N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer.

BACKGROUND & AIMS: N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated. METHODS: YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP). RESULTS: DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo. CONCLUSIONS: We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.

Novel Strategy to Drive the Intracellular Uptake of Lipid Nanoparticles for Photodynamic Therapy.

Nanoparticles' uptake by cancer cells upon reaching the tumor microenvironment is often the rate-limiting step in cancer nanomedicine. Herein, we report that the inclusion of aminopolycarboxylic acid conjugated lipids, such as EDTA- or DTPA-hexadecylamide lipids in liposome-like porphyrin nanoparticles (PS) enhanced their intracellular uptake by 25-fold, which was attributed to these lipids' ability to fluidize the cell membrane in a detergent-like manner rather than by metal chelation of EDTA or DTPA. EDTA-lipid-incorporated-PS (ePS) take advantage of its unique active uptake mechanism to achieve >95 % photodynamic therapy (PDT) cell killing compared to <5 % cell killing by PS. In multiple tumor models, ePS demonstrated fast fluorescence-enabled tumor delineation within minutes post-injection and increased PDT potency (100 % survival rate) compared to PS (60 %). This study offers a new nanoparticle cellular uptake strategy to overcome challenges associated with conventional drug delivery.

Nanostructure-Driven Indocyanine Green Dimerization Generates Ultra-Stable Phototheranostics Nanoparticles.

Indocyanine green (ICG) is the only near-infrared (NIR) dye approved for clinical use. Despite its versatility in photonic applications and potential for photothermal therapy, its photobleaching hinders its application. Here we discovered a nanostructure of dimeric ICG (Nano-dICG) generated by using ICG to stabilize nanoemulsions, after which ICG enabled complete dimerization on the nanoemulsion shell, followed by J-aggregation of ICG-dimer, resulting in a narrow, red-shifted (780 nm→894 nm) and intense (≈2-fold) absorbance. Compared to ICG, Nano-dICG demonstrated superior photothermal conversion (2-fold higher), significantly reduced photodegradation (-9.6 % vs. -46.3 %), and undiminished photothermal effect (7 vs. 2 cycles) under repeated irradiations, in addition to excellent colloidal and structural stabilities. Following intravenous injection, Nano-dICG enabled real-time tracking of its delivery to mouse tumors within 24 h by photoacoustic imaging at NIR wavelength (890 nm) distinct from the endogenous signal to guide effective photothermal therapy. The unprecedented finding of nanostructure-driven ICG dimerization leads to an ultra-stable phototheranostic platform.

Prolonged Circulating Lipid Nanoparticles Enabled by High-Density Gd-DTPA-Bis(stearylamide) for Long-Lasting Enhanced Tumor Magnetic Resonance Imaging.

Porphysomes (PS) were explored to incorporate different types of diethylenetriaminepentaacetic-acid-gadolinium-(III) (Gd-DTPA)-lipids into their bilayer membrane to assess PS potential as an MRI contrast agent. The Gd-dPS-BSA by integration of over 30% Gd-DTPA-bis(stearylamide) (Gd-DTPA-BSA)-lipids in PS construction resulted in exceptional serum stability and T1 and T2 relaxivity measurements of 13 mM-1 s-1 and 19 mM-1 s-1, respectively. The Gd-dPS-BSA demonstrated significantly enhanced retention in blood circulation with a half-life of 13.6 h and high tumor accumulation up to 19.5%ID/g at 72 h post-injection in select cancer mouse models. Additionally, Gd-dPS-BSA displayed excellent MRI tumor enhancement over 24, 48, and 72 h with contrast enhancements from the baseline of 35.8%, 38.2%, and 38.3%, respectively. Results reported here highlight a high-density incorporation of Gd-DTPA-BSA-lipids within PS, and other liposome formulations can enhance circulatory longevity, independently of particles' concentration, suggesting effective MRI contrast agent potential for Gd-dPS-BSA and potential utility of Gd-DTPA-BSA-lipids to enhance other liposomal-influenced diagnostic and therapeutic functions.

The dose threshold for nanoparticle tumour delivery.

