Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso‐Cyclization

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine‐type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso‐cyclization using visible‐light‐mediated photoredox catalysis. This cyclization enabled the construction of a 6, 6‐spirocyclic core structure through the addition of a carbon‐centered radical onto the aromatic ring. Biological evaluation of zephycarinatines and their derivatives revealed that the synthetic derivative with a keto group displays moderate inhibitory activity against LPS‐induced NO production. This approach could offer future opportunities to expand the chemical diversity of plicamine‐type alkaloids as well as providing useful intermediates for their syntheses

LPS-CXCL10 Predicts Responses to Bortezomib in Myeloma Patients

To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients

Tumor Occupation in the Spinal Canal and Clinical Symptoms of Cauda Equina Schwannoma: An Analysis of 22 Cases

Study DesignRetrospective, radiological study.PurposeTo determine the relationship between clinical symptoms and the extent of tumor occupation of the spinal canal by cauda equina schwannoma.Overview of LiteratureLittle is known about the relationship between the size of tumors of the cauda equina and the manifestation of clinical symptoms. We analyzed this relationship by estimating the percentage of tumor occupation (PTO) in the spinal canal in cauda equina schwannomas and by correlating this parameter with the presence and severity of clinical symptoms.MethodsTwenty-two patients (9 men and 13 women; age, 19–79 years; mean age, 55.3 years) who were radiologically diagnosed with schwannomas of the cauda equina between April 2004 and July 2014 were retrospectively analyzed. PTO was measured in axial and sagittal magnetic resonance imaging slices in which the cross-sectional area of the tumor was the largest. Data regarding clinical symptoms and results of physical examinations were collected from patient medical records. PTO differences between symptom-positive and -negative groups were analyzed for each variable.ResultsIn the 4 cases in which tumor presence was not related to clinical symptoms, PTO was 5%–10% (mean, 9%) in axial slices and 23%–31% (mean, 30%) in sagittal slices. In the 18 cases in which symptoms were associated with the tumor, PTO was 11%–86% (mean, 50%) in axial slices and 43%–88% (mean, 71%) in sagittal slices. PTO in axial slices was significantly higher in the presence of Déjèrine symptoms and/or muscle weakness, a positive straight leg raise test, and a positive Kemp sign.ConclusionsPTO >20% in axial slices and >40% in sagittal slices can be an indication of symptomatic cauda equina schwannoma

A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes.

Blood-brain barrier (BBB) characteristics are induced and maintained by cross-talk between brain microvessel endothelial cells and neighbouring elements of the neurovascular unit. While pericytes are the cells situated closest to brain endothelial cells morphologically and share a common basement membrane, they have not been used in co-culture BBB models for testing drug permeability. We have developed and characterized a new syngeneic BBB model using primary cultures of the three main cell types of cerebral microvessels. The co-culture of endothelial cells, pericytes and astrocytes mimick the anatomical situation in vivo. In the presence of both pericytes and astrocytes rat brain endothelial cells expressed enhanced levels of tight junction (TJ) proteins occludin, claudin-5 and ZO-1 with a typical localization at the cell borders. Further morphological evidence of the presence of interendothelial TJs was provided by electron microscopy. The transendothelial electrical resistance (TEER) of brain endothelial monolayers in triple co-culture, indicating the tightness of TJs reached 400Omegacm(2) on average, while the endothelial permeability coefficients (P(e)) for fluorescein was in the range of 3x10(-6)cm/s. Brain endothelial cells in the new model expressed glucose transporter-1, efflux transporters P-glycoprotein and multidrug resistance protein-1, and showed a polarized transport of rhodamine 123, a ligand for P-glycoprotein. To further characterize the model, drug permeability assays were performed using a set of 19 compounds with known in vivo BBB permeability. Good correlation (R(2)=0.89) was found between in vitroP(e) values obtained from measurements on the BBB model and in vivo BBB permeability data. The new BBB model, which is the first model to incorporate pericytes in a triple co-culture setting, can be a useful tool for research on BBB physiology and pathology and to test candidate compounds for centrally acting drugs

Effects of land use on trophic states and multi-taxonomic diversity in Japanese farm ponds

金沢大学環日本海域環境研究センターFarm ponds are among the most biodiverse anthropogenic freshwater habitats because of their small size, shallow water depth, and aquatic vegetation. Land-use changes, such as converting riparian vegetation to human use or changing the management practices of farm ponds, are assumed to be major factors that change such ecosystems from a clear-water state to a turbid state, leading to deterioration of water quality and biodiversity in such ponds. Using the database of a large-scale pond survey, we evaluated the effects of surrounding land use (landscape factors and modern pond management practices), fish abundance, and other environmental variables on total phosphorus concentration and taxonomic richness patterns of six biological indicators associated with changes in the trophic state. Local- and landscape-level vegetation structure associated with land use and total fish abundance were among the factors influencing the total phosphorus concentration of farm ponds, a main driver of trophic state changes. In addition, a transition from a clear-water state to a turbid state was associated with lower taxonomic richness of aquatic plants, macroinvertebrates, and adult Odonata, and a higher taxonomic richness of phytoplankton and fish. Based on these results, we discuss potential land-use and pond management strategies for conserving and/or restoring the water quality and biodiversity of farm ponds through maintenance of a clear-water state. © 2017 Elsevier B.V.Embargo Period 24 month