Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Tissue-specific profiling reveals modulation of cellular and mitochondrial oxidative stress in normal- and low-birthweight piglets throughout the peri-weaning period.

Weaning is known to induce important nutritional and energetic stress in piglets. Low-birthweight (LBW) piglets, now frequently observed in swine production, are more likely to be affected. The weaning period is also associated with dysfunctional immune responses, uncontrolled inflammation and oxidative stress conditions that are recognized risk factors for infections and diseases. Mounting evidence indicates that mitochondria, the main cellular sources of energy in the form of adenosine 5' triphosphate (ATP) and primary sites of reactive oxygen species production, are related to immunity, inflammation and bacterial pathogenesis. However, no information is currently available regarding the link between mitochondrial energy production and oxidative stress in weaned piglets. The objective of this study was to characterize markers of cellular and mitochondrial energy metabolism and oxidative status in both normal-birthweight (NBW) and LBW piglets throughout the peri-weaning period. To conduct the study, 30 multiparous sows were inseminated and litters were standardized to 12 piglets. All the piglets were weighted at day 1 and 120 piglets were selected and assigned to 1 of 2 experimental groups: NBW (n = 60, mean weight of 1.73 ± 0.01 kg) and LBW piglets weighing less than 1.2 kg (n = 60, 1.01 ± 0.01 kg). Then, 10 piglets from each group were selected at 14, 21 (weaning), 23, 25, 29 and 35 days of age to collect plasma and organ (liver, intestine and kidney) samples. Analysis revealed that ATP concentrations were lower in liver of piglets after weaning than during lactation (P < 0.05) thus suggesting a significant impact of weaning stress on mitochondrial energy production. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine, 8-OHdG) and proteins (carbonyls) measured in plasma increased after weaning and this coincides with a rise in enzymatic antioxidant activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD) (P < 0.05). Mitochondrial activities of both GPx and SOD are also significantly higher (P < 0.05) in kidney of piglets after weaning. Additionally, oxidative damage to macromolecules is more important in LBW piglets as measured concentrations of 8-OHdG and protein carbonyls are significantly higher (P < 0.05) in plasma and liver samples, respectively, than for NBW piglets. These results provide novel information about the nature, intensity and duration of weaning stress by revealing that weaning induces mitochondrial dysfunction and cellular oxidative stress conditions which last for at least 2 weeks and more severely impact smaller piglets.

Assessment of antioxidative and selenium status by seleno-dependent glutathione peroxidase activity in different blood fractions using a pig model: issues for clinical nutrition and research.

Blood seleno-dependent glutathione peroxidase (SeGPX) activity is widely used as a metabolic indicator of systemic antioxidative status despite inconsistent responses in the literature. This study aimed to compare SeGPX activity profiles in different blood fractions, expressed with different reference units, and assess their impact on interpretation of results. Two studies on selenium (Se) metabolism in gilts, including long-term and peri-oestrus SeGPX activity profiles, were submitted to analysis of variance with double repeated measures, after data set standardization. Differences between studies were experimental period (three post-pubertal oestrus or five post-pubertal oestrus +30 days of gestation) and sample type (whole blood or blood plasma). No difference was observed between whole-blood long-term profiles (three oestrus) for SeGPX activity/mg haemoglobin (SeGPXhb) vs. SeGPX activity/ml whole blood (SeGPXwb; p = 0.29). No long-term difference was observed in whole blood between profiles according to dietary Se provision (basal and dietary Se-supplemented groups; p ≥ 0.12). Blood plasma long-term profiles (five oestrus + 30 days gestation) for SeGPX/mg blood plasma protein (SeGPXpro) were different from SeGPX/ml blood plasma (SeGPXpla) according or not to Se provision (p ≤ 0.007 and p < 0.001 respectively). However, regardless of Se provision (p ≥ 0.80), when excluding gestation from the model, blood plasma profiles were similar. During the peri-oestrus period (day -4 to +3), regardless of Se provision, SeGPX activity profiles differed according to reference units in both studies (p < 0.001). However, considering Se provision, similar profiles were observed in whole blood and blood plasma (p ≥ 0.27) for basal Se groups, whereas in Se-supplemented groups they differed for both sample types (p ≤ 0.02). In conclusion, reference units influence interpretation of SeGPX activity according to physiological state. During oxidative stress periods, this effect depends upon dietary Se provision.

