Generation of artificial neural networks models in anticancer study

Artificial neural networks (ANNs) have several applications; one of them is the prediction of biological activity. Here, ANNs were applied to a set of 32 compounds with anticancer activity assayed experimentally against two cancer cell lines (A2780 and T-47D). Using training and test sets, the obtained correlation coefficients between experimental and calculated values of activity, for A2780, were 0.804 and 0.829, respectively, and for T-47D, we got 0.820 for the training set and 0.927 for the test set. Com paring multiple linear regression and ANN models, the latter were better suited in establishing relationships between compounds’ structure and their anticancer activity.info:eu-repo/semantics/publishedVersio

Protein-ligand docking study: diterpenes from Juniperus brevifolia as anticancer and antimicrobial agentes

REDCAT: Natural Products and related Redox Catalysts: Basic Research and Applications in Medicine and Agriculture, Aveiro, 25-27 Novembro de 2012.From leaves of Juniperus brevifolia, an endemic conifer from Azores, were isolated and structurally characterized, several dehydroabietane and sandaracopimarane derivatives. Some of them (1-4), displayed antiproliferative activity against cancer cell lines (HeLa, A-549 and MCF-7) and bactericidal effect against Bacillus cereus at different concentrations tested. However, it is not known how these compounds interact with most often proteins involved in the antimicrobial and cytotoxic mechanisms. Protein-ligand docking is mainly used to predict (energy and conformation wise) how small molecules bind to a protein of known 3D structure and to predict possible molecular targets for a set of compounds. In this work, the docking studies were performed, using the FlexScreen program, in order to pick molecular targets from a large set of common anticancer (63) and antimicrobial (39) targets to the selected compounds 1-4. The predicted interactions established between the compounds under study and the anticancer targets revealed that the compounds 1 and 3 interact preferentially with phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2, whereas compounds 2 and 4 interact preferentially with human mitochondrial peptide deformylase and -tubulin, respectively. Studying the interactions between the compounds 1 and 3 and the antimicrobial targets we predict that these compounds interact preferentially with RNA polymerase and peptide deformylase. These results provide additional understanding of the cytotoxic and antimicrobial effects of diterpenes studied. These preliminary computational docking predictions of therapeutic targets were established working with just 4 compounds, and to obtain more reliable predictions the number of compounds needs to be increased.Thanks are due to the University of Azores, FCT, FEDER, BIOPHARMAC - MAC/1/C104 and Project PEst-OE/QUI/UI0674/2011

QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity

Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression. The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatro phane-type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this study we applied quantitative structure–activity relationship (QSAR) methodology in order to identify the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to deter mine which structural modifications can be performed to improve their activity. Using experimental bio logical data at two concentrations (4 and 40 lg/ml), we developed a QSAR model for a set of 51 bioactive diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for bio logical activities at compound concentrations of 4 and 40 lg/ml were 0.758 and 0.729, respectively. Regarding the prediction ability, we get R2 pred values of 0.765 and 0.534 for biological activities at com pound concentrations of 4 and 40 lg/ml, respectively. Applying the cross-validation test to jatrophanes QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and 40 lg/ml concentrations, respectively. For the same concentrations, the obtained R2 pred values for jatro phanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and showed high prediction ability.info:eu-repo/semantics/publishedVersio

Therapeutic collaboration and resistance: describing the nature and quality of the therapeutic relationship within ambivalence events using the therapeutic collaboration coding system

We understand ambivalence as a cyclical movement between two opposing parts of the self. The emergence of a novel part produces an innovative moment, challenging the current maladaptive self-narrative. However, the novel part is subsequently attenuated by a return to the maladaptive self-narrative. This study focused on the analysis of the therapeutic collaboration in episodes in which a relatively poor-outcome client in narrative therapy expressed ambivalence. Method: For our analysis we used the Therapeutic Collaboration Coding System, developed to assess whether and how the therapeutic dyad is working within the therapeutic zone of proximal development (TZPD). Results: Results showed that when the therapist challenged the client after the emergence of ambivalence, the client tended to invalidate (reject or ignore) the therapist’s intervention. Conclusions: This suggests that in such ambivalence episodes the therapist did not match the client’s developmental level, and by working outside the TZPD unintentionally contributed to the maintaining the client’s ambivalence

