Functional characterization of a novel somatic oncogenic mutation of PIK3CB.

Class I phosphoinositide 3-kinase (PI3K) enzymes have attracted considerable attention as drug targets in cancer therapy over the last 20 years. The signaling pathway triggered by class I PI3Ks is dysregulated in a range of tumor types, impacting cell proliferation, survival and apoptosis. Frequent oncogenic mutations of PIK3CA have previously been discovered. In contrast, reports of PIK3CB mutations have been limited; however, in most cases, those that have been identified have been shown to be activating and oncogenic. The functional characterization of a PIK3CB catalytic domain mutant, p110ßE1051K, first discovered by others in castrate-resistant prostate cancer (mCRPC), is outlined in this report; our data suggest that p110ßE1051K is a gain-of-function mutation, driving PI3K signaling, tumorigenic cell growth and migration. Tumor cells expressing p110ßE1051K are sensitive to p110ß inhibition; its characterization as an oncogenic driver adds to the rationale for targeting p110ß and indicates a continuing need to further develop specific PI3K inhibitors for clinical development in cancer therapy.

Effects of functional electrical stimulation on gait function and quality of life for people with multiple sclerosis taking dalfampridine.

BACKGROUND: Multiple sclerosis (MS) can adversely affect gait, causing gait slowing, loss of balance, decreased functional mobility, and gait deficits, such as footdrop. Current treatments for gait dysfunction due to MS are pharmacologic, using dalfampridine, or orthotic, using an ankle-foot orthosis. Functional electrical stimulation (FES) to the fibular nerve stimulates active dorsiflexion and provides an alternative treatment for gait dysfunction caused by footdrop. The objective of this study was to determine the effect of FES on gait function and the impact of MS on walking and quality of life for people with MS taking a stable dalfampridine dose. METHODS: Participants demonstrating gait slowing and footdrop completed the Timed 25-Foot Walk (T25FW) test, 6-Minute Walk (6MW) test, GaitRite Functional Ambulation Profile, 12-item Multiple Sclerosis Walking Scale (MSWS-12), and 36-item Short Form Health Status Survey (SF-36) at screening without FES; the measures were repeated with FES at baseline, 1 month, and 3 months. RESULTS: Twenty participants (8 men and 12 women) completed this unblinded case series study. The mean age, duration of MS, and time taking dalfampridine were 51.7, 15.8, and 1.4 years, respectively. Changes from screening to baseline and screening to 3 months were analyzed. Significant improvement was noted from screening to baseline for the MSWS-12 (P = .024) and SF-36 Physical Function domain (P = .028) and from screening to 3 months for the T25FW (P = .015), MSWS-12 (P = .003), and SF-36 Physical Function (P = .032) and Role Limitation-Physical Health (P = .012) domains. CONCLUSIONS: Improvements above those induced pharmacologically suggest that FES can augment pharmacologic intervention and significantly improve gait function, decrease the impact of MS on walking, and improve quality of life for people with MS.

Long-Term Follow-up to a Randomized Controlled Trial Comparing Peroneal Nerve Functional Electrical Stimulation to an Ankle Foot Orthosis for Patients With Chronic Stroke.

BACKGROUND: Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle foot orthoses (AFO) for treatment of foot drop poststroke, but few long-term, randomized controlled comparisons exist. OBJECTIVE: Compare changes in gait quality and function between FES and AFOs in individuals with foot drop poststroke over a 12-month period. METHODS: Follow-up analysis of an unblinded randomized controlled trial (ClinicalTrials.gov #NCT01087957) conducted at 30 rehabilitation centers comparing FES to AFOs over 6 months. Subjects continued to wear their randomized device for another 6 months to final 12-month assessments. Subjects used study devices for all home and community ambulation. Multiply imputed intention-to-treat analyses were utilized; primary endpoints were tested for noninferiority and secondary endpoints for superiority. Primary endpoints: 10 Meter Walk Test (10MWT) and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test (6MWT), GaitRite Functional Ambulation Profile, and Modified Emory Functional Ambulation Profile (mEFAP). RESULTS: A total of 495 subjects were randomized, and 384 completed the 12-month follow-up. FES proved noninferior to AFOs for all primary endpoints. Both FES and AFO groups showed statistically and clinically significant improvement for 10MWT compared with initial measurement. No statistically significant between-group differences were found for primary or secondary endpoints. The FES group demonstrated statistically significant improvements for 6MWT and mEFAP Stair-time subscore. CONCLUSIONS: At 12 months, both FES and AFOs continue to demonstrate equivalent gains in gait speed. Results suggest that long-term FES use may lead to additional improvements in walking endurance and functional ambulation; further research is needed to confirm these findings.

The effects of peroneal nerve functional electrical stimulation versus ankle-foot orthosis in patients with chronic stroke: a randomized controlled trial.

BACKGROUND: Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle-foot orthoses (AFO) for treatment of foot drop poststroke, but few randomized controlled comparisons exist. OBJECTIVE: To compare changes in gait and quality of life (QoL) between FES and an AFO in individuals with foot drop poststroke. METHODS: In a multicenter randomized controlled trial (ClinicalTrials.gov #NCT01087957) with unblinded outcome assessments, 495 Medicare-eligible individuals at least 6 months poststroke wore FES or an AFO for 6 months. Primary endpoints: 10-Meter Walk Test (10MWT), a composite of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living, and Social Participation subscores on the Stroke Impact Scale (SIS), and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test, GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go, individual SIS domains, and Stroke-Specific Quality of Life measures. Multiply imputed intention-to-treat analyses were used with primary endpoints tested for noninferiority and secondary endpoints tested for superiority. RESULTS: A total of 399 subjects completed the study. FES proved noninferior to the AFO for all primary endpoints. Both the FES and AFO groups improved significantly on the 10MWT. Within the FES group, significant improvements were found for SIS composite score, total mFEAP score, individual Floor and Obstacle course time scores of the mEFAP, FAP, and BBS, but again, no between-group differences were found. CONCLUSIONS: Use of FES is equivalent to the AFO. Further studies should examine whether FES enables better performance in tasks involving functional mobility, activities of daily living, and balance.

