progression. Expression of KRT7 may occur in basal glandular cells as a result of their multipotentiality and susceptibility to immunophenotype changes induced by reflux

Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells

Background: Cellular plasticity confers cancer cells the ability to adapt to microenvironmental changes, a fundamental requirement for tumour progression and metastasis. The epithelial to mesenchymal transition (EMT) is a transcriptional programme associated with increased cell motility and stemness. Besides EMT, the mesenchymal to amoeboid transition (MAT) has been described during tumour progression but to date, little is known about its transcriptional control and involvement in stemness. The aim of this manuscript is to investigate (i) the transcriptional profile associated with the MAT programme and (ii) to study whether MAT acquisition in melanoma cancer cells correlates with clonogenic potential to promote tumour growth. Results: By using a multidisciplinary approach, we identified four different treatments able to induce MAT in melanoma cells: EphA2 overexpression, Rac1 functional inhibition using its RacN17 dominant negative mutant, stimulation with Ilomastat or treatment with the RhoA activator Calpeptin. First, gene expression profiling identified the transcriptional pathways associated with MAT, independently of the stimulus that induces the MAT programme. Notably, gene sets associated with the repression of mesenchymal traits, decrease in the secretion of extracellular matrix components as well as increase of cellular stemness positively correlate with MAT. Second, the link between MAT and stemness has been investigated in vitro by analysing stemness markers and clonogenic potential of melanoma cells undergoing MAT. Finally, the link between MAT inducing treatments and tumour initiating capability has been validated in vivo. Conclusion: Taken together, our results demonstrate that MAT programme in melanoma is characterised by increased stemness and clonogenic features of cancer cells, thus sustaining tumour progression. Furthermore, these data suggest that stemness is not an exclusive feature of cells undergoing EMT, but more generally is associated with an increase in cellular plasticity of cancer cells

Sedimentation-consolidation of a double porosity material

This paper studies the sedimentation-consolidation of a double porosity material, such as lumpy clay. Large displacements and finite strains are accounted for in a multidimensional setting. Fundamental equations are derived using a phenomenological approach and non-equilibrium thermodynamics, as set out by Coussy [Coussy, Poromechanics, Wiley, Chichester, 2004]. These equations particularise to three non-linear partial differential equations in one dimensional context. Numerical implementation in a finite element code is currently being undertaken

An elastoplastic framework for granular materials becoming cohesive through mechanical densification. Part II - the formulation of elastoplastic coupling at large strain

The two key phenomena occurring in the process of ceramic powder compaction are the progressive gain in cohesion and the increase of elastic stiffness, both related to the development of plastic deformation. The latter effect is an example of `elastoplastic coupling', in which the plastic flow affects the elastic properties of the material, and has been so far considered only within the framework of small strain assumption (mainly to describe elastic degradation in rock-like materials), so that it remains completely unexplored for large strain. Therefore, a new finite strain generalization of elastoplastic coupling theory is given to describe the mechanical behaviour of materials evolving from a granular to a dense state. The correct account of elastoplastic coupling and of the specific characteristics of materials evolving from a loose to a dense state (for instance, nonlinear --or linear-- dependence of the elastic part of the deformation on the forming pressure in the granular --or dense-- state) makes the use of existing large strain formulations awkward, if even possible. Therfore, first, we have resorted to a very general setting allowing general transformations between work-conjugate stress and strain measures; second, we have introduced the multiplicative decomposition of the deformation gradient and, third, employing isotropy and hyperelasticity of elastic response, we have obtained a relation between the Biot stress and its `total' and `plastic' work-conjugate strain measure. This is a key result, since it allows an immediate achievement of the rate elastoplastic constitutive equations. Knowing the general form of these equations, all the specific laws governing the behaviour of ceramic powders are finally introduced as generalizations of the small strain counterparts given in Part I of this paper.Comment: 18 pages, 1 figur