Nanoparticle delivery to solid tumours over the past ten years has stagnated at a median of 0.7% of the injected dose. Varying nanoparticle designs and strategies have yielded only minor improvements. Here we discovered a dose threshold for improving nanoparticle tumour delivery: 1 trillion nanoparticles in mice. Doses above this threshold overwhelmed Kupffer cell uptake rates, nonlinearly decreased liver clearance, prolonged circulation and increased nanoparticle tumour delivery. This enabled up to 12% tumour delivery efficiency and delivery to 93% of cells in tumours, and also improved the therapeutic efficacy of Caelyx/Doxil. This threshold was robust across different nanoparticle types, tumour models and studies across ten years of the literature. Our results have implications for human translation and highlight a simple, but powerful, principle for designing nanoparticle cancer treatments.

Porphyrin-lipid stabilized paclitaxel nanoemulsion for combined photodynamic therapy and chemotherapy.

BACKGROUND: Porphyrin-lipids are versatile building blocks that enable cancer theranostics and have been applied to create several multimodal nanoparticle platforms, including liposome-like porphysome (aqueous-core), porphyrin nanodroplet (liquefied gas-core), and ultrasmall porphyrin lipoproteins. Here, we used porphyrin-lipid to stabilize the water/oil interface to create porphyrin-lipid nanoemulsions with paclitaxel loaded in the oil core (PLNE-PTX), facilitating combination photodynamic therapy (PDT) and chemotherapy in one platform. RESULTS: PTX (3.1 wt%) and porphyrin (18.3 wt%) were loaded efficiently into PLNE-PTX, forming spherical core-shell nanoemulsions with a diameter of 120 nm. PLNE-PTX demonstrated stability in systemic delivery, resulting in high tumor accumulation (~ 5.4 ID %/g) in KB-tumor bearing mice. PLNE-PTX combination therapy inhibited tumor growth (78%) in an additive manner, compared with monotherapy PDT (44%) or chemotherapy (46%) 16 days post-treatment. Furthermore, a fourfold reduced PTX dose (1.8 mg PTX/kg) in PLNE-PTX combination therapy platform demonstrated superior therapeutic efficacy to Taxol at a dose of 7.2 mg PTX/kg, which can reduce side effects. Moreover, the intrinsic fluorescence of PLNE-PTX enabled real-time tracking of nanoparticles to the tumor, which can help inform treatment planning. CONCLUSION: PLNE-PTX combining PDT and chemotherapy in a single platform enables superior anti-tumor effects and holds potential to reduce side effects associated with monotherapy chemotherapy. The inherent imaging modality of PLNE-PTX enables real-time tracking and permits spatial and temporal regulation to improve cancer treatment.

Network meta-analysis of the treatment efficacy of different lasers for peri-implantitis.

The aim of this study was comparing different lasers with conventional non-surgical treatment (CNT) for the management of peri-implantitis, regarding probing depth (PD), plaque index (PLI), clinical attachment level (CAL), and sulcus bleeding index (SBI). Randomized controlled trials (RCTs) on different lasers and CNT for peri-implantitis were searched. Pairwise and network meta-analyses were performed to analyze the PD, PLI, CAL, and SBI outcomes. The risk of bias, evidence quality, statistical heterogeneity, and ranking probability were also evaluated. Eleven studies were included in this study, involving three types of lasers. Diode + CNT had significantly superior efficacy to CNT alone, regarding PD reduction, while Er:YAG + CNT had significantly superior efficacy than CNT in terms of the PLI, CAL, and SBI. The highest probability of being most effective for PD was diode + CNT (49%), while Er:YAG + CNT had the highest probability of improving the PLI, CAL, and SBI (66%, 53%, and 79%, respectively). Diode + CNT was significantly superior for PD management in peri-implantitis compared with CNT alone, while Er:YAG + CNT significantly improved the PLI, CAL, and SBI. Therefore, Er:YAG + CNT might be recommended methods considered for management of peri-implantitis.

Rational Design of Photosynthesis-Inspired Nanomedicines.

