Personalized, tumor-informed, circulating tumor DNA assay for detecting minimal residual disease in non-small cell lung cancer patients receiving curative treatments.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for detection of minimal residual disease (MRD), monitoring treatment response, and early detection of recurrence in cancer patients. In this study, we explored the utility of ctDNA-based MRD detection to predict recurrence in a real-world cohort of primarily early-stage non-small cell lung cancer (NSCLC) patients treated with curative intent. METHODS: Longitudinal plasma samples were collected post curative-intent treatment from 36 patients with stage I-IV NSCLC. A personalized, tumor-informed assay was used to detect and quantify ctDNA in plasma samples. RESULTS: Of the 24 patients with plasma samples available during the MRD window (within 6 months of curative surgery and before adjuvant therapy), ctDNA was detectable in two patients. Patients with ctDNA-positivity during the MRD window were 15 times more likely to recur compared to ctDNA-negative patients (HR: 15.0, 95% CI: 1.0-253.0, p = 0.010). At any time post-curative intent treatment, ctDNA-positivity was associated with significantly poorer recurrence-free survival compared to persistently ctDNA-negative patients (p < 0.0001). CONCLUSION: Our real-world data indicate that longitudinal, personalized, tumor-informed ctDNA monitoring is a valuable tool in patients with NSCLC receiving curative treatment to identify patients at high risk for recurrence.

Redefining Clinical Hyperprogression: The Incidence, Clinical Implications, and Risk Factors of Hyperprogression in Non-Small Cell Lung Cancer Treated with Immunotherapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) may be associated with hyperprogressive disease (HPD). However, there is currently no standardized definition of HPD, with its risk factors and clinical implications remaining unclear. We investigated HPD in lung cancer patients undergoing immunotherapy, aiming to redefine HPD, identify risk factors, and assess its impact on survival. METHODS: Clinical and radiologic data from 121 non-small cell lung cancer (NSCLC) patients with 136 immunotherapy cases were reviewed retrospectively. Three HPD definitions (Champiat et al., HPDc; Saâda-Bouzid et al., HPDs; and Ferrara et al., HPDf) were employed. Additionally, all new measurable lesions on the post-treatment CT scan were incorporated in measuring the sum of longest diameters (SLD) to define modified HPD (mHPD). RESULTS: Among the 121 patients, 4 (3.3%) had HPDc, 11 (9.1%) had HPDs, and none had HPDf. Adding all new measurable lesions increased HPD incidence by 5%-10% across definitions. Multivariate analysis revealed significantly lower progression-free survival (PFS) and overall survival (OS) for patients with HPDc (HR 5.25, P = .001; HR 3.75, P = .015) and HPDs (HR 3.74, P < .001; HR 3.46, P < .001) compared to those without. Patients with mHPD showed similarly poor survival outcomes as HPD patients. Liver metastasis at diagnosis was associated with HPDs, and a high tumor burden correlated with HPDc. CONCLUSIONS: The incidence and risk factors of HPD varied with different definitions, but mHPD identified more cases with poor outcomes. This comprehensive approach may enhance the identification of at-risk patients and lead to a better understanding of HPD in lung cancer during immunotherapy.

Deep response to a combination of mTOR inhibitor temsirolimus and dual immunotherapy of nivolumab/ipilimumab in poorly differentiated thyroid carcinoma with PTEN mutation: a case report and literature review.

Treating advanced thyroid cancer presents challenges due to its resistance to various treatment modalities, thereby limiting therapeutic options. To our knowledge, this study is the first to report the efficacy of temsirolimus in conjunction with dual immunotherapy of nivolumab/ipilimumab to treat heavily treated advanced PDTC. A 50-year-old female initially presented with a rapidly enlarging mass on her right neck. Subsequent diagnosis revealed poorly differentiated thyroid carcinoma, leading to a total thyroidectomy followed by post-operative radioablation therapy. After four years, an examination for persistent cough revealed a recurrence of the disease within multiple mediastinal nodes. Genetic analysis of blood samples uncovered somatic mutations in the tumor, specifically involving PTEN and TP53. The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. Consequently, temsirolimus, functioning as an mTOR inhibitor, was introduced as an adjunct to the nivolumab/ipilimumab regimen. This combination approach yielded remarkable clinical improvement and disease control for a duration of approximately six months. Temsirolimus likely suppressed the aberrantly activated PI3K/AKT/mTOR signaling pathway, facilitated by the PTEN genetic alteration, thus engendering an effective treatment response. This synergy between targeted agents and immunotherapy presents a promising therapeutic strategy for advanced PDTC patients with limited treatment alternatives. In previous clinical trials, mTOR inhibitors have demonstrated the ability to maintain stable disease (SD) in 65% to 74% for advanced thyroid cancer patients, including those with PDTC. When combined with other targeted therapies, the observed SD or partial response rates range from 80% to 97%. Many of these trials primarily involved differentiated thyroid carcinoma, with diverse genetic mutations. Thyroid cancer patients with alterations in the PI3K/mTOR/Akt appeared to benefit most from mTOR inhibitors. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

