A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III)

Abstract

Objective

To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).

Methods

STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.

Results

The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).

Interpretation

STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.

http://ift.tt/2pfoGdu

CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder

Abstract

Objectives

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin-4 (AQP4). The origin and trafficking of AQP4-specific B cells in NMOSD remains unknown.

Methods

Peripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naïve, memory, and CD27-IgD- double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single-cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy- and light chains and tested for AQP4 reactivity.

Results

Approximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4-specific VH sequences were observed in each peripheral B-cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4-specific B cells are closely related to an expanded population of DN B cells that may undergo antigen-specific B-cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B-cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome.

Interpretation

During an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4-specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B-cell compartment may be a potential biomarker of NMOSD activity.

http://ift.tt/2qV976O

Cancers, Vol. 9, Pages 49: Diagnostic and Therapeutic Potential of MicroRNAs in Lung Cancer

Lung cancer is the leading cause of deaths resulting from cancer owing to late diagnosis and limited treatment intervention. MicroRNAs are short, non-coding RNA molecules that regulate gene expression post-transcriptionally by translational repression or target messenger RNA degradation. Accumulating evidence suggests various roles for microRNAs, including development and progression of lung cancers. Because microRNAs are degraded to a much lesser extent in formalin-fixed paraffin-embedded specimens and are present not only in tumor tissues but also in body fluids, there is an increased potential in microRNA analyses for cancer research. In this review, recent studies of microRNA are introduced and briefly summarized, with a focus on the association of microRNAs with histological subtypes, genetic driver alterations, therapeutically-targeted molecules, and carcinogens. The reported circulating microRNA signature for the early detection of lung cancer and the implications of microRNAs as the modulators of tumor immune response are also introduced.

http://ift.tt/2qUOtEb

Materials Nanoarchitecturing via Cation-Mediated Protein Assembly: Making Limpet Teeth without Mineral

Teeth are designed to deliver high forces while withstanding the generated stresses. Aside from isolated mineral-free exception (e.g., marine polychaetes and squids), minerals are thought to be indispensable for tooth-hardening and durability. Here, the unmineralized teeth of the giant keyhole limpet (Megathura crenulata) are shown to attain a stiffness, which is twofold higher than any known organic biogenic structures. In these teeth, protein and chitin fibers establish a stiff compact outer shell enclosing a less compact core. The stiffness and its gradients emerge from a concerted interaction across multiple length-scales: packing of hydrophobic proteins and folding into secondary structures mediated by Ca²⁺ and Mg²⁺ together with a strong spatial control in the local fiber orientation. These results integrating nanoindentation, acoustic microscopy, and finite-element modeling for probing the tooth's mechanical properties, spatially resolved small- and wide-angle X-ray scattering for probing the material ordering on the micrometer scale, and energy-dispersive X-ray scattering combined with confocal Raman microscopy to study structural features on the molecular scale, reveal a nanocomposite structure hierarchically assembled to form a versatile damage-tolerant protein-based tooth, with a stiffness similar to mineralized mammalian bone, but without any mineral.

The teeth of the giant keyhole limpet (Megathura crenulata) are unmineralized but exhibit a stiffness, which is twofold higher than any known organic biogenic structures. This study reveals the structure–function relationship of a unique biological material.

http://ift.tt/2q0LMBO

A Synaptic Transistor based on Quasi-2D Molybdenum Oxide

Biological synapses store and process information simultaneously by tuning the connection between two neighboring neurons. Such functionality inspires the task of hardware implementation of neuromorphic computing systems. Ionic/electronic hybrid three-terminal memristive devices, in which the channel conductance can be modulated according to the history of applied voltage and current, provide a more promising way of emulating synapses by a substantial reduction in complexity and energy consumption. 2D van der Waals materials with single or few layers of crystal unit cells have been a widespread innovation in three-terminal electronic devices. However, less attention has been paid to 2D transition-metal oxides, which have good stability and technique compatibility. Here, nanoscale three-terminal memristive transistors based on quasi-2D α-phase molybdenum oxide (α-MoO₃) to emulate biological synapses are presented. The essential synaptic behaviors, such as excitatory postsynaptic current, depression and potentiation of synaptic weight, and paired-pulse facilitation, as well as the transition of short-term plasticity to long-term potentiation, are demonstrated in the three-terminal devices. These results provide an insight into the potential application of 2D transition-metal oxides for synaptic devices with high scaling ability, low energy consumption, and high processing efficiency.

A quasi-2D transition-metal oxide, α-phase molybdenum oxide (α-MoO₃), is used to fabricate nanoscale three-terminal memristive transistors. The essential biological synaptic behaviors, such as excitatory postsynaptic current, depression and potentiation of synaptic weight, paired-pulse facilitation, and the transition of short-term plasticity to long-term potentiation, are demonstrated in the three-terminal devices.

http://ift.tt/2pYPNsj

Ink-Free Reversible Optical Writing in Monolayers by Polymerization of a Trifunctional Monomer: Toward Rewritable “Molecular Paper”

A Langmuir–Blodgett film consisting of a dense array of trifunctional monomers bearing three 1,8-diazaanthracene units is polymerized at an air/water interface or after transfer on solid substrates. The transfer does not affect the excimer fluorescence of the film, indicating that the monomers' packing with their diazaanthracene units stacked face-to-face is retained—a prerequisite for successful polymerization. The monomer film can be polymerized in confined areas on solid substrates by UV irradiation with a confocal microscope laser. The underlying chemistry of the polymerization, a [4+4]-cycloaddition of the diazaanthracene units, leads to disappearance of the fluorescence in the irradiated regions which enables writing into the monolayer on a µm scale—thus the term "molecular paper." The reaction can be reversed by heating which leads to a recovery of the fluorescence and to erasing of the writing. Alternative pathways for this phenomenon are discussed and control experiments are conducted to rule them out.

"Molecular paper"—a nanometer thin, fluorescent film which can be depositedon various substrates and written onto by irradiation with a confocal microscope laser. Irradiation leads to disappearance of the fluorescence in the targeted area, allowing writing on a micrometer scale. This process is reversible by heating which recovers the film's fluorescence and "erases" the writing.

http://ift.tt/2q13WTK

Clickable Microgel Scaffolds as Platforms for 3D Cell Encapsulation

While microporous scaffolds are increasingly used for regenerative medicine and tissue repair applications, the most common techniques to fabricate these scaffolds use templating or top-down fabrication approaches. Cytocompatible bottom-up assembly methods afford the opportunity to assemble microporous systems in the presence of cells and create complex polymer-cell composite systems in situ. Here, microgel building blocks with clickable surface groups are synthesized for the bottom-up fabrication of porous cell-laden scaffolds. The facile nature of assembly allows for human mesenchymal stem cells to be incorporated throughout the porous scaffold. Particles are designed with mean diameters of ≈10 and 100 µm, and assembled to create varied microenvironments. The resulting pore sizes and their distribution significantly alter cell morphology and cytoskeletal formation. This microgel-based system provides numerous tunable properties that can be used to control multiple aspects of cellular growth and development, as well as providing the ability to recapitulate various biological interfaces.

Microgel "building blocks" are designed and assembled in the presence of cells to create polymer-cell composites. These materials have highly tunable mechanical and chemical properties, allowing for a highly versatile cell culture platform.

http://ift.tt/2qkiroO