Electrical Stimulation to Conductive Scaffold Promotes Axonal Regeneration and Remyelination in a Rat Model of Large Nerve Defect

BACKGROUND: Electrical stimulation (ES) has been shown to promote nerve regeneration when it was applied to the proximal nerve stump. However, the possible beneficial effect of establishing a local electrical environment between a large nerve defect on nerve regeneration has not been reported in previous studies. The present study attempted to establish a local electrical environment between a large nerve defect, and examined its effect on nerve regeneration and functional recovery. METHODOLOGY/FINDINGS: In the present study, a conductive scaffold was constructed and used to bridge a 15 mm sciatic nerve defect in rats, and intermittent ES (3 V, 20 Hz) was applied to the conductive scaffold to establish an electrical environment at the site of nerve defect. Nerve regeneration and functional recovery were examined after nerve injury repair and ES. We found that axonal regeneration and remyelination of the regenerated axons were significantly enhanced by ES which was applied to conductive scaffold. In addition, both motor and sensory functional recovery was significantly improved and muscle atrophy was partially reversed by ES localized at the conductive scaffold. Further investigations showed that the expression of S-100, BDNF (brain-derived neurotrophic factor), P0 and Par-3 was significantly up-regulated by ES at the conductive scaffold. CONCLUSIONS/SIGNIFICANCE: Establishing an electrical environment with ES localized at the conductive scaffold is capable of accelerating nerve regeneration and promoting functional recovery in a 15 mm nerve defect in rats. The findings provide new directions for exploring regenerative approaches to achieve better functional recovery in the treatment of large nerve defect

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified

Cyclic shear dynamic properties of geotextile-sandy soil interface

A series of cyclic direct shear tests of soil-reinforcement interfaces were performed by using a large-scale direct shear device. Woven geotextile and nonwoven geotextile were used as reinforcement materials. Chinese ISO standard sand was used as soil mass. When the vertical stresses are 30, 60 and 90 kPa respectively, the cyclic shear displacement amplitudes are 1, 3 and 5 mm respectively, and the sandy soil densities are 22%, 52% and 75% respectively, their influences on the cyclic shear properties of soil-reinforcement interfaces were studied, and the development laws of peak shear stresses and the relationships of shear stresses and shear displacements in the processes of cyclic shear tests on two kinds of geotextile-sandy soil interfaces were analyzed. Study result indicates that the cyclic shear softening phenomena appear on woven/nonwoven geotextile-sand interfaces, and the softening laws are different. When the vertical stress increases from 30 kPa to 90 kPa, the peak shear stress of woven geotextile-sandy soil interface increases by 72.9%, and the peak shear stress of nonwoven geotextile-sand interface increases by 167.5%, so the influence of vertical stress on the cyclic shear properties of geotextile-sandy soil interface is obvious. When the shear displacement amplitudes are 1, 3 and 5 mm respectively, the peak shear stresses of woven geotextile-sandy soil interface are 25.9, 27.9 and 29.8 kPa respectively, and the peak shear stresses of nonwoven geotextile-sandy soil interface are 21.8, 23.8 and 22.6 kPa respectively, which shows that the peak shear stress of woven geotextile-sandy soil interface increases with the increase of shear displacement amplitude, while the peak shear stress of nonwoven geotextile-sandy soil interface firstly increases and then decreases. Under the three sandy soil densities, the differences among the peak shear stresses of woven geotextile-sandy soil interface do not exceed 2 kPa, and the differences among the peak shear stresses of nonwoven geotextile-sandy soil interface do not exceed 3 kPa, which shows that the sandy soil density has no significant influence on the cyclic shear properties of woven/nonwoven geotextile-sandy soil interfaces. 3 tabs, 14 figs, 25 refs

Cyclic and post-cyclic behaviour from sand–geogrid interface large-scale direct shear tests

The understanding of cyclic and post-cyclic behaviours of the soil–geosynthetic interface is essential for the design of geosynthetic- reinforced soil structures under repeated loads, such as those induced by traffic, earthquakes and compaction. In this paper, a series of monotonic direct shear tests and cyclic direct shear integrating monotonic direct shear tests were conducted by using a large-scale direct shear testing device. The effect of normal stresses, cyclic shear amplitude and cycle number on the post-cyclic behaviour of the interface are investigated. In addition, the influence of cyclic shear on interface direct shear behaviour was discussed in detail. The test results indicated that both the peak and residual shear stresses of the interface during the post-cyclic shear phase increased linearly with normal stress and the number of cycles. The volume contraction, which was induced by the direct shear, decreased with the increase in normal stress. The interface apparent adhesion and friction angle increased with the cyclic shear

A molecular Debye-Hückel theory of solvation in polar fluids: An extension of the Born model

A dielectric response theory of solvation beyond the conventional Born model for polar fluids is presented. The dielectric response of a polar fluid is described by a Born response mode and a linear combination of Debye-Hückel-like response modes that capture the nonlocal response of polar fluids. The Born mode is characterized by a bulk dielectric constant, while a Debye-Hückel mode is characterized by its corresponding Debye screening length. Both the bulk dielectric constant and the Debye screening lengths are determined from the bulk dielectric function of the polar fluid. The linear combination coefficients of the response modes are evaluated in a self-consistent way and can be used to evaluate the electrostatic contribution to the thermodynamic properties of a polar fluid. Our theory is applied to a dipolar hard sphere fluid as well as interaction site models of polar fluids such as water, where the electrostatic contribution to their thermodynamic properties can be obtained accurately