Effects of 4-week downhill treadmill walking on the vertebral angle and postural muscle activity in participants with thoracic kyphosis and forward head posture: A comparative longitudinal study.

BACKGROUND: Maintaining correct posture and optimal spine function has become an important issue due to the increased use of computers and smartphones. OBJECTIVE: To investigate the effect of a 4-week downhill treadmill exercise (DTWE) program on participants with thoracic kyphosis and forward head posture (FHP). METHODS: Twenty-eight male participants were randomly assigned to the DTWE (n= 14) or standard treadmill walking exercise (STWE) (n= 14) group. They performed 30-minute exercise three times a week for 4 weeks. The vertebral angle was measured using a three-dimensional (3D) motion analysis system. Surface electromyography (EMG) was performed to record muscle activity in the thoracic erector spinae (TES), sternocleidomastoid muscle (SCM), and cervical erector spinae (CES). RESULTS: The DTWE group showed significant increases in the craniovertebral angle (CVA) and TES EMG activity and significant decreases in the thoracic kyphosis angle and SCM and CES EMG activity compared with those shown by the STWE group following the intervention (p< 0.05). However, lumbar lordosis or pelvic tilt angles did not differ significantly between the groups after the intervention (p> 0.05). CONCLUSIONS: DTWE can be effective in reducing thoracic kyphosis and FHP without causing compensatory movements of the lumbar spine and pelvis.

Effectiveness of non-immersive virtual reality exercises for balance and gait improvement in older adults: A meta-analysis.

BACKGROUND: Virtual reality (VR)-based physical exercise is an innovative and effective intervention strategy for healthcare in older adults. OBJECTIVE: This meta-analysis aimed to clarify the effects of VR-based balance exercise programs on various balancing abilities of older adults. In addition, the effect size of each variable was computed by total exercise time, sensor type, avatar presence, and feedback type to determine influencing factors that lead to the success of VR-based rehabilitation programs. METHODS: The databases searched were PubMed/Medline, CINAHL, NDSL, and Google Scholar. Inclusion criteria were: (1) independent older adults; (2) non-immersive VR exercise; (3) randomized controlled design; (4) both balance and gait data; and (5) written in English and Korean. The studies without information to compute effect sizes were excluded. Standardized mean difference was used to analyze the effect size (d). RESULTS: Twenty-five studies were finally included in this study. The main findings of this meta-analysis were as follows: (1) Non-immersive VR-based balance exercises are moderately and largely effective for improving overall balance function, (2) VR balance exercise was more effective for static balance than for gait, (3) VR exercise is more effective when avatars are presented and KP is provided as feedback. CONCLUSION: Total exercise time and mode of feedback are influencing factors that affect the effectiveness of VR-based balance exercises.

Effects of In Vitro Combination of Nitric Oxide Donors and Hypochlorite on Acanthamoeba castellanii Viability.