Molecular docking studies of the interaction between propargylic enol ethers and human DNA topoisomerase IIα

Having identified a novel human DNA topoisomerase IIa (TOP2) catalytic inhibitor from a small and structure-focused library of propargylic enol ethers, we decided to analyze if the chirality of these compounds plays a determinant role in their antiproliferative activity. In this study, we describe for the first time the synthesis of the corresponding enantiomers and the biological evaluation against a panel of representative human solid tumor cell lines. Experimental results show that chirality does not influence the reported antiproliferative activity of these compounds. Docking studies of corresponding enantiomers against TOP2 reinforce the finding that the biological effect is not chiral-dependent and that these family of compounds seem to act as TOP2 catalytic inhibitors.info:eu-repo/semantics/publishedVersio

Benzo[a]phenoxazinium chlorides functionalized with chloride atoms and/or ester groups

Proceedings of the 19th Int. Electron. Conf. Synth. Org. Chem.With the aim of contributing to the development of fluorescent near-infrared (NIR) probes with applications in biomedicine, our research group is committed to the development of new water-soluble benzo[a]phenoxazine derivatives and the evaluation of their photophysical and biological potential. Herein we report the photophysical behaviour in anhydrous ethanol of four synthesised benzo[a]phenoxazinium chlorides, possessing the (3-chloropropyl)amino and/or (4-ethoxy-4- oxobutyl)amino groups at 5- and 9-positions of the polycyclic system.Thanks are due to the Fundação para a Ciência e Tecnologia (FCT, Portugal) for financial support to the NMR portuguese network (PTNMR, Bruker Avance III 400-Univ. Minho), FCT and FEDER (European Fund for Regional Development)-COMPETE-QREN-EU for financial support to the Research Centres CFUM [PEst-C/FIS/UI0607/2011 (F-COMP-01-0124-FEDER-022711)] and CQ/UM [PEstC/QUI/UI0686/2013(FCOMP-01-0124-FEDER-022716)]. A post-doctoral grant to B. R. Raju (SFRH/BPD/62881/2009) is also acknowledged to FCT, POPH-QREN, FSE.info:eu-repo/semantics/publishedVersio

Behavior of prostate cancer cells in a nanohydroxyapatite/collagen bone scaffold

Prostate cancer (PCa) is the second leading cause of death among men in Europe and U.S. The metastatic dissemination pattern of PCa is unique, developing bone metastasis as the only site of progression, consequently with a prognosis very poor. The cancer cells interactions within the surrounding bone environment are critical for tumor growth and progression. Secreted protein, acidic and rich in cysteine (SPARC) is described to be involved in PCa cells migration and invasion into bone. Three-dimensional (3D) in vitro systems that are able to closely resemble the in vivo microenvironment are recently taking importance in cancer research. Original nanohydroxyapatite/collagen scaffolds were designed to resemble bone microenvironment in order to be applied as substitutes in bone defects and as potential biomaterials to mimic skeletal tumors. In fact, these 3D structures were cytocompatible and able to support osteoblast (MC3T3-E1) colonization and to promote bone ingrowth. Additionally, SPARC adsorption onto the scaffolds affected PC3 and LNCaP PCa cell lines behavior. PC3 cells were found to adapt and colonize the scaffolds, differing from LNCaP where cells underwent morphogenic changes and grew as clusters. Furthermore, for the tested SPARC concentration, SPARC plays a role in retaining LNCaP cells at the latter time points while with PC3 cells no significant differences were observed. This characterization study is required to establish a bone model to provide new insights into the poorly understood PCa mechanisms of metastasis to bone and the generation of improved therapies.info:eu-repo/semantics/publishedVersio

High frequency of psychosis in late-stage Parkinsońs disease.