Providing the plant extract silymarin to lactating sows: effects on litter performance and oxidative stress in sows.

Silymarin is an extract from the plant milk thistle that was shown to have antioxidant and hyperprolactinemic properties. Taking into account the essential role of prolactin for lactating sows and the systemic oxidative stress occurring during lactation, it is of interest to investigate the potential beneficial effects of silymarin on lactating sows. A study was therefore carried out to determine the effects of providing either 1 or 8 g/day of the plant extract silymarin to lactating sows. Sows in first, second or third parity were fed conventional diets during gestation and, at farrowing, were assigned as controls (CTL, n=33), or were fed 1 g/day (SYL1, n=33) or 8 g/day (SYL8, n=33) of silymarin. The silymarin was provided in two equal amounts per day, and was fed throughout a 20-day lactation. The performance of sows and their litters was assessed and circulating concentrations of prolactin (days 7 and 18), urea (days 7 and 18) and oxidative status, via protein carbonyls and superoxide dismutase activity (day 18), were measured in sows. Milk samples were obtained on day 18 to measure standard composition. There was no effect of silymarin (P>0.10) on circulating prolactin or urea, or on oxidative damage to proteins or antioxidant potential in sows. Lactation feed intake, backfat and BW of sows were unaffected by treatment (P>0.10) as was the case for milk composition and piglet growth (P>0.10). Results demonstrate that providing up to 8 g/day of the plant extract silymarin to lactating sows had no beneficial effects in terms of circulating prolactin concentrations or oxidative status of sows, or in terms of performances of sows and their litters.

Evidence that oxidative stress is higher in replacement gilts than in multiparous sows.

The recent success obtained in term of increasing the litter size of sows has not correlated with a reduction of replacement rate. There is thus an increased economic demand for gilts with optimal reproductive potential and longevity. Unfortunately, replacement gilts are known to be more susceptible to diseases and less productive than multiparous sows. Interestingly, reproductive performance, resistance to diseases and longevity could all be largely affected by oxidative stress. To investigate whether oxidative stress conditions could account for the poor longevity of gilts, three distinct groups of conventional Yorkshire × Landrace sows were formed based on their similar age and parity (gilts, second parity sows as well as fourth to fifth parity sows). All animals were slaughtered during the post-ovulatory period, and blood as well as tissue samples were collected. Biomarkers of oxidative damage to proteins (carbonyls) and DNA (8-OHdG) were analysed in samples. Specific mRNA expression of major antioxidants such as glutathione peroxidases 1, 3 and 4 (GPx1, GPx3, GPx4) as well as superoxide dismutases 1 and 2 (Sod1, Sod2) were monitored in liver and kidney samples by quantitative RT-PCR. Specific enzymatic activities of both GPx and SOD were measured by spectrophotometric assays. The plasma concentration of protein carbonyls was significantly different between the three groups with the highest concentration being observed in gilts (p ≤ 0.001). The mRNA expression levels of GPx1 and GPx4 were also significantly increased in the liver of gilts when compared to multiparous sows (p ≤ 0.05). SOD2 enzymatic activity was found to be higher in the liver of gilts than multiparous sows (p ≤ 0.05). Taken together, these results indicate that replacement gilts sustain significantly higher oxidative conditions than multiparous sows. Current findings may contribute to the design of nutritional regimens that will increase the productivity of gilts by counteracting oxidative stress.

Effects of the plant extract silymarin on prolactin concentrations, mammary gland development, and oxidative stress in gestating gilts.