Purpose: To investigate the combined anti-Acanthamoeba effects of nitric oxide (NO) donors and hypochlorite to maximize amoebicidal outcomes while minimizing damage to human corneal epithelial cells (HCECs). Methods: Acanthamoeba castellanii and primary cultured HCECs and keratocytes were treated with sodium hypochlorite (NaOCl), NO donors (sodium nitroprusside [SNP] and sodium nitrite [NaNO2]), or a combination of hypochlorite and NO donors. The viability of A. castellanii, HCECs, and keratocytes was assessed. Minimal inhibitory concentration (MIC) and fractional inhibitory concentration of NaOCl and NO donors were determined. The activation of mammalian targets of rapamycin (mTOR) and ERK and the expression of nitrite reductase and Nrf2 were assessed in HCECs using Western blot analysis. The cysticidal effects of combined NaOCl and NO donors were also evaluated. Results: A dose-dependent toxicity was observed in A. castellanii, HCECs, and keratocytes when treated with NaOCl and SNP. The range of tested NaNO2 concentrations showed no significant toxicity to HCECs; however, dose-dependent toxicity to A. castellanii was observed. The MIC of NaOCl against HCECs and A. castellanii was 8.0 mg/mL. The MIC of NaNO2 and SNP was 500 mM and 10 mM in both HCECs and A. castellanii, respectively. Weak attenuation of the mTOR and ERK phosphorylation was observed and Nrf2 expression decreased slightly after exposure of HCECs to 2.0 mg/mL NaOCl. For the combination treatment, NaOCl (0.125 mg/mL) was selected based on the safety of HCECs and the toxicity of A. castellanii. A more potent anti-Acanthamoeba effect and HCEC toxicity were observed when NaOCl was combined with SNP rather than NaNO2. Conclusions: Combined NaOCl and NO donors had a stronger anti-Acanthamoeba effect compared to either drug alone. Translational Relevance: This study demonstrates that the combined use of various drugs for the treatment of Acanthamoeba infection can enhance the anti-Acanthamoeba effect while minimizing the toxicity of the individual drug.

Effect of Magnetic Microparticles on Cultivated Human Corneal Endothelial Cells.

Purpose: To investigate effects of magnetic microparticles on movement of magnet controlled human corneal endothelial cells (HCECs). Methods: Immortalized HCEC line (B4G12) and primary culture of HCECs were exposed to two commercially available magnetic micro- or nanoparticles, SiMAG (average size 100 nm) and fluidMAG (average size <1000 nm). Cell viability assays and reactive oxygen species production assays were performed. Cellular structural changes, intracellular distribution of microparticles, and expression levels of proteins related to cellular survival were analyzed. Ex vivo human corneas were exposed to microparticles to further evaluate their effects. Magnetic particle-laden HCECs were cultured under the influence of a neodymium magnet. Results: No significant decrease of viability was found in HCECs after exposure to both magnetic particles at concentrations up to 20 µg/mL for 48 hours. However, high concentrations (40 µg/mL and 80 µg/mL) of SiMAG and FluidMAG significantly decreased viability in immortalized HCECs, and only 80 µg/mL of SiMAG and FluidMAG decreased viability in primary HCECs after 48 hours of exposure. There was relative stability of viability at various concentrations of magnetic particles, despite a dose-dependent increase of reactive oxygen species, lactate dehydrogenase, and markers of apoptosis. Ex vivo human cornea study further revealed that exposure to 20 µg/mL of SiMAG and fluidMAG for 72 hours was tolerable. Endocytosed magnetic particles were mainly localized in the cytoplasm. The application of a magnetic field during cell culture successfully demonstrated that magnetic particle-loaded HCECs moved toward the magnet area and that the population density of HCECs was significantly increased. Conclusions: We verified short-term effects of SiMAG and fluidMAG on HCECs and their ability to control movement of HCECs by an external magnetic field. Translational Relevance: A technology of applying magnetic particles to a human corneal endothelial cell culture and controlling the movement of cells to a desired area using a magnetic field could be used to increase cell density during cell culture or improve the localization of corneal endothelial cells injected into the anterior chamber to the back of the cornea.

Osteoporosis Pre-Screening Using Ensemble Machine Learning in Postmenopausal Korean Women.

As osteoporosis is a degenerative disease related to postmenopausal aging, early diagnosis is vital. This study used data from the Korea National Health and Nutrition Examination Surveys to predict a patient's risk of osteoporosis using machine learning algorithms. Data from 1431 postmenopausal women aged 40-69 years were used, including 20 features affecting osteoporosis, chosen by feature importance and recursive feature elimination. Random Forest (RF), AdaBoost, and Gradient Boosting (GBM) machine learning algorithms were each used to train three models: A, checkup features; B, survey features; and C, both checkup and survey features, respectively. Of the three models, Model C generated the best outcomes with an accuracy of 0.832 for RF, 0.849 for AdaBoost, and 0.829 for GBM. Its area under the receiver operating characteristic curve (AUROC) was 0.919 for RF, 0.921 for AdaBoost, and 0.908 for GBM. By utilizing multiple feature selection methods, the ensemble models of this study achieved excellent results with an AUROC score of 0.921 with AdaBoost, which is 0.1-0.2 higher than those of the best performing models from recent studies. Our model can be further improved as a practical medical tool for the early diagnosis of osteoporosis after menopause.