The sun is the most abundant source of energy on earth. Phototrophs have discovered clever strategies to harvest this light energy and convert it to chemical energy for biomass production. This is achieved in light-harvesting complexes, or antennas, that funnel the exciton energy into the reaction centers. Antennas contain an array of chlorophylls, linear tetrapyrroles, and carotenoid pigments spatially controlled by neighboring proteins. This fine-tuned regulation of protein-pigment arrangements is crucial for survival in the conditions of both excess and extreme light deficit. Photomedicine and photodiagnosis have long been utilizing naturally derived and synthetic monomer dyes for imaging, photodynamic and photothermal therapy; however, the precise regulation of damage inflicted by these therapies requires more complex architectures. In this Account, we discuss how two mechanisms found in photosynthetic systems, photoprotection and light harvesting, have inspired scientists to create nanomedicines for more effective and precise phototherapies. Researchers have been recapitulating natural photoprotection mechanisms by utilizing carotenoids and other quencher molecules toward the design of photodynamic molecular beacons (PDT beacons) for disease-specific photoactivation. We highlight the seminal studies describing peptide-linked porphyrin-carotenoid PDT beacons, which are locally activated by a disease-specific enzyme. Examples of more advanced constructs include tumor-specific mRNA-activatable and polyionic cell-penetrating PDT beacons. An alternative approach toward harnessing photosynthetic processes for biomedical applications includes the design of various nanostructures. This Account will primarily focus on organic lipid-based micro- and nanoparticles. The phenomenon of nonphotochemical quenching, or excess energy release in the form of heat, has been widely explored in the context of porphyrin-containing nanomedicines. These quenched nanostructures can be implemented toward photoacoustic imaging and photothermal therapy. Upon nanostructure disruption, as a result of tissue accumulation and subsequent cell uptake, activatable fluorescence imaging and photodynamic therapy can be achieved. Alternatively, processes found in nature for light harvesting under dim conditions, such as in the deep sea, can be harnessed to maximize light absorption within the tissue. Specifically, high-ordered dye aggregation that results in a bathochromic shift and increased absorption has been exploited for the collection of more light with longer wavelengths, characterized by maximum tissue penetration. Overall, the profound understanding of photosynthetic systems combined with rapid development of nanotechnology has yielded a unique field of nature-inspired photomedicine, which holds promise toward more precise and effective phototherapies.

Vepoloxamer Enhances Fibrinolysis of tPA (Tissue-Type Plasminogen Activator) on Acute Ischemic Stroke.

Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.

Stable J-Aggregation of an aza-BODIPY-Lipid in a Liposome for Optical Cancer Imaging.

Organic building blocks are the centerpieces of "one-for-all" nanoparticle development. Herein, we report the synthesis of a novel aza-BODIPY-lipid building block and its self-assembly into a liposomal nanoparticle (BODIPYsome). We observed optically stable NIR J-aggregation within the BODIPYsome that is likely attributed to J-dimerization. BODIPYsomes with cholesterol showed enhanced colloidal stability while maintaining a high extinction coefficient (128 mm-1 cm-1 ) and high fluorescence quenching (99.70±0.09 %), which enables photoacoustic (PA) properties from its intact structure and recovered NIR fluorescence properties when it is disrupted in cancer cells. Finally, its capabilities for optical imaging (PA/fluorescence) were observed in an orthotopic prostate tumor mouse model 24 h after intravenous administration. Overall, the BODIPYsome opens the door for engineering new building blocks in the design of optically stable biophotonic imaging agents.

Effect of Lasers on Dentine Hypersensitivity: Evidence From a Meta-analysis.

OBJECTIVES: The aim of the study was to evaluate the immediate and long-term desensitizing effect of lasers in reducing dentine hypersensitivity (DH) compared with negative controls. MATERIAL AND METHODS: Six databases were searched to identify relevant articles published up to June 8, 2018. Randomized controlled trials comparing lasers with placebo or no treatment control in adult patients who suffer from DH were included. The risk of bias was assessed according to the Cochrane guidelines, and the quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation tool. Inverse-variance random effects meta-analyses of standardized mean differences and 95% confidence intervals were performed using the RevMan 5.3 software. RESULTS: Twenty-two randomized controlled trials were finally included in the meta-analysis, and 21 studies of these were conducted to analyze the immediate and long-term effects. All types of lasers had better immediate and long-term desensitizing effects on DH than negative controls. The quality of evidence of the included studies showed that lasers compared with negative controls had moderate-quality immediate and long-term effects on DH. The statistical heterogeneity of these comparisons was high, for which the result of I2 ranged from 90% to 98%. CONCLUSIONS: Our results indicate that all types of lasers had a better desensitizing effect on DH than negative controls, both in immediate and long term. Furthermore, more high-quality studies with a large sample size are needed to confirm our results (PROSPERO CRD42018102260).

Porous zirconia ceramic as an alternative to dentin for in vitro dentin barriers cytotoxicity test.