The impacts of supplementing the diet of gestating gilts twice daily with 4 g of the plant extract silymarin on circulating hormonal concentrations, oxidative status, mammary development, and mammary gene expression at the end of gestation were determined. Gilts were fed conventional diets during gestation and on d 90 they were assigned as controls (CTL; n = 16) or treated (TRT; n = 17) animals. Treatment consisted of providing 4 g of silymarin twice daily until d 110, at which time all gilts were slaughtered to collect mammary tissue for compositional analyses and measures of gene expression and oxidative status, and liver and corpora lutea for measures of oxidative stress variables. Blood samples for hormonal assays and evaluation of oxidative stress biomarkers were obtained on d 89, 94, and 109 of gestation. Silymarin increased (P = 0.05) circulating concentrations of prolactin over all samples in the repeated in time analysis. In separate analyses for each sampling time, prolactin concentrations in TRT gilts tended (P < 0.10) to be greater than in CTL gilts on d 94 of gestation. Repeated in time analysis also revealed that silymarin reduced (P ≤ 0.05) plasmatic accumulation of biomarkers of oxidative damage to protein (protein carbonyls) between d 89 and 109. There was no effect (P > 0.10) of treatment on progesterone, estradiol, leptin, or 8-hydroxy-2'-deoxyguanosine concentrations. Percent fat in mammary parenchyma was greater (P ≤ 0.05), percent protein was lesser (P ≤ 0.05), and concentrations of both RNA (P ≤ 0.01) and DNA (P < 0.05) were lesser in TRT than CTL gilts. Mammary parenchyma from TRT gilts had lower (P ≤ 0.05) mRNA abundance for STAT5A and leptin and tended to have lower (P ≤ 0.10) abundance for STAT5B than CTL gilts. Silymarin reduced (P ≤ 0.001) protein carbonyls concentrations in liver of TRT gilts. No effect of treatment was observed on antioxidant gene expression and enzymatic activities in liver samples while total superoxide dismutase activity tended to be higher (P ≤ 0.10) in the corpora lutea of TRT animals when compared with CTL. This is the first demonstration that, in female pigs, silymarin can increase prolactin concentrations and protect against oxidative stress, yet the increase in prolactin was not enough to have beneficial effects on mammary gland development in late gestation.

Mitochondria as promising targets for nutritional interventions aiming to improve performance and longevity of sows.

Genetic selection and management changes during the last decades have significantly increased the average litter size of sows. However, this recent success has not correlated with an extension of longevity and reduction in replacement rate. Longevity or lifetime production of sows is determined by a combination of environmental and genetic factors. Nutrition is an environmental factor of importance, and it has long been appreciated that animals fed with specific diets may perform differently. The advent of modern science revealed that this is partly due to the ability of nutrients to act as signalling molecules that, through appropriate intracellular sensing mechanisms, can control gene expression and modulate cell functions. Based on this concept, nutrigenomics studies now aim to show that not only are certain nutrients essential for general health, but also that specific quantities of precise nutrients are necessary during critical periods of energy deficiency and oxidative stress such as gestation and lactation to ensure long-term productivity. The toxic molecules at the origin of oxidative stress, free radicals, are mainly generated as normal by-products of aerobic energy production by mitochondria. In all cells, mitochondria are dynamic organelles that are mainly known as the primary energy-generating system. Thus, when metabolic demands are elevated as it is for hyperprolific sows, mitochondria are heavily solicited for answering all energetic needs, and substantive amounts of free radicals are generated. As a result, optimal conditions in term of antioxidant protection and metabolic substrates availability are required to support mitochondrial function in these animals. This article discusses how performance and longevity of sows are linked to mitochondrial function and oxidative stress and reviews the major natural nutrients known for their antioxidant and/or energetic properties that are susceptible to impact mitochondria and likely improved sows productivity.

Photonic wire biosensor microarray chip and instrumentation with application to serotyping of Escherichia coli isolates.