BACKGROUND: Psychosis is a frequent non-motor symptom in Parkinson's disease (PD). Estimates of the frequency of Parkinsońs disease psychosis (PDP) vary widely. Knowledge about the frequency and phenomenology of psychosis in late-stage (LS) PD patients is limited.This study aimed to determine the frequency of psychosis in LSPD patients through clinical diagnostic interview (CDI) (gold standard), according to NINDS/NIMH diagnostic criteria for PDP. The secondary objectives were to characterize the phenomenology, to test selected instruments and assess their adequacy in comparison to CDI, and to assess the psychiatric comorbidities. METHODS: A cross-sectional study including LSPD patients (patients with ≥ 7 years from symptoms onset and Hoehn and Yahr scale score > 3 or a Schwab and England scale score < 50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Each patient was interviewed by a psychiatrist who performed a CDI. RESULTS: 92 LSPD patients were included. 55.4% experienced psychotic symptoms according to NINDS/NIMH diagnostic criteria for PDP. Hallucinations were present in 94.1% and delusions in 29.4% of the psychotic patients. Visual hallucinations were the most common (88.23%) psychotic symptom. 72.5% of LSPD patients with psychotic symptoms had at least one comorbid psychiatric diagnosis. Lower frequency of psychosis was found when the assessment was performed only through selected instruments rather than CDI. CONCLUSIONS: A high frequency (55.4%) of psychotic symptoms and comorbid psychiatric (72.5%) diagnosis were found in LSPD patients. The use of CDI, in addition to structured scales may increase the sensitivity of detecting psychotic symptoms

Dual-stage triterpenoids from an African medicinal plant targeting the malaria parasite

Sixteen triterpenoids (1–16), previously isolated from the aerial parts of the African medicinal plant Momordica balsamina or obtained by derivatization, were evaluated for their activity against liver stages of Plasmodium berghei, measuring the luminescence intensity in Huh-7 cells infected with a firefly lucif erase-expressing P. berghei line, PbGFP-Luccon. Toxicity of compounds (1–16) was assessed on the same cell line through the fluorescence measurement of cell confluency. The highest activity was displayed by a derivative bearing two acetyl residues, karavoate B (7), which led to a dose-dependent decrease in the P. berghei infection rate, exhibiting a very significant activity at the lowest concentration employed (1 lM) and no toxicity towards the Huh-7 cells. It is noteworthy that, in previous studies, this compound was found to be a strong inhibitor of blood-stages of Plasmodium falciparum, thus displaying a dual-stage antimalarial activity.info:eu-repo/semantics/publishedVersio

Clinical diagnostic criteria have a high impact on the frequency of dementia in late-stage Parkinson's disease

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: Cognitive impairment is a potential late feature of Parkinson's disease (PD). However, studies in patients with late-stage PD are lacking due to the particular characteristics of this population.Objectives: To evaluate the frequency of dementia in late-stage PD patients and to assess the impact of using different diagnostic criteria.Methods: We conducted a cross-sectional study to estimate the frequency of dementia in late-stage PD patients using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria as the primary outcome. We also applied other diagnostic criteria [MDS (Level I), DSM-IV, and DSM-5 criteria] to determine their applicability and impact on dementia frequency.Results: 93 participants with a mean age of 75.8 years (SD 6.8) and 16.5 years (SD 7.5) of disease duration were included. 64.3% were classified as demented using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria. We observed a high discrepancy on the frequency of dementia depending on the criteria applied [6.2% with MDS (Level I), 58.8% with DSM-IV, and 72.0% with DSM-5 criteria].Conclusions: We found a frequency of dementia below what was observed in similar populations. The particular characteristics of our sample may have contributed as protective factors for late-stage dementia. Dementia frequency varied depending on the criteria used mainly due to the presence of major depression.info:eu-repo/semantics/publishedVersio