1,131 publications from this institution
Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca(2+)-dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca(2+) in astrocytes, induced by uncaging Ca(2+), o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-d-aspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca(2+) elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca(2+) uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca(2+) uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA/kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.
Abstract The emerging modular building construction technique is gaining attention by researchers and investors because of its benefits such as short construction time, better quality control, minimal environmental effect and more economical. Composite modules have many advantages, including size reduction and improved fire resistance, over the steel modules, which encourage the application of modular construction on tall buildings. Current state‐of‐art lacks the proper connection technique for composite modular tall buildings. This paper presents novel inter‐module connection for composite modular tall buildings. Purposed inter‐module connection is very simple in geometric design, adequately strong to bear loads for tall buildings, easy to connect and disconnect, and applicable with internal joints and composite modules. Bolts through bolt holes connect modules vertically whereas gusset plate connects horizontally. Firstly, prototype is developed, and workability is confirmed. Performance and failure mechanism of proposed connector under tensile load are evaluated considering the effect of different parameters such as thickness of base plate, size and material of bolt. Results can be used to develop the design guideline for proposed inter‐module connection.
Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.
e22212 Background: Ribosome biogenesis driven by RNA polymerase 1 (Pol1) is a fundamental cellular process increased in malignancy. We have shown that CX-5461, a small molecule inhibitor of Pol1, selectively targets AML, lymphoma and myeloma cells in preclinical in-vivomodels with minimal effects on normal hematopoietic cells (Cancer Cell 2012). Methods: Key Eligibility Criteria; Relapsed HM, >1 prior therapy, no standard of care therapeutic options; ECOG PS: 0-2; Adequate organ function. CX-5461 is administered by 3 weekly IV infusion over 1 hour. Based on preclinical animal testing, dosing commenced at 25mg/m2, with planned escalations up to 450mg/m2. Biomarkers of Pol1 transcription inhibition (Pol1ti) include 47S ribosome subunit pre-rRNA FISH in PBMC and tumor tissue. Results: Since July 2014, 13 patients have been treated in 4 dose cohorts (table1).To date there have been no dose-limiting toxicities (n=12). The most common drug associated toxicity was skin rash (photosensitive grade 1-2 n=4 easily managed by sun avoidance and erythroderma grade 3 in one CTCL patient). Other adverse events (AEs) have been mild cytopenias related to underlying disease. 3 patients, 2 (MM) and 1 (DLBCL), have shown prolonged disease stabilisation receiving 6, 3 and 15 cycles of drug. The latter remains on drug after 10 months. PK analyses showed favorable and linear exposure with dose. Treatment with CX-5461 causes robust and significant Pol1ti 1hr post-infusion. Median Pol1ti 49.0% (Range:22.9- 69.9%, n=3), 51.1% (34.4 - 64.4%, n=4), 19.6% (-72.0 – 69.7%, n=4) and 46.5% (n=1) for cohorts 1-4 respectively. At 24hrs, Pol1 transcription levels rebound and return to baseline levels. Conclusions: CX-5461 is well tolerated with low grade manageable AEs to date. Inhibition of Pol1 transcription in PBMC indicated on-target drug activity in these initial dose cohorts. The trial continues in dose escalation. Clinical trial information: ACTRN12613001061729. Pt ID Age Sex Diagnosis Dose level mg/m2 No. of doses Best Response 1 73 M MM 25 6 SD 2 47 F MM 25 3 SD 3 54 F DLBCL 25 1 PD 4 79 F CTCL 50 2 mixed 5 26 F HD 50 1 PD 6 74 M CLL 50 1 Early PD 7 70 F DLBCL 50 15 SD 8 47 M MM 100 1 PD 9 78 M TPLL 100 1 Early PD 10 21 F DLBCL 100 2 PD 11 34 M HD 100 2 PD 12 74 F MM 170 1 NA 13 56 M MM 170 1 NA
Combined chemotherapy is often affected by the different physicochemical properties of chemotherapeutic drugs, which should be improved by the reasonable design of co-loaded preparations.A kind of simple but practical graphene oxide (GO) wrapped mesoporous silica nanoparticles (MSN) modified with hyaluronic acid (MSN@GO-HA) were developed for the co-delivery of cinnamaldehyde (CA) and doxorubicin (DOX), in order to enhance their combined treatment on tumor cells and reduce their application defects.The MSNCA@GODOX-HA was constructed by MSNCA (loading CA via physical diffusion) and GODOX-HA (modified with HA and loading DOX via π-π stacking) through the electrostatic adsorption, followed by the physicochemical characterization, serum stability and in vitro release study. Cytotoxicity on different cells was detected, followed by the tumor cell uptake tests. The intracellular reactive oxygen species (ROS) changes, mitochondrial functions and activities of caspase-3/-9 in MCF-7 cells were also evaluated, respectively.The MSNCA@GODOX-HA nanoparticles kept stable in FBS solution and achieved pH-responsive release behavior, which was beneficial to increase the accumulation of CA and DOX in tumor cells to enhance the treatment. MSNCA@GODOX-HA exerted higher cytotoxicity to MCF-7 human breast cancer cells than H9c2 cardiac myocyte cells, which were not only attributed to the active targeting to tumor cells by HA, but also related with the activation of intrinsic apoptotic pathway in MCF-7 cells induced by CA, which was mediated by the specific ROS signal amplification and the interference with mitochondrial function. Moreover, the efficacy of DOX was also enhanced by the above process.The establishment of the MSNCA@GODOX-HA nanoparticles played a role in promoting strengths and restricting shortcomings of CA and DOX, thereby exerting their function and achieving efficient treatment against cancer.
