The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Patterning of the chick forebrain anlage by the prechordal plate

We analysed the role of the prechordal plate in forebrain development of chick embryos in vivo. After transplantation to uncommitted ectoderm a prechordal plate induces an ectopic, dorsoventrally patterned, forebrain-like vesicle. Grafting laterally under the anterior neural plate causes ventralization of the lateral side of the forebrain, as indicated by a second expression domain of the homeobox gene NKX2.1. Such a lateral ventralization cannot be induced by the secreted factor Sonic Hedgehog alone, as this is only able to distort the ventral forebrain medially. Removal of the prechordal plate does not reduce the rostrocaudal extent of the anterior neural tube, but leads to significant narrowing and cyclopia. Excision of the head process results in the caudal expansion of the NKX2.1 expression in the ventral part of the anterior neural tube, while PAX6 expression in the dorsal part remains unchanged. We suggest that there are three essential steps in early forebrain patterning, which culminate in the ventralization of the forebrain. First, anterior neuralization occurs at the primitive streak stage, when BMP-4-antagonizing factors emanate from the node and spread in a planar fashion to induce anterior neural ectoderm. Second, the anterior translocation of organizer-derived cells shifts the source of neuralizing factors anteriorly, where the relative concentration of BMP-4-antagonists is thus elevated, and the medial part of the prospective forebrain becomes competent to respond to ventralizing factors. Third, the forebrain anlage is ventralized by signals including Sonic Hedgehog, thereby creating a new identity, the prospective hypothalamus, which splits the eye anlage into two lateral domains.     

Thymosin β4 is differentially expressed in the cerebrospinal fluid of Creutzfeldt‐Jakob disease patients: a MALDI‐TOF MS protein profiling study

MALDI‐TOF protein profiling analysis permits the detection of peptides and small proteins in complex protein mixtures with great accuracy. We applied this analysis to cerebrospinal fluid (CSF) from 15 patients affected by Creutzfeldt‐Jakob disease (CJD). We compared the levels of the normalized ion signals of 11 sporadic and 4 genetic CJD forms with those from ten healthy control subjects and eight non‐CJD relapsing‐remitting multiple sclerosis patients. In so doing, we detected 61 differentially expressed ion signals in CJD samples compared to controls. Among the 61 signals, 3 signals had significantly increased levels with high statistical significance (p <0.0001) and were located at 3238.3 m/z, 4963.7 m/z, and 8565.3 m/z. We characterized the 5.0 and 8.6 kDa proteins as thymosin β4 N‐acetylated and free ubiquitin, respectively, while the 3.2‐kDa peptide remained uncharacterized. Although elevated ubiquitin levels have previously been described in CJD, we have demonstrated for the first time the involvement of thymosin β4 in a neurodegenerative disease. To support the validity of thymosin β4 levels obtained by MALDI‐TOF analysis, an independent enzyme immunoassay analysis was performed. Moreover, a validation cohort consisting of CSF from three CJD patients, five healthy subjects, and six non‐CJD relapsing‐remitting multiple sclerosis patients was analyzed in a similar way, yielding superimposable results. We propose that thymosin β4 is a potential new candidate marker for the ante mortem diagnosis of CJD disease.     

Effect of treatment with 13-cis-retinoic acid and ara-C on the hematopoietic stem cells of patients with myelodysplastic syndromes

PURPOSE: To assess the "in vivo" effect of 13-cis-retinoic acid and low dose Ara-C in MDS as well as to establish "in vitro" advantage of retinoid dose-related growth pattern on bone marrow cultures as defined by culture timing and CFU-GM proliferative response. PATIENTS AND METHODS: We evaluated 28 patients diagnosed of MDS according to FAB classification, of whom 4 cases had RA, 8 cases SRA, 14 cases RAEB and 2 cases RAEB-T. Patients who had RA and SRA were treated with oral 13-cis-retinoic acid at doses of 20-40 mg daily for 4 months and those cases with RAEB and RAEB-T had subcutaneous Ara-C at doses of 3 mg/m2 twice a day for 21 days. The "in vivo" and "in vitro" effect of retinoic acid on the haemopoietic differentiation was evaluated by the growth CFU-GM in semisolid cell culture methods. RESULTS: Increasing in vitro concentrations of 13-cis retinoic acid did not enhance the growth of myelodysplastic progenitors. Nevertheless, our study did not find any beneficial therapeutic effect of retinoic compounds in MDS patients. In this study, low-dose Ara-C (3 mg/m2) showed similar effects when compared with higher doses reported by others. Furthermore, in terms of CFU-GM proliferation the concentration of colonies before and after treatment were fairly similar in all but two patients. CONCLUSIONS: The results drawn from our study demonstrated that there is no beneficial advantage of 13-cis-retinoic acid as a differentiation inducing agent on myelodysplastic patients. In contrast, lower doses of Ara-C showed similar effects on haemopoiesis of MDS patients than standard doses of 10-20 mg/m2 but with less side effects.     

