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Synthetic reactive oxygen species (ROS)-responsive biomaterials have emerged as a useful platform for regulating critical aspects of ROS-induced pathologies and can improve such hostile microenvironments. Here, we report a series of new hyperbranched poly(β-hydrazide ester) macromers (HB-PBHEs) with disulfide moieties synthesized via an "A2 + B4" Michael addition approach. The three-dimensional structure of HB-PBHEs with multiacrylate end groups endows the macromers with rapid gelation capabilities to form (1) injectable hydrogels via cross-linking with thiolated hyaluronic acid and (2) robust UV-cross-linked hydrogels. The disulfide-containing macromers and hydrogels exhibit H 2 O 2 -responsive degradation compared with the counterparts synthesized by a dihydrazide monomer without disulfide moieties. The cell viability under a high ROS environment can be well-maintained under the protection of the disulfide containing hydrogels.

Ovarian borderline tumors can show histologic features, such as different degrees of cellular proliferation, eosinophilic cells, autoimplants, and adenofibromatous architecture, the importance of which is not known. The aim of the study was to describe these features and correlate them with clinical characteristics. Eighty-three ovarian borderline tumors were studied for the aforementioned features. These were correlated with clinicopathologic features. Epithelial proliferation was associated with the T stage in serous tumors (P=0.0009), but not in mucinous tumors (P=0.97). It was positively associated with bilateral tumors (P=0.01) and the presence of autoimplants (P<0.0001). It was associated with the presence of eosinophilic cells, as tumors with extensive eosinophilic cells had a mean proliferation of 80.7%, for those with no such cells it was 23.8% (P<0.0001), and for those with a limited presence of eosinophilic cells it was 48.7% (P=0.03). Cellular proliferation was not associated with the size of the tumor. An adenofibromatous architecture was associated with unilateral tumors (P=0.02) and showed a trend (P=0.08) with regard to T stage in serous tumors. It was not associated with the size of the tumor. The presence of autoimplants was marginally associated (P=0.07) with bilateral tumors and it was not associated with the size of the tumor or the T stage. The presence of eosinophilic cells was not associated with the T stage, the size of the tumor, or bilateral tumors. The degree of epithelial proliferation, autoimplants, adenofibromatous architecture, and the presence of eosinophilic cells are important features in ovarian borderline tumors.

FOXA1 is a transcription factor essential for the binding and action of other transcription factors on the chromatin. It is the major regulator of endoderm differentiation. It has important roles in breast, prostate and endometrial cancer. It has never been studied in ovarian tumours. The aim of this study was to investigate its expression in ovarian epithelial neoplasms. A total of 195 primary ovarian epithelial borderline or malignant tumours were immunohistochemically studied for the expression of FOXA1. Nineteen percent of the tumours strongly and diffusely expressed FOXA1. Of these, 75.7% belong to the mucinous category (p < 0.0001). Seventy-five per cent of mucinous borderline tumours and 46.7% of mucinous carcinomas overexpressed FOXA1. Brenner tumours also expressed FOXA1. FOXA1 was rarely expressed in serous (6/115) and endometrioid tumours (1/11). Clear cell tumours were completely negative (0/16). Of normal structures, ciliated tubal cells, Walthard nests and transitional metaplasias of the tubal-mesothelial junction, all strongly expressed FOXA1. In conclusion, FOXA1 is found in ovarian mucinous and Brenner tumours., (Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Seromucinous ovarian tumors are rare and not adequately described in the literature and this is especially true for seromucinous carcinomas., Aim of the Study: To describe histological and clinical features of these tumors in comparison with the rest of ovarian epithelial tumors., Materials and Methods: Two hundred and forty one (241) ovarian tumors, borderline (n=92) or malignant (n=149), treated surgically without neoadjuvant chemotherapy, were examined., Results: Seromucinous borderline (SMBT) and malignant tumors (SMC) comprised 7.8% (n=7) and 4% (n=6) of all borderline tumors and carcinomas, respectively, studied. Mean age of diagnosis was 63.2 and 68.3years and mean size was 6.4cm and 12cm for SMBT and SMC, respectively. Seromucinous tumors were associated with endometriosis in 23.1% of the cases and they were bilateral in 30.8%. Microscopically, variety in cellular composition, papillary architecture and development into thick walled, occasionally muscular, cysts were the main findings. Medullary/paraovarian/tubal or deeply cortical localization was also characteristic. Stage predicted overall and progression-free survival (p<0.0001 and p=0.03, respectively). Five-year survival was 62% for patients with high grade serous carcinoma, 55% for seromucinous carcinoma, 100% for endometrioid carcinoma, 75% for clear cell carcinoma, and 80% for patients with mucinous carcinoma. Differences were not however statistically significant., Conclusion: Seromucinous tumors have unique features that support their classification as a different entity. Their localization and their often thick fibrous or/and muscular wall provides further evidence for an histogenesis from the secondary Müllerian system or vestigial structures., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes.