HPMA based nanoparticles for drug delivery applications

LAUREA MAGISTRALELa molecola N-(2-idrossipropil) metacrilammide (HPMA) è largamente usata a causa della sua biocompatibiltà per produrre polimeri idrosolubili per applicazioni nel campo del drug delivery, una discipilina sviluppatasi nell’ultimo secolo che sfrutta l’utilizzo di nuovi biomateriali per ottenere dei sistemi che migliorino l’efficacia e la biodistribuzione dei farmaci attualmente in commercio. Questo lavoro si propone di convertire delle procedure già ben consolidate per la produzione di nanoparticelle (NP) lipofile, ottenute tramite la polimerizzazione di macromonomeri a base di 2-idrossietil metacrilato (HEMA), sostituendolo con l’HPMA. Questi macromonomeri vengono poi polimerizzati in virtù del gruppo funzionale vinile, a dare un polimero a pettine che presenta la peculiarità di degradare tramite idrolisi dei legami estere della parte lipofila, lasciando come residuo il solo dorso del pettine. Per ottenere i macromonomeri a base di HPMA è stata utilizzata la polimerizzazione ad apertura di anello (ROP) di Lattide (LT) ed Ɛ-Caprolattone (CL), generando molecole del tipo HPMA-LAn o HPMA-CLn con diversa lunghezza di catena lipofila, che permette di controllare il degrado. Il catalizzatore precedentemente utilizzato era lo stagno ottanoato Sn(Oct)2, il quale ha dato ottimi risultati per la produzione di HPMA-LAn (monomero analizzato tramite 1H-NMR, GPC e MALDI-TOF), ma scarsamente controllati per la sintesi di HPMA-CLn. è stata quindi presa in considerazione la possibilità di utilizzare la polimerizzazione in solvente (toluene o tetraidrofurano) con la molecola 1,5,7-triazabiciclodec-5-ene come catalizzatore. I prodotti ottenuti sono stati utilizzati come materiali di partenza per la produzione di nanoparticelle per il trasporto di farmaci lipofili. Varie strategie sono state esaminate con i macromonomeri HPMA-LAn: 1) Polimerizzazione a radicali liberi in emulsione (emulsion FRP) è stata utilizzata per ottenere NP di copolimero con il PEGMAm, molecola idrofila largamente usata come stabilizzante di NP, che permette la riduzione di utilizzo di surfattante nel processo di polimerizzazione in emulsione. 2) Polimerizzazione in solvente per ottenere una soluzione di copolimero poly(HPMA-LAn)-PEGMAm utilizzata per ottenere NP via nanoprecipitazione flash. Come prova che questi sistemi fossero adatti per le applicazioni biomediche, è stata provata la stabilità in PBS per 30 giorni con misure successive tramite Dynamic Light Scattering (DLS) e la biodegradabilità in medium cellulare. L’abilità al carico e rilascio dei farmaci (e.g. desometasone) è stata verificata per le particelle prodotte, provando l’efficacia dei polimeri a base di HPMA come veicoli di farmaci. Per validare ulteriormente le potenzialità delle formulazioni, sono state studiate anche la tossicità su cellule del tipo 4T1 e l’uptake cellulare con il metodo della fluorimetria, in modo da integrare le analisi in vitro con delle valutazioni in vivo. Infine è stata analizzata l’omopolimerizzazione del poliHPMA con l’ambizione di creare un blocco idrofilo per un polimero anfifilico attraverso il trasferimento per addizione-frammentazione radicalica (RAFT). Aggiungendo delle unità lipofile con lo stesso meccanismo, si potrebbe creare un polimero dalla struttura controllata adatto all’applicazione nella produzione di nanoparticelle.N-(2-hydroxypropyl) methacrylamide (HPMA) is widely used to produce water-soluble polymers for drug delivery applications due to its non-immunogenic properties. In this work well-established procedures to obtain lipophilic nanoparticles (NPs) from macromonomers obtained by the functionalization of 2-hydroxyethyl methacrylate (HEMA), were tried to be converted in HPMA-based. Ring Opening Polymerization (ROP) of HPMA with Lactide (LT) and Ɛ-Caprolactone (CL) was performed to obtain HPMA-LA n or HPMA-CL n reactive macromonomers with different average chain length, the first gave expected results with Sn(Oct) 2 , the second lead us to investigate alternative ways (1,5,7-Triazabicyclodec-5-ene as ROP catalyst). The HPMA modification allowed to produce lipophilic macromonomers as a starting materials aimed to obtain polymer nanoparticles suitable for drug delivery applications of hydrophobic drugs. Different strategies were explored for HPMA-LA n macromonomers; first, emulsion free radical polymerization was conducted to obtain monodispersed PEGylated polymer NPs, then solvent polymerization was performed giving a solution of poly(HPMA-LAn)-based polymer which was then adopted to obtain NPs through flash nanoprecipitation. Since such NPs are aimed to drug delivery applications it was proved their fast degradability in biological medium. The ability to load and release a drug (i.e. dexamethasone) was also verified for the NPs synthesized through the different strategies proposed, proving the effectiveness of the HPMA functionalization presented to obtain a system able to deliver lipophilic drugs. NPs toxicity and cellular uptake were studied too to enlarge the set of in vivo evaluations. Finally, HPMA homopolymerization was then tried to have an hydrophilic block as starting point for obtaining an amphiphilic polymer by Radical Addition-Fragmentation Transfer (RAFT) polymerization, suitable for NPs production and thus to get a polymer with a more controlled structure