OBJECTIVES: This study assessed the potential of porous zirconia ceramic as an alternative to dentin via an in vitro dentin barrier cytotoxicity test. METHODS: The permeability of dentin and porous zirconia ceramic was measured using a hydraulic-conductance system, and their permeability was divided into two groups: high and low. Using an in vitro dentin barrier test, the cytotoxicity of dental materials by dentin and porous zirconia ceramic was compared within the same permeability group. The L-929 cell viability was assessed by MTT assay. RESULTS: The mean (SD) permeability of the high and low group for dentin was 0.334 (0.0873) and 0.147 (0.0377) µl min-1 cm-2 cm H2O-1 and for zirconia porous ceramic was 0.336 (0.0609) and 0.146 (0.0340) µl min-1 cm-2 cm H2O-1. The cell viability of experimental groups which are the low permeability group was higher than that of the high permeability group for both dentin and porous zirconia ceramic as a barrier except for Maxcem Elite™ by porous zirconia ceramic. There was no significant difference between dentin and porous zirconia ceramic in cell viability, within either the high or low permeability group for all materials. The SD for cell viability of the porous zirconia ceramic was less than that of the dentin, across all materials within each permeability group, except for Maxcem Elite™ in the high permeability group. CONCLUSIONS: Porous zirconia ceramic, having similar permeability to dentin at the same thickness, can be used as an alternative to dentin for in vitro dentin barrier cytotoxicity tests. CLINICAL RELEVANCE: In vitro dentin barrier cytotoxicity tests when a standardized porous zirconia ceramic was used as a barrier could be useful for assessing the potential toxicity of new dental materials applied to dentin before applying in clinical and may resolve the issue of procuring human teeth when testing proceeds.

Synthesis and Characterization of ß-Tricalcium Phosphate Derived From Haliotis sp. Shells.

PURPOSE: To develop a methodology for the synthesis of ß-tricalcium phosphate (ß-TCP, Ca3(PO4)2) from the shell of Haliotis sp. (abalone shell) and to verify its characterization and biocompatibility. MATERIALS AND METHODS: Calcium oxide (CaO) was synthesized from abalone shell by sintering and was suspended in distilled water to prepare calcium hydroxide (Ca(OH)2). For the synthesis of calcium carbonate (CaCO3), carbon dioxide was used to infuse Ca(OH)2 at pH 7.4. CaCO3 was reacted with phosphoric acid at pH 6.0 to obtain dicalcium phosphate (CaHPO4). Subsequently, ß-TCP was synthesized by a chemical reaction between CaHPO4 and CaO at 950°C to 1100°C for 3 hours. Fourier transform infrared spectroscopy (FT-IR) and x-ray diffraction (XRD) was performed to verify the physiochemical characteristics of the composite synthesized from abalone shell. RESULTS: FT-IR and XRD results showed that ß-TCP was successfully synthesized from abalone shell. The synthesized ß-TCP did not affect cell viability of either normal human oral keratinocytes or osteoblastic MG-63 cells. These data indicate that ß-TCP synthesized from abalone shell is biologically safe. CONCLUSIONS: ß-TCP (Ca3(PO4)2) synthesized from abalone shell can be used as a potential source of bone grafting material.

Effects of desensitizing toothpastes on the permeability of dentin after different brushing times: An in vitro study.

PURPOSE: To investigate the effects of three commercially available desensitizing toothpastes on dentin permeability, and compare the efficacy of each product for reducing dentin permeability in the short term according to the frequency and duration of usage. METHODS: 100 dentin discs with no caries were prepared from freshly extracted human third molar teeth. The dentin discs were brushed with three desensitizing toothpastes or with a non-desensitizing toothpaste and distilled water, which served as control. The 100 dentin slices were randomly divided into two groups (n= 50): one group underwent continuous brushing (brushed for 3 minutes continuously), and the other group underwent discontinuous brushing (brushed three times, each time for 1 minute). Then, the two groups were divided into five subgroups (n = 10) for the five brushing applications. Dentin permeability was measured with a hydraulic permeability system before and after brushing. RESULTS: All desensitizing toothpastes reduced dentin permeability significantly after treatment. Sensodyne Repair and Protect (calcium sodium phosphosilicate) and discontinuous brushing reduced dentin permeability significantly compared with continuous brushing. Dentin permeability values showed no significant difference between the three toothpastes after 3 minutes of continuous brushing. When comparing the three toothpastes under discontinuous brushing conditions after 3 minutes, Sensodyne Repair and Protect (calcium sodium phosphosilicate) reduced dentin permeability significantly. CLINICAL SIGNIFICANCE: Sensodyne Repair and Protect (calcium sodium phosphosilicate) and discontinuous brushing reduced dentin permeability significantly compared with continuous brushing. Moreover, brushing with Sensodyne Repair and Protect (calcium sodium phosphosilicate) resulted in the lowest dentin permeability compared with those of the other two toothpastes. These results indicated that Sensodyne Repair and Protect may relieve dentin hypersensitivity.