The design and optimization of the external occulter geometry is one of the most discussed topics among solar coronagraph designers. To improve the performance of future coronagraphs and to stretch their inner fields of view toward the solar limb, the new concept of coronagraphs in formation flight has been introduced in the scientific debate. Solar coronagraphs in formation flight require several mechanical and technological constraints to be met, mainly due to the large dimension of the occulter and to the spacecraft's reciprocal alignment. The occulter edge requires special attention to minimize diffraction while being compatible with the handling and integrating of large delicate space components. Moreover, it is practically impossible to set up a full-scale model for laboratory tests. This article describes the design and laboratory tests on a demonstrator for a coronagraph to be operated in formation flight. The demonstrator is based on the principle of the linear edge, thus the presented results cannot be directly extrapolated to the case of the flying circular occulter. Nevertheless, we are able to confirm the results of other authors investigating on smaller coronagraphs and provide further information on the geometry and tolerances of the optimization system. The described work is one of the results of the ESA STARTIGER program on formation flying coronagraphs ["The STARTIGER's demonstrators: toward a new generation of formation flying solar coronagraphs," in 2010 International Conference on Space Optics (ICSO) (2010), paper 39].

Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC(50) = 20 nM) in a cell-based signal transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds in human liver microsomes. We finally report the pharmacokinetic properties of our lead compound cis-64a.

Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.

A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.

The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.

R115777 (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. Taking its roots into Janssen's ketoconazole and retinoic acid catabolism programs, our interest into Ras prenylation process led us stepwise to identify the key structural features of R115777. Methodology, structure activity relationships, and pharmacology will be presented. R115777 is currently in phase III clinical evaluation.

This single-subject study addresses the issue of investigation and remediation of an acquired reading impairment observed in a Spanish-English bilingual speaker. Detailed bilingual reading testing showed parallel disturbances in the two languages, both from a qualitative and a quantitative point of view, with characteristics of letter-by-letter and aphasic alexia. On the basis of this mixed pattern, common to both languages, a two-step computer-assisted remediation programme was designed for English, then for Spanish, using a crossover AB-AB design. Therapy A consisted of tasks aimed at the inhibition of letter-by-letter reading. This was alternated with therapy B, which was designed to address phonological assembly. Results on therapy reveal transfer of gains when common reading processing are involved and language-specific gains with a greater benefit on the mother tongue when phonological representations are required in therapy and assessment. Consequences for language choice in bilingual aphasia therapy are discussed on the basis of these results.

R115777 [(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone] is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. The majority of sensitive cell lines had a wild-type ras gene. Tumor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777. Tumor cell lines bearing mutant K-ras genes required higher concentrations for inhibition of cell growth, with 50% of the cell lines resistant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation. However, inhibition of K-RasB protein-processing could not be detected. Oral administration b.i.d. of R115777 to nude mice bearing s.c. tumors at doses ranging from 6.25-100 mg/kg inhibited the growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras genes. Histological evaluations revealed heterogeneity in tumor responses to R115777. In LoVo human colon tumors, treatment with R115777 produced a prominent antiangiogenic response. In CAPAN-2 human pancreatic tumors, an antiproilferative response predominated, whereas in C32 human melanoma, marked induction of apoptosis was observed. The heterogeneity of histological changes associated with antitumor effects suggested that R115777, and possibly farnesyl protein transferase inhibitors as a class, alter processes of transformation related to tumor-host interactions in addition to inhibiting tumor-cell proliferation.

All-trans-retinoic acid (RA) regulates epithelial differentiation and growth through activation of specific nuclear RA receptors (RARs). Because high-rate metabolism largely impairs the biological efficacy of RA, we have sought for compounds capable of inhibiting the metabolic breakdown of the retinoid. This study identifies R115866 as a novel inhibitor of the cytochrome P450 (CYP)-mediated metabolism of RA. In vitro, nanomolar concentrations of R115866 inhibited the conversion of RA by CYP26, a RA-inducible RA metabolizing enzyme. In vivo, oral administration of R115866 (2.5 mg/kg) to rats induced marked and transient increases of endogenous RA levels in plasma, skin, fat, kidney, and testis. Consistent with its ability to enhance endogenous RA content in tissues, R115866 was found to exert retinoidal activities. Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver. Furthermore, we found that the keratinization-suppressive and CYP26-inducing activities of R115866 could be reversed by concomitant administration of the RAR antagonist, AGN193109. Our data characterize R115866 as a potent, orally active inhibitor of RA metabolism, capable of enhancing RA levels and displaying retinoidal actions. These activities are reversed by RAR antagonism, supporting the idea that the actions of R115866 result from increased availability of endogenous RA and improved RAR triggering.