In Search of a better bottom line; Ethnicity in the workplace

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By promoting cell differentiation, miR-100 sensitizes basal-like breast cancer stem cells to hormonal therapy

Basal-like breast cancer is an aggressive tumor subtype with a poor response to conventional therapies. Tumor formation and relapse are sustained by a cell subset of Breast Cancer Stem Cells (BrCSCs). Here we show that miR-100 inhibits maintenance and expansion of BrCSCs in basal-like cancer through Polo-like kinase1 (Plk1) down-regulation. Moreover, miR-100 favors BrCSC differentiation, converting a basal like phenotype into luminal. It induces the expression of a functional estrogen receptor (ER) and renders basal-like BrCSCs responsive to hormonal therapy. The key role played by miR-100 in breast cancer free-survival is confirmed by the analysis of a cohort of patients' tumors, which shows that low expression of miR-100 is a negative prognostic factor and is associated with gene signatures of high grade undifferentiated tumors. Our findings indicate a new possible therapeutic strategy, which could make aggressive breast cancers responsive to standard treatments

Polymer nanocarriers to enhance the efficiency of platinum-based chemotherapeutics

The aim of this Thesis was to design and prepare polymer nanocarriers capable of encapsulating, carrying and delivering platinum-based chemotherapeutics. Polymer nanocarrier have been widely studied and employed as platinum drug delivery systems with the primary scope to overcome limitations presented by platinum-based chemotherapeutics. The conjugation of platinum onto polymers, however, presents some challenges, and, although there has been great progress in the field of drug delivery in the past years, to date only three polymer nanocarriers for platinum drugs have found their way to the clinic. In this Thesis, hydrophilic block copolymers were synthesised via reversible addition fragmentation chain transfer (RAFT) polymerisation or N-carboxyanhydride ring-opening polymerization (NCA-ROP). Upon attachment of a hydrophobic platinum drug the block copolymer becomes amphiphilic and can self-assemble in aqueous media into nanoparticles of different morphology depending on the block copolymer features. Spherical micelles consisting of a poly(methacrylic acid) core which conjugates and encapsulates the platinum chemotherapeutic and a hydrophilic shell made of sugar blocks were prepared and their biological activities compared in vitro. Among the sugars considered here, fructose based micelles showed promising results in terms of their targeting ability towards breast cancer cells. Consequently, fructose-shelled micelles were selected to explore the effect of different loading quantities of platinum drug. It was discovered that the amount of platinum in the core of the micelle highly influences the internal morphology of the micelle which, in turn, affects the micelle-cell interactions. Micelles with low dual drug loading had better cellular uptake and higher toxicity than the micelles with high drug loading, despite having the same fructose-based outer shell. Interestingly, this aspect had been neglected by literature so far, and is important to explore. Micelles made of a fructose shell were then compared to micelles with a non-targeting hydrophilic shell made of poly(ethylene glycol) methyl ether methacrylate (PEGMEMA). The aim was to compare the process of cellular uptake and the mechanism of platinum release inside the cell. For this scope, a fluorescent platinum drug was synthesised as a probing tool. Finally, a polymer vesicle based on PEG and poly(glutamic acid) was designed to co-deliver a platinum drug and the cancer inhibitor, paclitaxel, simultaneously. The two drugs have a synergistic effect when used in combination or co-delivered by the vesicles. Moreover, a viability study using multicellular tumour spheroids (MCTS) showed a significant decrease in cell proliferation when the MCTS were treated with single drug, a combination of free drugs and dual-drug loaded vesicles compared with untreated MCTS. An improvement is observed in the case of the dual-drug vesicles