The free-volume structure of a polymer melt, poly(vinyl methylether) from molecular dynamics simulations and cavity analysis

10 pages, 6 figures, 2 tables.In this work we analyze and compare the free volume of a polymer system poly(vinyl methylether) (PVME) at 300 K obtained by the two direct but different approaches: Positron annihilation lifetime spectroscopy (PALS) and computer simulations. The free volume is calculated from the simulated cells of PVME by means of numerical methods based on grid scanning and probing the structure with a probe of a given radius RP. The free-volume structure was found to be percolated for small probes at RP=0.53 Å. As the probe radius increases, the cavity structure breaks into isolated cavities, reaching a maximum of the cavity number at RP=0.78 Å. We further develop methods for a geometrical analysis of the free-volume cavities by considering their shape. The geometrical computations show that the cavities have elongated shape with side-to-length ratio corresponding to approximately 1:0.55 and with an average length of 6 Å. Based on the overlap between the computed cavities and simplified geometrical representations, the best match of the cavity shape is obtained for the approximation to the ellipsoidal shape (overlap on 84.4%). A match with other examined shapes follows the sequence: ellipsoid>cylinder>bar>sphere>cube. Finally, the computed geometrical parameters are used as input parameters into the quantum-mechanical models for the orthopositronium (o-Ps) lifetime in various free-volume hole geometries. Comparison with the experimental data gives support for two ideas about the existence of an o-Ps particle in the polymeric matrix: (i) the positronium cannot localize in a portion of very small cavities; (ii) and in the case of the percolated cavities, several o-Ps particles occupy some subcavities in the same cavity. Additionally, radial distribution functions of the free volume indicate the existence of two kinds of free volume, a structured one, corresponding to interstitial spaces along the polymer chain, and the so-called “bulk free volume,” distributed randomly in the structure. PALS measurements seem to be mainly related with this bulk free volume. The cavities represented by the idealized geometries are visualized in three-dimensional space providing a unique representation on the free-volume structures.This work was supported by the VEGA Agency, Slovakia under Grant No. 2/0014/09(J.B.)and Project No. MAT2007-63681 (Spanish Ministry of Education), Grant No. IT-436-07 (Basque Government) and Project No. 2007SK0008 between Slovak Academy of Sciences (SAS) and Spanish Research Council (CSIC) Support from the project Spanish MEC Grant No. CSD2006-53 is also acknowledged.Peer reviewe

Component dynamics in polyvinylpyrrolidone concentrated aqueous solutions

2H-nuclear magnetic resonance (NMR) and neutron scattering (NS) on isotopically labelled samples have been combined to investigate the structure and dynamics of polyvinylpyrrolidone (PVP) aqueous solutions (4 water molecules/monomeric unit). Neutron diffraction evidences the nanosegregation of polymer main-chains and water molecules leading to the presence of water clusters. NMR reveals the same characteristic times and spectral shape as those of the slower process observed by broadband dielectric spectroscopy in this system [S. Cerveny, J. Chem. Phys. 128, 044901 (2008)]10.1063/1.2822332. The temperature dependence of such relaxation time crosses over from a cooperative-like behavior at high temperatures to an Arrhenius behavior at lower temperatures. Below the crossover, NMR features the spectral shape as due to a symmetric distribution of relaxation times and the underlying motions as isotropic. NS results on the structural relaxation of both components-isolated via H/D labeling-show (i) anomalously stretched and non-Gaussian functional forms of the intermediate scattering functions and (ii) a strong dynamic asymmetry between the components that increases with decreasing temperature. Strong heterogeneities associated to the nanosegregated structure and the dynamic asymmetry are invoked to explain the observed anomalies. On the other hand, at short times the atomic displacements are strongly coupled for PVP and water, presumably due to H-bond formation and densification of the sample upon hydration. © 2012 American Institute of Physics.Financial support from the projectsMAT2007-63681 and IT-436-07 (G.V.) is acknowledged.Peer Reviewe

TNF-α inhibits GDNF levels in Sertoli cells, through a NF-κB-dependent, HES1-dependent mechanism

Glial cell line-derived neurotrophic factor (GDNF) is a soluble molecule crucial for the regulation of the spermatogonial stem cells (SSC) of the testis. The effects of GDNF on target cells have been extensively described, but mechanisms underlying GDNF regulation are currently under investigation. In the nervous system, GDNF expression is regulated by pro-inflammatory cytokines including lipopolysaccharide (LPS), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) but the effect of these cytokines on GDNF expression in the testis is unclear

Development of a Potential Gallium-68-Labelled Radiotracer Based on DOTA-Curcumin for Colon-Rectal Carcinoma: From Synthesis to In Vivo Studies

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative (68Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68Ga-DOTA-C21 exhibits decent stability (57 \ub1 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 \ub1 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68Ga-DOTA-C21 is 3.57 \ub1 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 \ub1 0.2. High amount of activity (12.73 \ub1 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 \ub1 3.3% ID/g), lungs (8.42 \ub1 0.8% ID/g), liver (5.81 \ub1 0.5% ID/g) and heart (4.70 \ub1 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer

Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer

Impact of immunochemotherapy with R-bendamustine or R-CHOP for treatment naïve advanced-stage follicular lymphoma: A subset analysis of the FOLL12 trial by Fondazione Italiana Linfomi

: We conducted a post hoc analysis of the FOLL12 trial to determine the impact of different initial immunochemotherapy (ICT) regimens on patient outcomes. Patients were selected from the FOLL12 trial, which included adults with stage II-IV follicular lymphoma (FL) grade 1-3a and high tumor burden. Patients were randomized 1:1 to receive either standard ICT followed by rituximab maintenance (RM) or the same ICT followed by a response-adapted approach. ICT consisted of rituximab-bendamustine (RB) or rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), per physician's decision. A total of 786 patients were included in this analysis, 341 of whom received RB and 445 R-CHOP. RB was more frequently prescribed to older subjects, females, patients without bulky disease, and those with grade 1-2 FL. After a median of 56 months of follow-up, R-CHOP and RB had similar progression-free survival (PFS) (Hazard Ratio for RB 1.11, 95% CI 0.87-1.42, p = 0.392). Standard RM was associated with improved PFS compared to response-adapted management both after R-CHOP and RB. Grade 3-4 hematologic adverse events were more frequent with R-CHOP during induction treatment and more frequent with RB during RM. Grade 3-4 infections were more frequent with RB. RB was also associated with a higher incidence of transformed FL. R-CHOP and RB showed similar activity and efficacy, but with different safety profiles and long-term events, suggesting that the treating physician should carefully select the most appropriate chemotherapy regimen for each patient based on patient's individual characteristics, choices, and risk profile

Labelling of

In spite of the hazard due to the radiation exposure, preparation of 90Y- and 177Lu-labelled radiopharmaceuticals is still mainly performed using manual procedures. In the present study the performance of a commercial automatic synthesizer based on disposable cassettes for the labelling of 177Lu- and 90Y-DOTA-conjugated biomolecules (namely, DOTATOC and PSMA-617) was evaluated and compared to a manual and a semiautomated approach. The dose exposure of the operators was evaluated as well. More than 300 clinical preparations of both 90Y- and 177Lu-labelled radiopharmaceuticals have been performed using the three different methods. The mean radiochemical yields for 90Y-DOTATOC were 96.2±4.9%, 90.3±5.6%, and 82.0±8.4%, while for 177Lu-DOTATOC they were 98.3%  ± 0.6, 90.8%  ± 8.3, and 83.1±5.7% when manual, semiautomated, and automated approaches were used, respectively. The mean doses on the whole hands for yttrium-90 preparations were 0.15±0.4 mSv/GBq, 0.04±0.1 mSv/GBq, and 0.11±0.3 mSv/GBq for manual, semiautomated, and automated synthesis, respectively, and for lutetium-177 preparations, they were 0.02±0.008 mSv/GBq, 0.01±0.03 mSv/GBq, and 0.01±0.02 mSv/GBq, respectively. In conclusion, the automated approach guaranteed reliable and reproducible preparations of pharmaceutical grade therapeutic radiopharmaceuticals in a decent RCY. The radiation exposure of the operators remained comparable to the manual approach mainly due to the fact that a dedicated shielding was still not available for the system

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

The structure and the dynamics of poly(vinyl methyl ether) PVME and in PVME concentrated water solution : a study by neutron scattering and fully atomistic molecular dynamics simulations

175 p. : il.El agua juega un papel fundamental en los procesos biológicos. Una gran parte de ella se encuentra cerca de biomoléculas fundamentales afectando a sus propias funcionalidades. Por ello el estudio del agua en sistemas confinados y en mezclas es un tema de suma importancia y las soluciones poliméricas representan un sistema adecuado para este tipo de estudios. Los polímeros son sistemas sencillos y pueden ser usados como modelos para estudiar los sistemas biológicos así como para estudiar el comportamiento del agua en los procesos biológicos. Por otra parte, según el valor de la temperatura de transición vítrea del sistema, la dinámica del polímero puede aparecer congelada con respecto a la escala de tiempo del experimento permitiendo estudiar la dinámica y la estructura del agua a bajas temperaturas y en una matriz conocida. Esta tesis doctoral está enfocada en la estructura y la dinámica de la solución compuesta por poly(vinyl metil ether)PVME y agua estudiada a través del uso combinado de técnicas de neutrones, simulaciones atomísticas de dinámica molecular, difracción de rayos X y espectroscopía dieléctrica. En primer lugar se ha estudiado el PVME seco y luego se ha investigado la solución con dos objectivos: (i) estudiar cómo el agua afecta a la estructura y a la dinámica del PVME; (ii) estudiar la dinámica del agua en un entorno polimérico a bajas temperaturas. El Capítulo 1 es una introducción 1 a los polímeros y el agua, en el Capítulo 2 y 3 están explicadas respectivamente las técnicas experimentales utilizadas y las simulaciones de dinámica molecular, en el Capítulo 4 se estudian la estructura y la dinámica del PVME seco y en el Capítulo 5 la solución. Finalmente los resultados están resumidos en el Capítulo de las Conclusiones