A complete photonic wire molecular biosensor microarray chip architecture and supporting instrumentation is described. Chip layouts with 16 and 128 independent sensors have been fabricated and tested, where each sensor can provide an independent molecular binding curve. Each sensor is 50 µm in diameter, and consists of a millimeter long silicon photonic wire waveguide folded into a spiral ring resonator. An array of 128 sensors occupies a 2 × 2 mm2 area on a 6 × 9 mm2 chip. Microfluidic sample delivery channels are fabricated monolithically on the chip. The size and layout of the sensor array is fully compatible with commercial spotting tools designed to independently functionalize fluorescence based biochips. The sensor chips are interrogated using an instrument that delivers sample fluid to the chip and is capable of acquiring up to 128 optical sensor outputs simultaneously and in real time. Coupling light from the sensor chip is accomplished through arrays of sub-wavelength surface grating couplers, and the signals are collected by a fixed two-dimensional detector array. The chip and instrument are designed so that connection of the fluid delivery system and optical alignment are automated, and can be completed in a few seconds with no active user input. This microarray system is used to demonstrate a multiplexed assay for serotyping E. coli bacteria using serospecific polyclonal antibody probe molecules.

Interplay between crystal phase purity and radial growth in InP nanowires.

The interplay between crystal phase purity and radial growth in InP nanowires is investigated. By modifying the growth rate and V/III ratio, regions of high or low stacking fault density can be controllably introduced into wurtzite nanowires. It is found that regions with high stacking fault density encourage radial growth. Through careful choice of growth conditions pure wurtzite InP nanowires are then grown which exhibit narrow 4.2 K photoluminescence linewidths of 3.7 meV at 1.490 meV, and no evidence of emission related to stacking faults or zincblende insertions.

White matter tract abnormalities in first-episode psychosis.

Fibers connecting fronto-temporal and fronto-medial structures that pass through the anterior limb of the internal capsule (ALIC) subserve executive and psychomotor functioning. Both of these functions are adversely affected in schizophrenia, and may be abnormal at illness onset. In a study of first-episode psychosis, we used diffusion tensor imaging (DTI) and cognitive testing to examine ALIC integrity. Fourteen early psychosis patients and 29 healthy volunteers were included. Symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). All structural and diffusion scans were acquired on a GE Signa 1.5T scanner. A T1-weighted 3D FSPGR Inversion Recovery imaging series was acquired for manual seeding in structural space. Diffusion tensor imaging (DTI) was performed, and all DTI images were co-registered to structural space. Seeds were manually drawn bilaterally on the coronal plane at a specified location. Diffusion images were post-processed for subsequent Tract-based Spatial Statistics (TBSS) analysis. First-episode psychosis patients had significantly smaller fronto-medial and fronto-temporal AIC tract volumes compared to healthy volunteers on the left and the right (p-values<0.04). No differences in mean fractional anisotropy (FA) were seen within either left or right tracts (p-values>0.05), nor did TBSS reveal any other differences in FA values between groups in other regions. Relationships between tract volumes and symptom severity were not observed in this study.

Enhanced photonic crystal cavity-waveguide coupling using local slow-light engineering.

This Letter introduces an enhanced cavity-waveguide coupling architecture based upon slow-light engineering in a two-port photonic crystal system. After analyzing the system transmittance using coupled-mode theory, the system is probed experimentally and shown to have increased transmittance due to the enhanced cavity-waveguide coupling. Such a coupling architecture may facilitate next-generation planar lightwave circuitry such as onchip quantum information processing or high precision light-matter sensing applications.

Intervertebral disk disease with spinal cord penetration in a Yucatan pig.

A 9-month-old female Yucatan pig was euthanized after acute onset of paraplegia. Gross and microscopic examination revealed dorsal dissection of the nucleus of the L2-L3 intervertebral disk through the annulus fibrosus, extrusion of nucleus pulposus material through the overlying dura mater and into the spinal cord, and associated acute spinal hemorrhage and necrosis. This is, to the authors' knowledge, the first reported case of intervertebral disk disease in swine.

Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness.

