The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents

Cancer cells exhibit an altered metabolism which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. This provides anabolic support and selective growth advantage for cancer cells. Recently, a new concept has arisen suggesting that these metabolic changes may be due, in part, to an attenuated mitochondrial function which results from the inhibition of the pyruvate dehydrogenase complex (PDC). This mitochondrial complex links glycolysis to the Krebs cycle and the current understanding of its regulation involves the cyclic phosphorylation and dephosphorylation by specific pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs).     

Iloperidone: a new benzisoxazole atypical antipsychotic drug. Is it novel enough to impact the crowded atypical antipsychotic market?

Iloperidone is a new-generation atypical antipsychotic agent, acting as a serotonin/dopamine (5-HT(2A)/D(2)) antagonist, under development by Vanda Pharmaceuticals for the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like risperidone, and shows a multiple receptor binding profile, sharing this feature with the other atypical antipsychotic agents. Administered orally, the drug is highly bound to plasma proteins and extensively metabolised. Several clinical trials have been carried out, to check efficacy, safety and side effects. In order to introduce iloperidone as an agent for the treatment of schizophrenia, a short overview of the disease and of the most important antipsychotic drugs available or under development will be reported. Iloperidone pharmacokinetics and pharmacodynamics are presented herein, together with an evaluation of clinical safety and efficacy results.     

HIV-Tat dependent chemotaxis and invasion, key aspects of Tat mediated pathogenesis

Extracellular Tat acts as a pleiotropic molecule inducing several biological effects on different target cells. Tat stimulates the chemotaxis of numerous cell types and it appears to have oncogenic activities, including acting as a co-factor for Kaposi's sarcoma. The Tat protein has been shown to bind integrins through an RGD amino acid motif. Tat is an angiogenic factor able to induce the migration and invasion of endothelial and KS cells through the interaction of its basic domain with the VEGF receptor VEGFR2 (Flk-1/KDR). We have also found that Tat is able to mimic chemokines, activating monocyte migration through the `chemokine like' cysteine-core domain. Tat is a chemoattractant for dendritic cells, and both the RGD and basic domains appear to be involved in this response. In a recent study we demonstrated that Tat is chemotactic for PMN and induces Ca<sup>2+</sup> mobilization in vitro. Experiments using synthetic peptides showed that Tat activities on PMN are mediated by the `chemokine like' region. Finally Tat is also able to induce B cell chemotaxis, while its activity on helper T cells has not yet been clarified. Here we review data on Tat-dependent chemotaxis and discuss the possible implications in Tat mediated pathogenesis. This revised version was published online in July 2006 with corrections to the Cover Date.     

Controlled Insulin Release from Chitosan Microparticles

This study deals with the production of chitosan microparticles containing insulin by interfacial crosslinkage of chitosan solubilized in the aqueous phase of a water/oil dispersion in the presence of ascorbyl palmitate. The use of ascorbyl palmitate as interfacial crosslinker is based on its amphiphilic properties allowing its disposition at the water/oil interface of the preparative dispersion, thus permitting covalent bond formation with the amino groups of chitosan when its oxidation to dehydroascorbyl palmitate takes place during microparticle preparation. This preparation method produced microparticles characterized by high loading levels of insulin, completely releasing the drug in about 80 h at an almost constant release rate as determined by spectrophotometric and spectrofluorimetric methods. In contrast, the replacement of ascorbyl palmitate by dehydroascorbyl palmitate provided microparticles incompletely releasing the incorporated drug and characterized by a non-constant release rate over time due to the higher lipophilicity of dehydroascorbyl palmitate which hinders its disposition at the water/oil interface and thus decreases the crosslinking efficiency and increases the lipophilicity of the microparticle surface. The efficiency of the spectrofluorimetric and spectrophotometric methods used for determination of the stability and release of the insulin from the chitosan microparticles is also discussed.     

Superconducting Properties and Electron Scattering Mechanisms in a Nb Film with a Single Weak-Link Excavated by Focused Ion Beam

Granularity is one of the main features restricting the maximum current which a superconductor can carry without losses, persisting as an important research topic when applications are concerned. To directly observe its effects on a typical thin superconducting specimen, we have modeled the simplest possible granular system by fabricating a single artificial weak-link in the center of a high-quality Nb film using the focused ion beam technique. Then, its microstructural, magnetic, and electric properties in both normal and superconducting states were studied. AC susceptibility, DC magnetization, and magneto-transport measurements reveal well-known granularity signatures and how they negatively affect superconductivity. Moreover, we also investigate the normal state electron scattering mechanisms in the Boltzmann theory framework. The results clearly demonstrate the effect of the milling technique, giving rise to an additional quadratic-in-temperature contribution to the usual cubic-in-temperature sd band scattering for the Nb film. Finally, by analyzing samples with varying density of incorporated defects, the emergence of the additional contribution is correlated to a decrease in their critical temperature, in agreement with recent theoretical results.     

Effectiveness and safety of ustekinumab in naïve or TNF-inhibitors failure psoriatic arthritis patients: a 24-month prospective multicentric study

The current prospective observational study aimed to evaluate the long-term (24 months), real-life effectiveness of ustekinumab in psoriatic arthritis (PsA). Consecutive patients with moderate-severe PsA and active psoriasis who begun ustekinumab treatment were evaluated prospectively (January 2015–March 2017). Clinimetric scores and biochemical values were assessed at baseline (T0), at 6 (T6), 12 (T12), and 24 (T24) months. Friedman test and generalized linear models were used to compare variables over time. Regression analysis to identify determinants of minimal disease activity (MDA) at T6 and of treatment discontinuation was conducted. Sixty-five patients (43.1% men; age 49.4?±?11.6 years) were enrolled; ustekinumab was prescribed as a first (20%), second (33.8%), third (26.5%), fourth (15.4%), or fifth (4.6%) line biological therapy. Significant decrease in tender/swollen joints, Visual Analogue Scale of pain (VASp) and general health (VASgh), Disease Activity in PsA (DAPSA), Psoriasis Area Severity Index (PASI), Leeds Enthesitis Index (LEI), Health Assessment Questionnaire modified for spondyloarthritis (HAQ-S), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) was achieved. MDA was reached by 30.7, 47.0, and 34.0% of patients respectively at T6, T12, and T24. In multivariable models, mono-oligoarthritis was independently associated to MDA at T6 (OR 9.02; 95% CI 1.41, 57.71), while baseline CRP (OR 1.12; 95% CI 1.00, 1.26) and LEI (OR 0.50; 95% CI 0.25, 0.97) to ustekinumab discontinuation. More patients used disease-modifying antirheumatic drugs at T0 (35.3%) than at T24 (8.5%). Only nine episodes of infection and no serious adverse events were registered. In a real-life clinical setting, ustekinumab was safe and effective in PsA. Comedication tapering was often possible.