Effect of the manual stretching maneuver for hallux valgus.

BACKGROUND: Hallux valgus (HV), which is one of the most common musculoskeletal abnormalities of the foot, is defined as the medial deviation of the first metatarsophalangeal (MTP) joint and the lateral deviation of the great toe. OBJECTS: This study aimed to investigate the immediate effects of a manual stretching maneuver (MSM) in subjects with HV. METHODS: Twenty-five subjects with a total of 25 feet with mild HV participated in the study. The MSM, consisting of global stretching of the foot and toes, traction of the hallux, local stretching for hallux, and mobilization of the MTP joint of the hallux. The HV angle between the line of the first metatarsal bone and the proximal phalanx were measured using a goniometer. The cross-sectional area (CSA) of the AbdH was measured using ultrasonography. Zebris FDM was used to measure the static plantar pressure and the movement of the center of pressure (COP) standing on one foot. The dependent variables before and after treatment were compared using paired t-tests. The significance level was set at .05. RESULTS: The HV angle significantly decreased from 20.25° to 16.96°. The CSA of the AbdH significantly increased from 14.00 mm2 to 16.11 mm2. The peak pressure on the hallux and 1st, 2nd and 3rd metatarsals increased significantly. The contact area and total pressure on the hallux significantly increased. The sway of the COP on the length of the minor axis and velocity significantly decreased. CONCLUSION: This study suggests that the MSM can be effective in decreasing the HV angle in subjects with mild HV. However, further longitudinal clinical studies are required to investigate the long-term effects of the MSM in subjects with HV.

Retinal cytotoxicity of silica and titanium dioxide nanoparticles.

The retina plays a key role in human vision. It is composed of cells that are essential for vision signal generation. Thus far, conventional medications have been ineffective for treating retinal diseases because of the intrinsic blood-retinal barrier. Nanoparticles (NPs) are promising effective platforms for ocular drug delivery. However, nanotoxicity in the retinal tissue has not received much attention. This study used R28 cells (a retinal precursor cell line that originated from rats) to investigate the safety of two commonly used types of NPs: silica nanoparticles (SiO2NPs, 100 nm) and titanium dioxide nanoparticles (TiO2NPs, 100 nm). Cellular viability and reactive oxygen species generation were measured after 24, 48, and 72 h of exposure to each NP. Cellular autophagy and the mTOR pathways were evaluated. The retinal toxicity of the NPs was investigated in vivo in rat models. Both types of NPs were found to induce significant dose-dependent toxicity on the R28 cells. A significant elevation of reactive oxygen species generation was also observed. Increased autophagy and decreased mTOR phosphorylation were observed after SiO2NPs and TiO2NPs exposure. The diffuse apoptosis of the retinal cellular layers was detected after intravitreal injection.

Novel Corneal Endothelial Cell Carrier Couples a Biodegradable Polymer and a Mesenchymal Stem Cell-Derived Extracellular Matrix.

Here, we report a transparent, biodegradable, and cell-adhesive carrier that is securely coupled with the extracellular matrix (ECM) for corneal endothelial cell (CEC) transplantation. To fabricate a CEC carrier, poly(lactide-co-caprolactone) (PLCL) solution was poured onto the decellularized ECM (UMDM) derived from in vitro cultured umbilical cord blood-MSCs. Once completely dried, ECM-PLCL was then peeled off from the substrate. It was 20 µm thick, transparent, rich in fibronectin and collagen type IV, and easy to handle. Surface characterizations exhibited that ECM-PLCL was very rough (54.0 ± 4.50 nm) and uniformly covered in high density by ECM and retained a positive surface charge (65.2 ± 57.8 mV), as assessed via atomic force microscopy. Human CECs (B4G12) on the ECM-PLCL showed good cell attachment, with a cell density similar to the normal cornea. They could also maintain a cell phenotype, with nicely formed cell-cell junctions as assessed via ZO-1 and N-cadherin at 14 days. This was in sharp contrast to the CEC behaviors on the FNC-coated PLCL (positive control). A function-related marker, Na+/K+-ATPase, was also identified via western blot and immunofluorescence. In addition, primary rabbit CECs showed a normal shape and they could express structural and functional proteins on the ECM-PLCL. A simulation test confirmed that CECs loaded on the ECM-PLCL were successfully engrafted into the decellularized porcine corneal tissue, with a high engraftment level and cell viability. Moreover, ECM-PLCL transplantation into the anterior chamber of the rabbit eye for 8 weeks proved the maintenance of normal cornea properties. Taken together, this study demonstrates that our ECM-PLCL can be a promising cornea endothelium graft with an excellent ECM microenvironment for CECs.

