Synthesis, radiolabeling, and pre-clinical evaluation of [44Sc]Sc-AAZTA conjugate PSMA inhibitor, a new tracer for high-efficiency imaging of prostate cancer.

PURPOSE: The aim of this work was to demonstrate the suitability of AAZTA conjugated to PSMA inhibitor (B28110) labeled with scandium-44 as a new PET tracer for diagnostic imaging of prostate cancer. BACKGROUND: Nowadays, scandium-44 has received significant attention as a potential radionuclide with favorable characteristics for PET applications. A polyaminopolycarboxylate heptadentate ligand based on a 1,4-diazepine scaffold (AAZTA) has been thoroughly studied as chelator for Gd3+ ions for MRI applications. The excellent results of the equilibrium, kinetic, and labeling studies led to a preliminary assessment of the in vitro and in vivo behavior of [44Sc][Sc-(AAZTA)]- and two derivatives, i.e., [44Sc][Sc (CNAAZTA-BSA)] and [44Sc][Sc (CNAAZTA-cRGDfK)]. RESULTS: B28110 was synthesized by hybrid approach, combining solid-phase peptide synthesis (SPPS) and solution chemistry to obtain high purity (97%) product with an overall yield of 9%. Subsequently, the radioactive labeling was performed with scandium-44 produced from natural calcium target in cyclotron, in good radiochemical yields (RCY) under mild condition (pH 4, 298 K). Stability study in human plasma showed good RCP% of [44Sc]Sc-B28110 up to 24 h (94.32%). In vivo PET/MRI imaging on LNCaP tumor-bearing mice showed high tracer accumulation in the tumor regions as early as 20 min post-injection. Ex vivo biodistribution studies confirmed that the accumulation of 44Sc-PSMA-617 was two-fold lower than that of the radiolabeled B28110 probes. CONCLUSIONS: This work demonstrated the suitability of B28110 for the complexation with scandium-44 at room temperature and the high performance of the resulting new tracer based on AAZTA chelator for the diagnosis of prostate cancer using PET.

Replacement of the Lorentz law for the shape of the spectral lines in the infrared region.

We propose a new phenomenological law for the shape of the spectral lines in the infrared, which accounts for the exponential decay of the extinction coefficient in the high-frequency region, observed in many spectra. We apply this law to the measured infrared spectra of LiF, NaCl, and MgF2, finding good agreement over a wide range of frequencies.

Chaoticity threshold in magnetized plasmas: numerical results in the weak coupling regime.

The present paper is a numerical counterpart to the theoretical work [Carati et al., Chaos 22, 033124 (2012)]. We are concerned with the transition from order to chaos in a one-component plasma (a system of point electrons with mutual Coulomb interactions, in a uniform neutralizing background), the plasma being immersed in a uniform stationary magnetic field. In the paper [Carati et al., Chaos 22, 033124 (2012)], it was predicted that a transition should take place when the electron density is increased or the field decreased in such a way that the ratio ωp/ωc between plasma and cyclotron frequencies becomes of order 1, irrespective of the value of the so-called Coulomb coupling parameter Γ. Here, we perform numerical computations for a first principles model of N point electrons in a periodic box, with mutual Coulomb interactions, using as a probe for chaoticity the time-autocorrelation function of magnetization. We consider two values of Γ (0.04 and 0.016) in the weak coupling regime Γ â‰ª 1, with N up to 512. A transition is found to occur for ωp/ωc in the range between 0.25 and 2, in fairly good agreement with the theoretical prediction. These results might be of interest for the problem of the breakdown of plasma confinement in fusion machines.

B25716/1: a novel albumin-binding Gd-AAZTA MRI contrast agent with improved properties in tumor imaging.

The aim of this study is to describe the synthesis of, relaxometric characterization of, pharmacokinetic properties of, and animal imaging experiments with a new, low molecular weight gadolinium complex with high binding affinity toward serum albumin. The gadolinium(III) chelate (B25716/1) is based on the structure of the heptadentate ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6 methylperhydro-1,4-diazepine (AAZTA) covalently conjugated to an analogue of deoxycholic acid. The study was conducted as a comparison with that of an analogous complex based on the octadentate diethylenetriaminepentaacetic acid ligand B22956/1 (whose albumin binding properties were previously assessed). The structural modification with respect to B22956/1 leads to a system that can host two coordinated water molecules in fast exchange with bulk water with potential higher efficiency as an MRI contrast agent. On interaction with human serum albumin the expected-field-independent-relaxation enhancement is not observed, possibly as a consequence of the displacement of one of the two inner-sphere water molecules of the gadolinium complex. At clinically relevant magnetic fields, however, the plasma relaxivity of B25716/1 is markedly higher than that shown by B22956/1, owing to concomitant synergistic contributions from the electronic correlation time and water molecules in the second coordination sphere. The capability of B25716/1 to enhance tumor regions in magnetic resonance images was assessed in vivo at 3 T on a xenograft tumor mouse model prepared with PC-3 cells. B25716/1 displays signal enhancements approximately double those observed for B22956/1, in agreement with the findings of the in vitro relaxivity investigations.

Transition from order to chaos, and density limit, in magnetized plasmas.

