The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC).
CRPC xenografts were established with PC3 ...cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC.
Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients.
Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.
Gemcitabine (2,2-difluorodeoxycytidine dFdC) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its ...major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function.
In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) cohort I; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2.
Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups.
Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Corticospinal and corticobulbar descending pathways act in parallel with brainstem systems, such as the reticulospinal tract, to ensure the control of voluntary movements via direct or indirect ...influences onto spinal motoneurons. The aim of this study was to investigate the corticobulbar projections from distinct motor cortical areas onto different nuclei of the reticular formation. Seven adult macaque monkeys were analysed for the location of corticobulbar axonal boutons, and one monkey for reticulospinal neurons' location. The anterograde tracer BDA was injected in the premotor cortex (PM), in the primary motor cortex (M1) or in the supplementary motor area (SMA), in 3, 3 and 1 monkeys respectively. BDA anterograde labelling of corticobulbar axons were analysed on brainstem histological sections and overlapped with adjacent Nissl‐stained sections for cytoarchitecture. One adult monkey was analysed for retrograde CB tracer injected in C5‐C8 hemispinal cord to visualise reticulospinal neurons. The corticobulbar axons formed bilateral terminal fields with boutons terminaux and en passant, which were quantified in various nuclei belonging to the Ponto‐Medullary Reticular Formation (PMRF). The corticobulbar projections from both PM and SMA tended to end mainly ipsilaterally in PMRF, but contralaterally when originating from M1. Furthermore, the corticobulbar projection was less dense when originating from M1 than from non‐primary motor areas (PM, SMA). The main nuclei of bouton terminals corresponded to the regions where reticulospinal neurons were located with CB retrograde tracing. In conclusion, the corticobulbar projection differs according to the motor cortical area of origin in density and laterality.
The corticobulbar (corticoreticular) projections to the ponto‐medullary reticular formation (PMRF) from premotor (PM) and supplementary motor (SMA) cortical areas are denser than that originating from primary motor cortical area (M1). Corticobulbar axon terminals in PMRF coming from M1 are predominantly contralateral, whereas PM and SMA project more densely ipsilaterally. When originating from PM and SMA, corticobulbar terminals are located more medially than when originating from M1.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Functional recovery from central nervous system injury is likely to be partly due to a rearrangement of neural circuits. In this context, the corticobulbar (corticoreticular) motor projections onto ...different nuclei of the ponto‐medullary reticular formation (PMRF) were investigated in 13 adult macaque monkeys after either, primary motor cortex injury (MCI) in the hand area, or spinal cord injury (SCI) or Parkinson's disease‐like lesions of the nigro‐striatal dopaminergic system (PD). A subgroup of animals in both MCI and SCI groups was treated with neurite growth promoting anti‐Nogo‐A antibodies, whereas all PD animals were treated with autologous neural cell ecosystems (ANCE). The anterograde tracer BDA was injected either in the premotor cortex (PM) or in the primary motor cortex (M1) to label and quantify corticobulbar axonal boutons terminaux and en passant in PMRF. As compared to intact animals, after MCI the density of corticobulbar projections from PM was strongly reduced but maintained their laterality dominance (ipsilateral), both in the presence or absence of anti‐Nogo‐A antibody treatment. In contrast, the density of corticobulbar projections from M1 was increased following opposite hemi‐section of the cervical cord (at C7 level) and anti‐Nogo‐A antibody treatment, with maintenance of contralateral laterality bias. In PD monkeys, the density of corticobulbar projections from PM was strongly reduced, as well as that from M1, but to a lesser extent. In conclusion, the densities of corticobulbar projections from PM or M1 were affected in a variable manner, depending on the type of lesion/pathology and the treatment aimed to enhance functional recovery.
In intact adult macaques, the corticobulbar projections are denser when originating from PM than from M1. After unilateral lesion of M1, the projection from the ipsilesional PM was strongly reduced, both in presence or absence of anti‐Nogo‐A antibody treatment. After 1‐methyl‐4phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) lesion (and following cell therapy), the projections from both PM and M1 also decreased. In contrast, after cervical cord hemi‐section, the projection from M1 increased, but only in presence of anti‐Nogo‐A antibody treatment.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The goal of this work is to apply the idea of the city in 15 min to railway stations that can become the starting point of the analysis as they represent the “gateway”, where users start their last ...mile of travel after getting off the train. Within the research, 11 railway stations located in the Lombardy Region in Italy were identified and analyzed. To perform the analysis, an analytical index was implemented and determined for each station: this index summarizes the main features of the station itself in relation to the territory in which it is located. The adopted approach is comparative: it is not important the absolute value of the index of each station, but the comparison between the different indices. In this way it is possible on the one hand to classify the stations and on the other hand to identify and propose possible interventions to improve the role of a railway station in a territory. The proposed model is expandable and replicable: it is possible to add other useful indicators for the calculation of the index of each station and it is also possible to perform the analysis in different territorial contexts. In fact, it is a decision support tool able to provide indications and information for the planning and programming of the railway system and of the city; among the potential users of the proposed model there are railway station managers and administrations.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population average level during typical ...neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.