Planar waveguide tilted Bragg grating refractometer fabricated through physical micromachining and direct UV writing.

A set of rapid prototyping techniques are combined to construct a laterally-tilted Bragg grating refractometer in a novel planar geometry. The tilted Bragg grating is fabricated in a silica-on-silicon planar substrate using a dual beam direct UV writing (DUW) technique. Lateral cladding mode confinement is subsequently achieved by physically micromachining two trenches either side of the direct UV written waveguide. The resulting device is demonstrated as an effective refractometer, displaying a comparable sensitivity to tilted Bragg gratings in a fiber optical geometry, but with the added advantages of planar integration.

Integrated optic glass microcantilevers with Bragg grating interrogation.

A new method for creating microcantilevers in glass allows integration of optical waveguides and Bragg gratings. Devices are fabricated by high precision sawing, followed by direct UV writing of waveguides with Bragg gratings and then chemical etching to release the freestanding glass structures. Optical measurement of the Bragg gratings together with piezo-actuation allows the mechanical resonances to be probed. By measuring the mechanical damping coefficient of the cantilever as a function of the gas pressure in a vacuum system the transition from the viscous to the molecular flow regime can be observed.

In situ loss measurement of direct UV-written waveguides using integrated Bragg gratings.

The propagation loss of a direct UV-written silica-on-silicon waveguide is measured using an elegant nondestructive method. The technique uses integrated Bragg grating structures, which are observed from opposing launch directions to obtain information about the optical power at different positions along the length of the waveguide. Critically, the technique is ratiometric and independent of coupling loss and grating variability. This high-precision measurement is suitable for low-loss planar waveguides. From this data, the propagation loss of the UV-written waveguides was observed to be 0.235+/-0.006 dB/cm.

Adaptive changes in gait of older and younger adults as responses to challenges to dynamic balance.

The study proposed to identify balance strategies used by younger and older adults during gait under proprioceptive, visual, and simultaneous proprioceptive-visual challenges. Participants ambulated under 4 conditions: consistent, noncompliant surface; inconsistent, compliant surface (C); consistent, noncompliant surface with vision obscured (NCVO); and inconsistent, compliant surface with vision obscured (CVO). Balance adaptations were measured as changes in gait velocity, cadence, and gait-stability ratio (GSR). Participants were 5 younger (mean age = 27.2) and 5 older (mean age = 68) healthy adults. Significant age differences were found for GSR (p = .03) on all surfaces. Older adults adopted a more stable gait pattern than younger adults regardless of the challenge presented by surface. Significant condition differences were found for velocity (p < .001) and cadence (p = .001). All participants exhibited significantly decreased velocity and increased cadence on surfaces C and CVO. Gait speed and cadence did not significantly change in NCVO. Younger and older adults exhibited similar adaptive balance strategies, slowing and increasing steps/s, under proprioceptive and proprioceptive-visual challenges to dynamic balance.

Association of balance measures and perception of fall risk on gait speed: a multiple regression analysis.

Gait speed, commonly modified to adapt to the balance and stability challenges of aging, is related to measures of balance and mobility. This study investigated associations between age, Berg Balance Scale, Activities-Specific Balance Confidence (ABC) Scale, One Question Fear of Falling (1QFOF), and gait speed in adults using regression analysis. Results suggested an interaction between 1QFOF and ABC scores. An expanded five-variable model explained 49% of gait speed variance. Age, ABC, and 1QFOF-ABC interactions were significantly associated with gait speed. Regression analysis is useful in investigating associations between performance variables and function. Continued research needs to identify optimal variable combinations and improve prediction of function.

Randomized trial of supplementary interviewing techniques to enhance recall of sexual partners in contact interviews.

BACKGROUND: People with multiple sex partners tend to forget a significant proportion when recalling them. METHODS: Randomized trial of supplementary interviewing techniques during routine partner notification contact interviews for chlamydia, gonorrhea, and syphilis in Colorado Springs, CO. Cases with multiple sex partners in the last 3 months (n = 123) participated. Interviewers prompted nonspecifically and read back the list of elicited partners after cases recalled partners on their own. We then randomly assigned cases to receive 1 of 3 sets of recall cues: (1) an experimental set of cues consisting of locations where people meet partners, role relationships, network ties, and first letters of names; (2) another experimental set including common first names; and (3) control cues referring to individual characteristics (e.g., physical appearance). RESULTS: Nonspecific prompting and reading back the list each increased the number of additional partners elicited and located by 3% to 5% on average. On average, the combined location/role/letter/network cues elicited more additional partners (0.57) than did the first-name (0.29) and individual characteristics (0.28) cues. The location and first-name cues were the most effective in eliciting located partners. The supplementary techniques increased the number of new cases found by 12% and, importantly, identified branches of the sexual network that would not otherwise have been discovered. CONCLUSION: Elicitation of sex partners can be enhanced in contact interviews with simple interviewing techniques, resulting in improved network ascertainment and sexually transmitted disease case finding.