A Secure Grid Medical Data Manager Interfaced to the gLite Middleware

The medical community is producing and manipulating a tremendous volume of digital data for which computerized archiving, processing and analysis is needed. Grid infrastructures are promising for dealing with challenges arising in computerized medicine but the manipulation of medical data on such infrastructures faces both the problem of interconnecting medical information systems to Grid middlewares and of preserving patients’ privacy in a wide and distributed multi-user system. These constraints are often limiting the use of Grids for manipulating sensitive medical data. This paper describes our design of a medical data management system taking advantage of the advanced gLite data management services, developed in the context of the EGEE project, to fulfill the stringent needs of the medical community. It ensures medical data protection through strict data access control, anonymization and encryption. The multi-level access control provides the flexibility needed for implementing complex medical use-cases. Data anonymization prevents the exposure of most sensitive data to unauthorized users, and data encryption guarantees data protection even when it is stored at remote sites. Moreover, the developed prototype provides a Grid storage resource manager (SRM) interface to standard medical DICOM servers thereby enabling transparent access to medical data without interfering with medical practice.     

Data structures for symbolic multi-valued model-checking

Multi-valued logics provide an interesting alternative to classical boolean logic for modeling and reasoning about systems. Such logics can be used for reasoning about partially-specified systems, effectively encode vacuity detection and query-checking problems, help in detecting inconsistencies, and many others.In our earlier work, we identified a useful family of multi-valued logics: those specified over finite distributive lattices where negation preserves involution, i.e., for every element a of the logic. Such structures are called quasi-boolean algebras, and model-checking over these not only extends the domain of applicability of automated reasoning to new problems, but can also speed up solutions to some classical verification problems.Symbolic model-checking over quasi-boolean algebras can be cast in terms of operations over multi-valued sets: sets whose membership functions are multi-valued. In this paper, we propose and empirically evaluate several choices for implementing multi-valued sets with decision diagrams. In particular, we describe two major approaches: (1) representing the multi-valued membership function canonically, using MDDs or ADDs; (2) representing multi-valued sets as a collection of classical sets, using a vector of either MBTDDs or BDDs. The naive implementation of (2) includes having a classical set for each value of the algebra. We exploit a result of lattice theory to reduce the number of such sets that need to be represented.The major contribution of this paper is the evaluation of the different implementations of multi-valued sets, done via a series of experiments and using several case studies.

Valorization of galvanic sludge in sulfoaluminate cement

Every year increasing amounts of industrial waste are generated worldwide. Depending on their characteristics, wastes can represent an important source of secondary raw materials in order to replace natural resources. In this study, galvanic sludge (LDG) was used as raw material in sulfoaluminate cement. This waste was incorporated to sulfoaluminate cement (CSA), at a weight ratio of 25%, to compose an blended sulfoaluminate cement (BCSA). The compressive strength, drying shrinkage and products of hydration were determined. The efficiency of CSA towards the retention of chromium (the main pollutant present in the sludge) was also investigated. Compressive strength higher than 30 MPa was obtained. The main product of hydration (ettringite) was also identified and the encapsulation of Cr in hydration phases was verified.     

Optical second harmonic generation in CsLiB6O10 nanocrystallites incorporated to the olygoether photopolymer matrices induced by acustical field

Optical second harmonic generation in CsLiB₆O₁₀ (CLBO) large-sized nanocrystallites (15–40 nm) incorporated into the olygoether photopolymer matrices has been found at liquid helium temperature (LHeT). The second harmonic generation (SHG) has been measured for the source wavelength of the YAG : Nd laser ( = 1.06 m). Increasing acoustical power (up to 18.1 W/cm²) and acoustical frequencies at 14 kHz give maximal values of the output SHG. The measured SHG ₂₂₂ tensor component was comparable with the one for the traditional nonlinear optical crystals such as KH₂PO₄, KTiOPO₄, LiNbO₃. With decreasing temperature below 28 K the acoustically induced SHG signal strongly increases. A correlation between the acoustically induced SHG and low-frequency Raman modes has been found. The maximal acoustically induced SHG has been observed for the nanocrystallite concentration about 3.1% (in weighting units) and the crystallite sizes lying within the 35–40 nm. The SHG tensor coefficients were higher than for the proper CLBO crystals at least on the 13%. Advantageous and drawbacks of the presented model are discussed. The theory of the observed phenomena is explained on the ground of ab initio band energy calculations with taking into account of anharmonic electron-phonon interactions.     

Rapid Screening of Lectins for Multivalency Effects with a Glycodendrimer Microarray

Multivalency is an important phenomenon in protein–carbohydrate interactions. In order to evaluate glycodendrimers as multivalent inhibitors of carbohydrate binding proteins, we displayed them on a microarray surface. Valencies were varied from 1 to 8, and corrections were made for the valencies so that all surfaces contained the same amount of the sugar ligand. Five different carbohydrates were attached to the dendrimers. A series of fluorescent lectins was evaluated, and for each of them a binding profile was obtained from a single experiment showing both the specificity of the lectin for a certain sugar and whether it prefers multivalent ligands or not. Very distinct binding patterns were seen for the various lectins. The results were rationalized with respect to the interbinding distances of the lectins.     

Coke formation in pyrolysis furnaces in the petrochemical industry

In the petrochemical industry, an industrial pyrolysis furnace is a complicated piece of equipment that functions as both a reactor and high-pressure steam generator. During service, hard deposits of carbon (coke) build up on the inner wall of the tube, reducing heat transfer and restricting the flow of the hydrocarbon feedstocks. In this paper, an overview of coke formation, the impact of coke formation, and the methods by which coke formation can be prevented, as well as methods that can be successful in decoking of pyrolysis furnaces, is presented.