Development of Classification Models for Identifying “True” P-glycoprotein (P-gp) Inhibitors Through Inhibition, ATPase Activation and Monolayer Efflux Assays

P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over-expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as “true” P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function

Hand rehabilitation with sonification techniques in the subacute stage of stroke

After a stroke event, most survivors suffer from arm paresis, poor motor control and other disabilities that make activities of daily living difficult, severely affecting quality of life and personal independence. This randomized controlled trial aimed at evaluating the efficacy of a music-based sonification approach on upper limbs motor functions, quality of life and pain perceived during rehabilitation. The study involved 65 subacute stroke individuals during inpatient rehabilitation allocated into 2 groups which underwent usual care dayweek) respectively of standard upper extremity motor rehabilitation or upper extremity treatment with sonification techniques. The Fugl-Meyer Upper Extremity Scale, Box and Block Test and the Modified Ashworth Scale were used to perform motor assessment and the McGill Quality of Life-it and the Numerical Pain Rating Scale to assess quality of life and pain. The assessment was performed at baseline, after 2 weeks, at the end of treatment and at follow-up (1 month after the end of treatment). Total scores of the Fugl-Meyer Upper Extremity Scale (primary outcome measure) and hand and wrist sub scores, manual dexterity scores of the affected and unaffected limb in the Box and Block Test, pain scores of the Numerical Pain Rating Scale (secondary outcomes measures) significantly improved in the sonification group compared to the standard of care group (time*group interaction < 0.05). Our findings suggest that music-based sonification sessions can be considered an effective standardized intervention for the upper limb in subacute stroke rehabilitation

The effect of 12C + 12C rate uncertainties on s-process yields

The slow neutron capture process in massive stars (the weak s-process) produces most of the s-only isotopes in the mass region 60 < A < 90. The nuclear reaction rates used in simulations of this process have a profound effect on the final s-process yields. We generated 1D stellar models of a 25 solar mass star varying the 12C + 12C rate by a factor of 10 and calculated full nucleosynthesis using the post-processing code PPN. Increasing or decreasing the rate by a factor of 10 affects the convective history and nucleosynthesis, and consequently the final yields.Comment: Conference proceedings for the Nuclear Physics in Astrophysics IV conference, 8-12 June 2009. 4 pages, 3 figures. Accepted for publication to the Journal of Physics: Conference Serie

Conventional and algorithmic music listening before radiotherapy treatment: A randomized controlled pilot study

Music listening is a widespread approach in the field of music therapy. In this study, the effects of music listening on anxiety and stress in patients undergoing radiotherapy are investigated. Sixty patients with breast cancer who were candidates for postoperative curative radiotherapy were recruited and randomly assigned to three groups: Melomics-Health (MH) group (music listening algorithmically created, n = 20); individualized music listening (IML) group (playlist of preferred music, n = 20); no music group (n = 20). Music listening was administered for 15 min immediately before simulation and during the first five radiotherapy sessions. The State-Trait Anxiety Inventory (STAI) and the Psychological Distress Inventory (PDI) were administered before/after treatment. Cochran’s Q test and McNemar test for paired proportions were performed to evaluate if the proportion of subjects having an outcome score below the critical value by treatment and over time was different, and if there was a change in that proportion. The MH group improved in STAI and PDI. The IML group worsened in STAI at T1 and improved STAI-Trait at T2. The IML group worsened in PDI at T2. The No music group generally improved in STAI and PDI. Clinical and music listening-related implications are discussed defining possible research perspectives in this field

The in vivo effect of chelidonine on the stem cell system of planarians

The presence of adult pluripotent stem cells and the amazing regenerative capabilities make planarian flatworms an extraordinary experimental model to assess in vivo the effects of substances of both natural and synthetic origin on stem cell dynamics. This study focuses on the effects of chelidonine, an alkaloid obtained from Chelidonium majus. The expression levels of molecular markers specific for stem or differentiated cells were compared in chelidonine-treated and control planarians. The use of these markers demonstrates that chelidonine produces in vivo a significant anti-proliferative effect on planarian stem cells in a dosedependent fashion. In response to chelidonine treatment mitotic abnormalities were also observed and the number of cells able to proceed to anaphase/telophase appeared significantly reduced with respect to the controls. Our results support the possibility that chelidonine acts on cell cycle progression by inhibition of tubulin polymerization. These studies provide a basis for preclinical evaluation in vivo of the effects of chelidonine on physiologically proliferating stem cells

Measurement of 1323 and 1487 keV resonances in 15N({\alpha}, {\gamma})19F with the recoil separator ERNA

The origin of fluorine is a widely debated issue. Nevertheless, the ^{15}N({\alpha},{\gamma})^{19}F reaction is a common feature among the various production channels so far proposed. Its reaction rate at relevant temperatures is determined by a number of narrow resonances together with the DC component and the tails of the two broad resonances at E_{c.m.} = 1323 and 1487 keV. Measurement through the direct detection of the 19F recoil ions with the European Recoil separator for Nuclear Astrophysics (ERNA) were performed. The reaction was initiated by a 15N beam impinging onto a 4He windowless gas target. The observed yield of the resonances at Ec.m. = 1323 and 1487 keV is used to determine their widths in the {\alpha} and {\gamma} channels. We show that a direct measurement of the cross section of the ^{15}N({\alpha},{\gamma})^{19}F reaction can be successfully obtained with the Recoil Separator ERNA, and the widths {\Gamma}_{\gamma} and {\Gamma}_{\alpha} of the two broad resonances have been determined. While a fair agreement is found with earlier determination of the widths of the 1487 keV resonance, a significant difference is found for the 1323 keV resonance {\Gamma}_{\alpha} . The revision of the widths of the two more relevant broad resonances in the 15N({\alpha},{\gamma})19F reaction presented in this work is the first step toward a more firm determination of the reaction rate. At present, the residual uncertainty at the temperatures of the ^{19}F stellar nucleosynthesis is dominated by the uncertainties affecting the Direct Capture component and the 364 keV narrow resonance, both so far investigated only through indirect experiments.Comment: 8 pages, 11 figures. Accepted for publication in PR

Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson's disease

Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson's disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24-36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patient

First Measurement of the He3+He3-->He4+2p Cross Section down to the Lower Edge of the Solar Gamow Peak

We give the LUNA results on the cross section measurement of a key reaction of the proton-proton chain strongly affecting the calculated neutrino luminosity from the Sun: He3+He3-->He4+2p. Due to the cosmic ray suppression provided by the Gran Sasso underground laboratory it has been possible to measure the cross section down to the lower edge of the solar Gamow peak, i.e. as low as 16.5 keV centre of mass energy. The data clearly show the cross section increase due to the electron screening effect but they do not exhibit any evidence for a narrow resonance suggested to explain the observed solar neutrino flux.Comment: 5 pages, RevTeX, and 2 figures in PostScript Submitted for publicatio

267 Occupation and Multiple Sclerosis: an Italian case-control study

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