Though prostate cancer is often indolent, it is nonetheless a leading cause of cancer death. Defining the underlying molecular genetic alterations may lead to new strategies for prevention or treatment. Towards this goal, we performed array-based comparative genomic hybridization (CGH) on 86 primary prostate tumors. Among the most frequent alterations not associated with a known cancer gene, we identified focal deletions within 5q21 in 15 out of 86 (17%) cases. By high-resolution tiling array CGH, the smallest common deletion targeted just one gene, the chromatin remodeler chromodomain helicase DNA-binding protein 1 (CHD1). Expression of CHD1 was significantly reduced in tumors with deletion (P=0.03), and compared with normal prostate (P=0.04). Exon sequencing analysis also uncovered nonsynonymous mutations in 1 out of 7 (14%) cell lines (LAPC4) and in 1 out of 24 (4%) prostate tumors surveyed. RNA interference-mediated knockdown of CHD1 in two nontumorigenic prostate epithelial cell lines, OPCN2 and RWPE-1, did not alter cell growth, but promoted cell invasiveness, and in OPCN2-enhanced cell clonogenicity. Taken together, our findings suggest that CHD1 deletion may underlie cell invasiveness in a subset of prostate cancers, and indicate a possible novel role of altered chromatin remodeling in prostate tumorigenesis.

Temperature-independent silicon subwavelength grating waveguides.

We demonstrate, by experiment and numerical calculations, temperature-independent subwavelength grating waveguides with a periodic composite core composed of alternating regions of silicon and SU-8 polymer. The polymer has a negative thermo-optic (TO) material coefficient that cancels the large positive TO effect of the silicon. Measurements and Bloch mode calculations were carried out over a range of silicon-polymer duty ratios. The lowest measured TO coefficient at a wavelength of 1550 nm is 1.8×10(-6) K(-1); 2 orders of magnitude smaller than a conventional silicon photonic wire waveguide. Calculations predict the possibility of complete cancellation of the silicon waveguide temperature dependence.

Comparative assessment of drug-eluting balloons in an advanced porcine model of coronary restenosis.

The advent of drug-eluting balloon (DEB) therapy has represented an important development in interventional cardiology. Nevertheless, preclinical data with this technology remain scant, and comparative studies have not previously been published. Bare metal stents were implanted in the coronary arteries of 15 pigs followed by balloon angioplasty. Animals were allocated to treatment with a 60-second inflation of one of four different balloon catheters: a conventional untreated plain angioplasty balloon (PBA, Biotronik AG), the Pantera Lux DEB (3.0 µg/mm2 paclitaxel; BTHC excipient, Biotronik AG), the Elutax DEB (2.0 µg/mm2 paclitaxel; no excipient; Aachen Resonance), or the SeQuent Please DEB (3.0 µg/mm2 paclitaxel; iopromide excipient: B. Braun). Twenty-eight days following balloon deployment, animals underwent repeat angiography for quantitative coronary angiography analysis and euthanasia for histopathologic assessment. By histology, the mean neointimal thickness was 0.44 ± 0.19 mm with PBA, 0.35 ± 0.13 mm with Pantera Lux , 0.61 ± 0.20 mm with Elutax , and 0.47 ± 0.21 mm with SeQuent Please DEB (p=0.02). In comparison with PBA, deployment of the Pantera Lux or the SeQuent Please DEB resulted in delayed healing characterised by significant increases in fibrin, neointimal cell vacuity and delayed re-endothelialisation. In conclusion, investigation of comparative DEB performance in a porcine model of advanced coronary restenosis reveals significant heterogeneity of neointimal suppression between the devices tested with numerically lowest values seen in the Pantera Lux group. On the other hand, evidence of delayed healing was observed in the most effective DEB groups.

The whey fermentation product malleable protein matrix decreases triglyceride concentrations in subjects with hypercholesterolemia: a randomized placebo-controlled trial.