It is known that a plasma in a magnetic field, conceived microscopically as a system of point charges, can exist in a magnetized state, and thus remain confined, inasmuch as it is in an ordered state of motion, with the charged particles performing gyrational motions transverse to the field. Here, we give an estimate of a threshold, beyond which transverse motions become chaotic, the electrons being unable to perform even one gyration, so that a breakdown should occur, with complete loss of confinement. The estimate is obtained by the methods of perturbation theory, taking as perturbing force acting on each electron that due to the so-called microfield, i.e., the electric field produced by all the other charges. We first obtain a general relation for the threshold, which involves the fluctuations of the microfield. Then, taking for such fluctuations, the formula given by Iglesias, Lebowitz, and MacGowan for the model of a one component plasma with neutralizing background, we obtain a definite formula for the threshold, which corresponds to a density limit increasing as the square of the imposed magnetic field. Such a theoretical density limit is found to fit pretty well the empirical data for collapses of fusion machines.

Dificultades de acceso al sistema de procesamiento linguístico en diferentes poblaciones infantiles / Difficulties of access to the language processing system in different pediatric populations

El estudio del lenguaje en niños presupone la puesta en marcha de un marco teórico que permita indagar en procesos de la evolución lingüística, con un criterio conceptual, abierto y sensible a los diferentes signos y síntomas que exhiben los niños en su desarrollo. La Psicología Cognitiva ofrece un marco de referencia que se ha considerado útil para ese objetivo. En ese contexto, considerar que la mente humana, con sede en el cerebro, está constituida por módulos o procesadores de diferente información, con aptitud de registro bastante independiente entre ellos, conectados por accesos, admite su aplicación para analizar cómo procede un sistema individual frente a los distintos estímulos lingüísticos que recibe. Con ese criterio se analizaron las producciones de poblaciones portadoras de cuadros diferentes: Neurofibromatosis 1, Síndrome de Prader – Willi, Trastorno Generalizado del Desarrollo y Trastorno Específico del Lenguaje, de manera de interpretar la modalidad particular de procesamiento de cada una, presuponiendo el hallazgo de marcadores clínicos descriptivos de las dificultades de acceso al sistema lingüístico.

The study of language in children implies the need for atheoretical framework that allows investigation of the pro-cesses of language development from a conceptual point ofview, open and sensitive to the different signs and symp-toms children present with during growth. Cognitive psy-chology provides a reference framework that is considereduseful for this aim. In this context, the human mind, loca-ted in the brain, is considered to consist of modules or pro-cessors for different kinds of information with a quite inde-pendent capacity of registration among them, connectedby accesses. This construct allows us to analyze how eachindividual system proceeds in the face of the different lin-guistic stimuli it receives. Based on this construct, langua-ge production of children with different pathologies wereanalyzed: Neurofibromatosis type 1, Prader–Willi syndro-me, pervasive developmental disorder, and specific lan-guage impairment, to evaluate the specific way of proces-sing in each of these conditions, taking into account thefinding of descriptive clinical markers of difficulties of accessto the language system.

[Occupational accidents in temporary work]. / Il fenomeno infortunistico nel lavoro interinale.

In 2000 in Italy about 470,000 workers found jobs provided by Temporary Work Agencies, i.e., more than twice the number in 1999. Temporary Work is an expanding phenomenon since it well suits the flexibility requirements of business: 77% of Temporary Work is in the manufacturing industry, involving mostly unskilled workers. The young age, low level of qualification, poor training, and lack of knowledge of the working environment are factors that can favour occupational accidents. There are studies that relate the frequency of labour accidents to the level of training and job experience. There are no data in the literature about occupational accidents during temporary work. Our study concerns sixteen temporary work Agencies that employed more than 250,000 manual workers in 2000. From the occupational accident registers of these agencies, we analysed all accidents concerning manual workers employed during 2000, with reference to: the number of accidents with up to three days prognosis, age, sex, nationality, prognosis pattern and cause. The agencies supplied data regarding the number of hours worked during 2000. We considered 5259 accidents: the overall frequency index (FI) was 92.1, with a considerable difference between the three main agencies (87.5) and the others. The mean age accident was 27.8 years, mean duration of sick leave 13.7 days, and the main causes were work tools (51.5%); 76% of the accidents concerned unskilled manual workers. The above indexes are definitely higher than those provided by INAIL (italian compulsory insurances) for the metalworking (38.1), construction (47.7) and mining (58.8) sectors during 1997. There is evidence that temporary work is related to an increased risk of occupational accidents. Further studies are required to confirm this evidence.

Hepatocyte-directed MR contrast agents. Can we take advantage of bile acids?

A series of gadolinium complexes conjugated to bile acids was prepared and investigated as possible hepatospecific MR imaging contrast agents. In the design of such compounds, features such as the nature of the bile acid, the site of conjugation on the bile acid skeleton, and the global charge of the conjugate were taken into account. Relaxivity measurements carried out in human serum indicate interaction of the conjugates with human serum proteins; even small structural variations significantly affect relaxivity in human serum. Pharmacokinetic data (biliary elimination in the range of 18.4-45.6%) show that bile acids can be used as address moieties to transport gadolinium complexes through hepatocytes. For a homogeneous series of compounds, differing only in the bile acid residue conjugated, it was unexpectedly found that cholic acid is twice as efficient an address moiety as cholylglycine or cholyltaurine. Preliminary results show that none of the conjugates is transported through the basolateral membrane of hepatocytes by the Na+/taurocholate carrier.