Two reforms of public hospitals have been launched by the French government in 1991 and 1996 aimed at lowering costs and increasing the quality of services and ultimately the safety of patients. As concerns maternity hospitals, several new rules have been imposed upon. For example, those who performed less than 300 births a year should be closed. The basic idea was to concentrate technical resources and human skills in middle-size and important hospitals for saving money, and simultaneously, raising the safety level for mothers and babies. However, negative adverse effects fastly appeared: to avoid closure, some small maternity homes tried to convince future mothers not to go to well-equipped hospitals, even if their cases appeared complex and their health at risk. An experience of partnership between maternity hospitals (care providers), the Sickness Insurance Fund (the financing body) and the Administration was carried out in the Auvergne region. It was based on the observation of a large number of indicators concerning the activity of hospitals, the size and quality of their equipment, the satisfaction of their patients ... etc ... for designing the rights and duties of each partner. Instead of planning from the summit, a process of mutually-agreed contract was established.

The present article examines 2 predictions concerning conditional reasoning in children derived from a revised version of Markovits's model of conditional reasoning. The first study examined the prediction that younger children (8 years of age) would have greater difficulty in responding correctly to premises where the antecedent was strongly associated with the consequent than to premises where the association was weaker; for example, "If something is a car, then it has a motor" should be more difficult than "If something is a refrigerator, then it has a motor." A total of 55 children in grades 2 and 3 (average age: 8 years) and 49 children in grades 5 and 6 (average age: 11 years) were given either 2 strongly associated problems or weakly associated counterparts. Results indicated that 8-year-olds did better on the weakly associated problems than on the strongly associated problems, but there was no difference among the 11-year-olds. The second study examined the prediction that younger children (8 years of age) would have greater difficulty in responding correctly to causal premises ("If a rock is thrown at a window, the window will break") than to corresponding ad hoc premises ("A rock is something that can be used to break a window"). A total of 53 children in grades 2 and 3 (average age: 8 years) and 49 children in grades 5 and 6 (average age: 11 years) were given either 2 causal problems or ad hoc counterparts. Results indicated that 8-year-old did better on the ad hoc problems than on the causal problems, but there was no difference among the 11-year-olds. These studies are interpreted as consistent with the idea that 1 major factor in the development of reasoning in this age level is the development of children's ability to explore their own knowledge base.

The complete genomic sequence of the gene responsible for the predominant form of polycystic kidney disease, PKD1, was determined to provide a framework for understanding the biology and evolution of the gene, and to aid in the development of molecular diagnostics. The DNA sequence of a 54 kb interval immediately upstream of the poly(A) addition signal sequence of the PKD1 transcript was determined, and then analyzed using computer methods. A leucine-rich repeat (LRR) motif was identified within the resulting predicted protein sequence of the PKD1 gene. By analogy with other LRR-containing proteins, this may explain some of the disease-related renal alterations such as mislocalization of membrane protein constituents and changes in the extracellular matrix organization. Finally, comparison of the genomic sequence and the published partial cDNA sequence showed several differences between the two sequences. The most significant difference detected predicts a novel carboxy-terminus for the PKD1 gene product.

R76713 (6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H- benzotriazole) is a selective, non-steroidal aromatase inhibitor containing an asymmetric carbon atom. In this paper, we compare the effects of R76713 (racemate) with its enantiomers R83839 (the levo-isomer) and R83842 (the dextro-isomer) on steroid biosynthesis in rat cells in vitro and in the rat in vivo. In rat granulosa cells, aromatase activity was inhibited by 50% at concentrations of 0.93 nM of R76713, 240 nM of R83839 and 0.44 nM of R83842, revealing a 545-fold difference in activity between both enantiomers. Up to 1 microM, none of the compounds had any effect on steroid production in primary cultures of rat testicular cells. Above this concentration all three compounds showed a similar slight inhibition of androgen synthesis with a concomitant increase in the precursor progestins, indicative for some effect on the 17-hydroxylase/17,20-lyase enzyme. In rat adrenal cells none of the compounds showed any effect on corticosterone synthesis. At concentrations above 1 microM there was an increase in the levels of 11-deoxycorticosterone pointing towards an inhibition of the 11-hydroxylase enzyme. This increase was more pronounced for R83839 than for R76713 and R83842. In vivo, in PMSG-primed rats, R83842 reduced plasma estradiol by 50%. 2 h after oral administration of 0.0034 mg/kg, whereas 0.011 mg/kg of R76713 and 0.25 mg/kg of R83839 were needed to obtain the same result. Oral administration of up to 20 mg/kg of the compounds did not significantly affect plasma levels of adrenal steroids in LHRH/ACTH-injected rats. Plasma testosterone was lowered at 10 and 20 mg/kg of R83842 and at the highest dose (20 mg/kg) of R76713 and R83839. In conclusion, the present study shows that the aromatase inhibitory activity of R76713 resides almost exclusively in its dextro-isomer R83842. R83842 exhibits a specificity for aromatase as compared to other enzymes involved in steroid biosynthesis of at least a 1000-fold in vitro as well as in vivo. This confirms the extreme selectivity previously found for the racemate.