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•Subpopulations of GABAAR-responding neurons exist in mouse and human neuronal networks•DS networks exhibit a larger fraction of neurons with depolarizing GABA responses•Restoring physiological GABA-mediated inhibition rescues anxiety behavior in DS mice•Heterogeneous GABAergic responses coexist in control and DS human iPSC neurons
Behavioral neuroscience; Developmental neuroscience; Cellular neuroscience
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract In vitro neuronal cultures exhibit spontaneous electrophysiological activity that can be modulated by chemical stimulation and can be monitored over time by using Micro-Electrode Arrays ...(MEAs), devices composed by a glass substrate and metal electrodes. Dissociated networks respond to transmitters, their blockers and many other pharmacological substances, including neurotoxic compounds. In this paper we present results related to the effects, both acute (i.e. 1 hour after the treatment) and chronic (3 days after the treatment), of increasing glutamatergic transmission induced by the application of rising concentrations of glutamate and its agonists (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid — AMPA, N-methyl-D-aspartate — NMDA and AMPA together with cyclothiazide — CTZ). Increase of available glutamate was obtained in two ways: 1) by direct application of exogenous glutamate and 2) by inhibiting the clearance of the endogenously released glutamate through DL-threo-β-benzyloxyaspartate (TBOA). Our findings show that fine modulations (i.e. low concentrations of drug) of the excitatory synaptic transmission are reflected in the electrophysiological activation of the network, while intervention leading to excessive direct stimulation of glutamatergic pathways (i.e. medium and high concentrations of drug) results in the abolishment of the electrophysiological activity and eventually cell death. The results obtained by means of the MEA recordings have been compared to the analysis of cell viability to confirm the excitotoxic effect of the applied drug. In conclusion, our study demonstrates that MEA-coupled cortical networks are very sensitive to pharmacological manipulation of the excitatory ionotropic glutamatergic transmission and might provide sensitive endpoints to detect acute and chronic neurotoxic effects of chemicals and drugs for predictive toxicity testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The corticotectal projections, together with the corticobulbar (corticoreticular) projections, work in parallel with the corticospinal tract (CST) to influence motoneurons in the spinal cord both ...directly and indirectly
the brainstem descending pathways. The tectospinal tract (TST) originates in the deep layers of the superior colliculus. In the present study, we analyzed the corticotectal projections from two motor cortical areas, namely the premotor cortex (PM) and the primary motor cortex (M1) in eight macaque monkeys subjected to either a cortical lesion of the hand area in M1 (
= 4) or Parkinson's disease-like symptoms PD (
= 4). A subgroup of monkeys with cortical lesion was subjected to anti-Nogo-A antibody treatment whereas all PD monkeys were transplanted with Autologous Neural Cell Ecosystems (ANCEs). The anterograde tracer BDA was used to label the axonal boutons both
and
in the ipsilateral superior colliculus. Individual axonal boutons were charted in the different layers of the superior colliculus. In intact animals, we previously observed that corticotectal projections were denser when originating from PM than from M1. In the present M1 lesioned monkeys, as compared to intact ones the corticotectal projection originating from PM was decreased when treated with anti-Nogo-A antibody but not in untreated monkeys. In PD-like symptoms' monkeys, on the other hand, there was no consistent change affecting the corticotectal projection as compared to intact monkeys. The present pilot study overall suggests that the corticotectal projection is less affected by M1 lesion or PD symptoms than the corticoreticular projection previously reported in the same animals.
In Europe, urban areas represent the “engine” of economic growth and employment in a territory: about 85% of the EU’s GDP (gross domestic product) is generated in european cities. Several European ...cities, due to the extensive economic activities in urban areas, have to deal with and manage issues related to or caused by transport and mobility such as congestion, air pollution, safety and noise pollution. In 2010, for example, about 73% of European citizens lived in urban areas; this percentage is estimated to increase to more than 80% by 2050. In addition to the direct impact generated by traffic, urban mobility can also influence social development, social exclusion, and accessibility for people with reduced mobility. Consequently, the need to adopt sustainable transport systems is now a global goal that can no longer be postponed. To promote sustainable mobility models, current planning strategies have used smart growth interventions to move from mono-centric city structures to poly-centric, more localized configurations. For example, the idea of the 15-minute city is gradually growing in importance from both a policy and social perspective. The basis of the idea is the promotion of interventions to increase the supply of local services, such as schools, public transportation systems, health care facilities, dining facilities, jobs, recreation areas, and retail stores. In this way, local areas are created that are sustainable, inclusive, and walkable within a small radius on foot or by bicycle. Starting from these considerations, the aim of this work is to apply the idea of the city in 15 min to railway stations: in this perspective, the railway station becomes the starting point of the analysis as it represents the “door of the house”, from where users start their last mile trips after getting off the train. For some railway stations located in Northern Italy, an analytical index has been defined that summarizes the characteristics of the station in relation to the territory in which it is located. In this way, it is possible to classify the stations on the one hand and, on the other, to identify and propose improvements aimed at relaunching the role of a railway station in a territory.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population
level during typical neurodevelopment ...and partially in brain disorders. However, no investigation has specifically assessed whether a
of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in wild-type (WT) and down syndrome (DS) neuronal networks, as assessed at increasing scales of complexity (cultures, brain slices, behaving mice). Nevertheless, WT mice presented a much lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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