Controlling Spatial Heat and Light Distribution by Using Photothermal Enhancing Auto-Regulated Liposomes (PEARLs).

Photothermal therapy (PTT) is enhanced by the use of nanoparticles with a large optical absorption at the treatment wavelength. However, this comes at the cost of higher light attenuation that results in reduced depth of heating as well as larger thermal gradients, leading to potential over- and under-treatment in the target tissue. These limitations can be overcome by using photothermal enhancing auto-regulating liposomes (PEARLs), based on thermochromic J-aggregate forming dye-lipid conjugates that reversibly alter their absorption above a predefined lipid phase-transition temperature. Under irradiation by near-infrared light, deeper layers of the target tissue revert to the intrinsic optical absorption, halting the temperature rise and enabling greater light penetration and heat generation at depth. This effect is demonstrated in both nanoparticle solutions and in gel phantoms containing the nanoparticles.

Theranostic lipid nanoparticles for cancer medicine.

Disease heterogeneity within and between patients necessitates a patient-focused approach to cancer treatment. This exigency forms the basis for the medical practice termed personalized medicine. An emerging, important component of personalized medicine is theranostics. Theranostics describes the co-delivery of therapeutic and imaging agents in a single formulation. Co-delivery enables noninvasive, real-time visualization of drug fate, including drug pharmacokinetic and biodistribution profiles and intratumoral accumulation. These technological advances assist drug development and ultimately may translate to improved treatment planning at the bedside. Nanocarriers are advantageous for theranostics as their size and versatility enables integration of multiple functional components in a single platform. This chapter focuses on recent developments in advanced lipid theranostic nanomedicine from the perspective of the "all-in-one" or the "one-for-all" approach. The design paradigm of "all-in-one" is the most common approach for assembling theranostic lipid nanoparticles, where the advantages of theranostics are achieved by combining multiple components that each possesses a specific singular function for therapeutic activity or imaging contrast. We will review lipoprotein nanoparticles and liposomes as representatives of the "all-in-one" approach. Complementary to the "all-in-one" approach is the emerging paradigm of the "one-for-all" approach where nanoparticle components are intrinsically multifunctional. We will discuss the "one-for-all" approach using porphysomes as a representative. We will further discuss how the concept of "one-for-all" might overcome the regulatory hurdles facing theranostic lipid nanomedicine.

Determining color difference thresholds in denture base acrylic resin.

STATEMENT OF PROBLEM: In restorative prostheses, color is important, but the choice of color difference formula used to quantify color change in acrylic resins is not straightforward. PURPOSE: The purpose of this in vitro study was to choose a color difference formula that best represented differences between the calculated color and the observed imperceptible to unacceptable color and to determine the corresponding perceptibility and acceptability threshold of color stability for denture base acrylic resins. MATERIAL AND METHODS: A total of 291 acrylic resin denture base plates were fabricated and subjected to radiation tests from zero to 42 hours in accordance with ISO 7491:2000. Color was measured with a portable spectrophotometer, and color differences were calculated with 3 International Commission on Illumination (CIE) formulas: CIELab, CMC(1:1), and CIEDE2000. Thirty-four observers with no deficiencies in color perception participated in psychophysical perceptibility and acceptability assessments under controlled conditions in vitro. These 2 types of assessments were regressed to each observer by each formula to generate receiver operator characteristic (ROC) curves. Areas under the curves (AUCs) were then calculated and analyzed to exclude observers with poor color discrimination. AUCs were subjected to 1-way ANOVA (α=.05) to deter the statistical significance of discriminability among the 3 formulas in terms of perceptibility and acceptability judgments. Student-Newman-Keuls tests (α=.05) were used for post hoc comparison. RESULTS: CMC(1:1) and CIEDE2000 formulas performed better for imperceptible to unacceptable color differences, with corresponding CMC(1:1) and CIEDE2000 values for perceptibility of 2.52 and 1.72, respectively, and acceptability thresholds of 6.21 and 4.08, respectively. CONCLUSIONS: Formulas CMC(1:1) and CIEDE2000 possess higher discriminability than that of CIELab in the assessment of perceptible color difference threshold of denture base acrylic resin. A statistically significant difference exists between perceptibility and acceptability thresholds for denture base acrylic resin.