Malleable protein matrix (MPM) is a unique whey-derived ingredient obtained through a fermentation process using proprietary lactic acid bacteria strains from the Lactobacillus kefiranofaciens species. Because evidence from animal models suggests that MPM decreases serum lipid concentrations, the purpose of the present trial was to assess the hypothesis that MPM exerts lipid-lowering effects in humans. A total of 161 subjects (50% male; age 54.5 ± 9.8 yr, body mass index 26.3 ± 3.6 kg/m(2)) with hypercholesterolemia with baseline low-density lipoprotein cholesterol (LDL-C) levels of 181 ± 30 mg/dL and normal triglyceride (TG) levels (131 ± 55 mg/dL) were randomized to receive MPM (2 × 15 g/d) or matching placebo. A 6-wk run-in phase was followed by a double-blind 12-wk treatment phase after randomization. The data were analyzed on an intention-to-treat basis. The primary outcome measure was the percentage change of LDL-C. The secondary outcome measures were changes in TG and high-density lipoprotein cholesterol concentrations as well as changes in other cardiovascular risk factors. After 12 wk of treatment, the relative TG decrease from baseline reached 9.8%, whereas LDL-C was slightly decreased (by 1.5%) following MPM treatment compared with placebo in the intention-to-treat cohort. The treatment effect on TG reduction was much higher in the subset of subjects having TG levels at baseline of 150 mg/dL or above (n=42), reaching 20.0% compared with placebo. High-density lipoprotein cholesterol concentrations, blood pressure, and fasting blood glucose remained unchanged, whereas a positive treatment effect was seen on hemoglobin A(1c). The MPM product was tolerated well without severe adverse events. In conclusion, MPM has significant TG-lowering properties in subjects with combined hypercholesterolemia and higher TG levels. Its effects on LDL-C concentrations and glucose metabolism deserve further investigation.

Real-time cancellation of temperature induced resonance shifts in SOI wire waveguide ring resonator label-free biosensor arrays.

A comprehensive investigation of real-time temperature-induced resonance shift cancellation for silicon wire based biosensor arrays is reported for the first time. A reference resonator, protected by either a SU8 or SiO(2) cladding layer, is used to track temperature changes. The temperature dependence of resonators in aqueous solutions, pertinent to biosensing applications, is measured under steady-state conditions and the operating parameters influencing these properties are discussed. Real-time measurements show that the reference resonator resonances reflect the temperature changes without noticeable time delay, enabling effective cancellation of temperature-induced shifts. Binding between complementary IgG protein pairs is monitored over 4 orders of magnitude dynamic range down to a concentration of 20 pM, demonstrating a resolvable mass of 40 attograms. Reactions are measured over time periods as long as 3 hours with high stability, showing a scatter corresponding to a fluid refractive index fluctuation of ± 4 × 10(-6) in the baseline data. Sensor arrays with a SU8 protective cladding are easy to fabricate, while oxide cladding is found to provide superior stability for measurements involving long time scales.

Continuously apodized fiber-to-chip surface grating coupler with refractive index engineered subwavelength structure.

We demonstrate a fully etched, continuously apodized fiber-to-chip surface grating coupler for the first time (to our knowledge). The device is fabricated in a single-etch step and operates with TM-polarized light, achieving a coupling efficiency of 3.7 dB and a 3 dB bandwidth of 60 nm. A subwavelength microstructure is employed to generate an effective medium engineered to vary the strength of the grating and thereby maximize coupling efficiency, while mitigating backreflections at the same time. Minimum feature size is 100 nm for compatibility with deep-UV 193 nm lithography.

A 'living' prosthetic iris.

AIM: To design and demonstrate dynamic pupils, which react to light for use with ocular prostheses. METHODS: The realism of ocular prostheses is limited by the immobility of the pupil. Our solution is to use a liquid crystal display (LCD) in the prosthesis to vary the pupil size as a function of the ambient light. Several liquid crystal cells were fabricated and tested for survivability through the ocular prosthesis manufacturing process. The dynamic pupil is controlled by a novel and entirely autonomous, self-powered passive electronic circuit using a solar cell, matching the minimum diameter of the pupil. RESULTS: The first LCD surviving the rugged conditions of the ocular prosthesis manufacturing steps and an entirely passive circuit controlling the pupil have been demonstrated for the first time to our knowledge. A design for a complete prosthesis with a dynamic pupil has been proposed. Finally, a standard device for the mass production of ocular prostheses is presented. CONCLUSION: We have shown that a practical solution for an autonomous self-powered dynamic pupil is possible, given the constraints of size, fabrication process, weight, cost and manufacturability on a mass scale. We envision that the LCD could be mass produced, and only the final steps for the integration of the iris matched to a patient would be necessary before assembly using standard processing steps for the production of the prosthesis. Using a clinical trial, we hope to demonstrate that the dynamic pupil will have a positive impact on the quality of life of patients.