The effects of combinatorial chemistry and technologies on drug discovery and biotechnology : A mini review

The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of "combinatorial thinking" in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided

A consensus panel review of central nervous system effects of the exposure to low-intensity extremely low-frequency magnetic fields

BACKGROUND: A large number of studies explored the biological effects of extremely low-frequency (0-300 Hz) magnetic fields (ELF-MFs) on nervous system both at cellular and at system level in the intact human brain reporting several functional changes. However, the results of different studies are quite variable and the mechanisms of action of ELF-MFs are still poorly defined. The aim of this paper is to provide a comprehensive review of the effects of ELF-MFs on nervous system. METHODS: We convened a workgroup of researchers in the field to review and discuss the available data about the nervous system effects produced by the exposure to ELF-MFs. MAIN FINDINGS/DISCUSSION: We reviewed several methodological, experimental and clinical studies and discussed the findings in five sections. The first section analyses the devices used for ELF-MF exposure. The second section reviews the contribution of the computational methods and models for investigating the interaction between ELF-MFs and neuronal systems. The third section analyses the experimental data at cellular and tissue level showing the effects on cell membrane receptors and intracellular signaling and their correlation with neural stem cell proliferation and differentiation. The fourth section reviews the studies performed in the intact human brain evaluating the changes produced by ELF-MFs using neurophysiological and neuropsychological methods. The last section shows the limits and shortcomings of the available data, evidences the key challenges in the field and tracks directions for future research

Equilibrium reconstruction for Single Helical Axis reversed field pinch plasmas

Single Helical Axis (SHAx) configurations are emerging as the natural state for high current reversed field pinch (RFP) plasmas. These states feature the presence of transport barriers in the core plasma. Here we present a method for computing the equilibrium magnetic surfaces for these states in the force-free approximation, which has been implemented in the SHEq code. The method is based on the superposition of a zeroth order axisymmetric equilibrium and of a first order helical perturbation computed according to Newcomb's equation supplemented with edge magnetic field measurements. The mapping of the measured electron temperature profiles, soft X-ray emission and interferometric density measurements on the computed magnetic surfaces demonstrates the quality of the equilibrium reconstruction. The procedure for computing flux surface averages is illustrated, and applied to the evaluation of the thermal conductivity profile. The consistency of the evaluated equilibria with Ohm's law is also discussed.Comment: Submitted to Plasma Physics and Controlled Fusio

Histological validation of diagnoses of thyroid cancer among adults in the registries of Belarus and the Ukraine

In order to evaluate the diagnostic reliability of the thyroid cancers listed in adult registries from the Ukraine and Belarus, a histological review was organised of 327 randomly selected thyroid carcinoma cases diagnosed between 1960 and 1999. A final diagnosis was reached at a 5-day consensus conference by six pathologists who met around a multiheaded microscope. The study concluded with a comparison between the final diagnosis and the initial diagnosis. The pathologists agreed with the initial diagnosis of malignancy in 286 cases (88%). A final diagnosis of papillary, follicular or medullary thyroid carcinoma was reached in 86, 4, and 6% of the cases respectively. In 2.8% of the cases reviewed, diagnostic discrepancies persisted. The percentage of agreement between the final diagnosis and the initial diagnosis was 93%, with a weighted κ-statistic of 0.61 (confidence interval 95% (CI 95%): [0.45-0.77]). In all, 89% of the 286 confirmed cancer cases were in agreement for the type of cancer, with a κ-statistic of 0.56 (CI95%: [0.43-0.69]). The level of agreement differed according to cancer categories, with concordance rates of 94, 40 and 33% for papillary, follicular and medullary thyroid carcinomas respectively. The low prevalence of follicular thyroid carcinomas in the adult population studied calls for further exploration. The discrepancies and classification difficulties encountered were analysed. © 2003 Cancer Research UK

A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice

The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist—an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo

Status and future development of Heating and Current Drive for the EU DEMO

The European DEMO is a pulsed device with pulse length of 2 hours. The functions devoted to the heating and current drive system are: plasma breakdown, plasma ramp-up to the flat-top where fusion reactions occur, the control of the plasma during the flat-top phase, and finally the plasma ramp-down. The EU-DEMO project was in a Pre-Concept Design Phase during 2014-2020, meaning that in some cases, the design values of the device and the precise requirements from the physics point of view were not yet frozen. A total of 130 MW was considered for the all phases of the plasma: in the flat top, 30 MW is required for neoclassical tearing modes (NTM) control, 30 MW for burn control, and 70 MW for the control of thermal instability (TI), without any specific functions requested from each system, Electron Cyclotron (EC), Ion Cyclotron (IC), or Neutral Beam (NB) Injection. At the beginning of 2020, a strategic decision was taken, to consider EC as the baseline for the next phase (in 2021 and beyond). R&D on IC and NB will be risk mitigation measures. In parallel with progresses in Physics modelling, a decision point on the heating strategy will be taken by 2024. This paper describes the status of the R&D development during the period 2014-2020. It assumes that the 3 systems EC, IC and NB will be needed. For integration studies, they are assumed to be implemented at a power level of at least 50 MW. This paper describes in detail the status reached by the EC, IC and NB at the end of 2020. It will be used in the future for further development of the baseline heating method EC, and serves as starting point to further develop IC and NB in areas needed for these systems to be considered for DEMO

Supervised team management, with or without structured psychotherapy, in heavy users of a mental health service with borderline personality disorder: a two-year follow-up preliminary randomized study

<p>Abstract</p> <p>Background</p> <p>Individuals affected by severe Borderline Personality Disorder (BPD) are often heavy users of Mental Health Services (MHS). Short-term treatments currently used in BPD therapy are useful to target disruptive behaviors but they are less effective in reducing heavy MHS use. Therefore, alternative short-term treatments, less complex than long-term psychodynamic psychotherapies but specifically oriented to BPD core problems, need to be developed to reduce MHS overuse. This study aimed to evaluate the efficacy of adding Sequential Brief Adlerian Psychodynamic Psychotherapy (SB-APP) to Supervised Team Management (STM) in BPD treatment compared to STM alone in a naturalistic group of heavy MHS users with BPD. Effectiveness was evaluated 6 times along a two-year follow-up.</p> <p>Methods</p> <p>Thirty-five outpatients who met inclusion criteria were randomly assigned to two treatment groups (STM = 17; SB-APP = 18) and then compared. Clinical Global Impression (CGI) and CGI-modified (CGI-M) for BPD, Global Assessment of Functioning (GAF), State-Trait Anger Expression Inventory (STAXI), and Symptom Checklist-90 Revised (SCL-90-R) were administered at T1, T3, T6, T12, T18 and T24. At T12 the Working Alliance Inventory-Short Form (WAI-S) was also completed. At the one-year follow-up, SB-APP group did not receive any additional individual psychological support. MHS team was specifically trained in BPD treatment and had regular supervisions.</p> <p>Results</p> <p>All patients improved on CGI, GAF, and STAXI scores after 6 and 12 months, independently of treatment received. SB-APP group showed better outcome on impulsivity, suicide attempts, chronic feelings of emptiness, and disturbed relationships. We found a good stabilization at the one year follow-up, even after the interruption of brief psychotherapy in the SB-APP group.</p> <p>Conclusions</p> <p>Although STM for BPD applied to heavy MHS users was effective in reducing symptoms and improving their global functioning, adding a time-limited and focused psychotherapy was found to achieve a better outcome. In particular, focusing treatment on patients' personality with a specific psychotherapeutic approach (i.e. SB-APP) seemed to be more effective than STM alone.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT1356069">NCT1356069</a></p

Status and future development of Heating and Current Drive for the EU DEMO

The European DEMO is a pulsed device with pulse length of 2 hours. The functions devoted to the heating and current drive system are: plasma breakdown, plasma ramp-up to the flat-top where fusion reactions occur, the control of the plasma during the flat-top phase, and finally the plasma ramp-down. The EU-DEMO project was in a Pre-Concept Design Phase during 2014-2020, meaning that in some cases, the design values of the device and the precise requirements from the physics point of view were not yet frozen. A total of 130 MW was considered for the all phases of the plasma: in the flat top, 30 MW is required for neoclassical tearing modes (NTM) control, 30 MW for burn control, and 70 MW for the control of thermal instability (TI), without any specific functions requested from each system, Electron Cyclotron (EC), Ion Cyclotron (IC), or Neutral Beam (NB) Injection. At the beginning of 2020, a strategic decision was taken, to consider EC as the baseline for the next phase (in 2021 and beyond). R&D on IC and NB will be risk mitigation measures. In parallel with progresses in Physics modelling, a decision point on the heating strategy will be taken by 2024. This paper describes the status of the R&D development during the period 2014-2020. It assumes that the 3 systems EC, IC and NB will be needed. For integration studies, they are assumed to be implemented at a power level of at least 50 MW. This paper describes in detail the status reached by the EC, IC and NB at the end of 2020. It will be used in the future for further development of the baseline heating method EC, and serves as starting point to further develop IC and NB in areas needed for these systems to be considered for DEMO