Optically controlled pore formation in self-sealing giant porphyrin vesicles.

Efforts to develop self-contained microreactors and artificial cells have been limited by difficulty in generating membranes that can be robustly and repeatedly manipulated to load and release cargo from phospholipid compartments. Here we describe a purely optical method to form pores in a membrane generated from porphyrin-phospholipid conjugates electro-assembled into microscale giant porphyrin vesicles and manipulated using confocal microscopy. The pores in the membrane resealed within a minute allowing for repeated pore formation with precise spatial and temporal control and optical gating to allow selective diffusion of biomolecules across the membrane. Temporal control of pore formation was illustrated by performing sequential DNA hybridization reactions. A biotin-avidin based strategy was developed to selectively attach enzymes to the interior of the vesicle, demonstrating spatial control and the potential of giant porphyrin vesicles as versatile microreactors.

Nanoparticle-enabled, image-guided treatment planning of target specific RNAi therapeutics in an orthotopic prostate cancer model.

The abilities to deliver siRNA to its intended action site and assess the delivery efficiency are challenges for current RNAi therapy, where effective siRNA delivery will join force with patient genetic profiling to achieve optimal treatment outcome. Imaging could become a critical enabler to maximize RNAi efficacy in the context of tracking siRNA delivery, rational dosimetry and treatment planning. Several imaging modalities have been used to visualize nanoparticle-based siRNA delivery but rarely did they guide treatment planning. We report a multimodal theranostic lipid-nanoparticle, HPPS(NIR)-chol-siRNA, which has a near-infrared (NIR) fluorescent core, enveloped by phospholipid monolayer, intercalated with siRNA payloads, and constrained by apoA-I mimetic peptides to give ultra-small particle size (<30 nm). Using fluorescence imaging, we demonstrated its cytosolic delivery capability for both NIR-core and dye-labeled siRNAs and its structural integrity in mice through intravenous administration, validating the usefulness of NIR-core as imaging surrogate for non-labeled therapeutic siRNAs. Next, we validated the targeting specificity of HPPS(NIR)-chol-siRNA to orthotopic tumor using sequential four-steps (in vivo, in situ, ex vivo and frozen-tissue) fluorescence imaging. The image co-registration of computed tomography and fluorescence molecular tomography enabled non-invasive assessment and treatment planning of siRNA delivery into the orthotopic tumor, achieving efficacious RNAi therapy.

Assisting drinking with an affordable BCI-controlled wearable robot and electrical stimulation: a preliminary investigation.

BACKGROUND: The aim of the present study is to demonstrate, through tests with healthy volunteers, the feasibility of potentially assisting individuals with neurological disorders via a portable assistive technology for the upper extremities (UE). For this purpose the task of independently drinking a glass of water was selected, as it is one of the most basic and vital activities of the daily living that is unfortunately not achievable by individuals severely affected by stroke. METHODS: To accomplish the aim of this study we introduce a wearable and portable system consisting of a novel lightweight Robotic Arm Orthosis (RAO), a Functional Electrical Stimulation (FES) system, and a simple wireless Brain-Computer Interface (BCI). This system is able to process electroencephalographic (EEG) signals and translate them into motions of the impaired arm. Five healthy volunteers participated in this study and were asked to simulate stroke patient symptoms with no voluntary control of their hand and arm. The setup was designed such as the volitional movements of the healthy volunteers' UE did not interfere with the evaluation of the proposed assistive system. The drinking task was split into eleven phases of which seven were executed by detecting EEG-based signals through the BCI. The user was asked to imagine UE motion related to the specific phase of the task to be assisted. Once detected by the BCI the phase was initiated. Each phase was then terminated when the BCI detected the volunteers clenching their teeth. RESULTS: The drinking task was completed by all five participants with an average time of 127 seconds with a standard deviation of 23 seconds. The incremental motions of elbow extension and elbow flexion were the primary limiting factors for completing this task faster. The BCI control along with the volitional motions also depended upon the users pace, hence the noticeable deviation from the average time. CONCLUSION: Through tests conducted with healthy volunteers, this study showed that our proposed system has the potential for successfully assisting individuals with neurological disorders and hemiparetic stroke to independently drink from a glass.