Moxifloxacin releasing intraocular implant based on a cross-linked hyaluronic acid membrane.

Intraocular antibiotic delivery is an important technique to prevent bacterial infection after ophthalmic surgery, such as cataract surgery. Conventional drug delivery methods, such as antibiotic eye drops, have limitations for intraocular drug delivery due to the intrinsic barrier effect of the cornea. Therefore, frequent instillation of antibiotic eyedrops is necessary to reach a sufficient bactericidal concentration inside the eye. In this study, an intraocular implant, MXF-HA, that combines hyaluronic acid (HA) and moxifloxacin (MXF) was developed to increase the efficiency of intraocular drug delivery after surgery. MXF-HA is manufactured as a thin, transparent, yellow-tinted membrane. When inserted into the eye in a dry state, MXF-HA is naturally hydrated and settles in the eye, and the MXF contained therein is delivered by hydrolysis of the polymer over time. It was confirmed through in vivo experiments that MXF delivery was maintained in the anterior chamber of the eye at a concentration sufficient to inhibit Pseudomonas aeruginosa and Staphylococcus aureus for more than 5 days after implantation. These results suggest that MXF-HA can be utilized as a potential drug delivery method for the prevention and treatment of bacterial infections after ophthalmic surgery.

Co-relation with novel phosphorylation sites of IκBα and necroptosis in breast cancer cells.

BACKGROUND: Phosphorylation of NF-kappaB inhibitor alpha (IκBα) is key to regulation of NF-κB transcription factor activity in the cell. Several sites of IκBα phosphorylation by members of the IκB kinase family have been identified, but phosphorylation of the protein by other kinases remains poorly understood. We investigated a new phosphorylation site on IκBα and identified its biological function in breast cancer cells. METHODS: Previously, we observed that aurora kinase (AURK) binds IκBα in the cell. To identify the domains of IκBα essential for phosphorylation by AURK, we performed kinase assays with a series of IκBα truncation mutants. AURK significantly promoted activation of IκBα at serine 32 but not serine 36; by contrast, IκB kinase (IKK) family proteins activated both of these residues. We also confirmed phosphorylation of IκBα by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and nano-liquid chromatography hybrid quadrupole orbitrap mass spectrometer (nanoLC-MS/MS; Q-Exactive). RESULTS: We identified two novel sites of serine phosphorylation, S63 and S262. Alanine substitution of S63 and S262 (S63A and S262A) of IκBα inhibited proliferation and suppressed p65 transcription activity. In addition, S63A and/or S262A of IκBα regulated apoptotic and necroptotic effects in breast cancer cells. CONCLUSIONS: Phosphorylation of IκBα by AURK at novel sites is related to the apoptosis and necroptosis pathways in breast cancer cells.

Immediate effect of insoles on balance in older adults.

BACKGROUND: In recent years, fall prevention in older adults has received considerable attention in healthcare. Among many interventions, insoles are considered cost-effective and easily adopted tools to improve balance in older people. Numerous studies have verified the immediate effects of insoles on balance in older adults. However, there is still lack of consensus regarding the immediate benefits of using insoles on balance improvement. RESEARCH QUESTION: Given this, a meta-analysis was conducted to provide more conclusive evidence about the immediate effect of insoles on balance in older adults and answer the question: "Do insoles influence balance in older people?" METHODS: PubMed, NDSL, Medline, Google Scholar, and Web of Science were searched from March to August 2018. The key terms were "insole", "elderly", "gait", "balance", "shoe", "foot", and "postural". Finally, seven primary studies were selected for this meta-analysis. The balance related outcomes were coded to compute effect sizes and the overall effect size of the standardized mean differences was analyzed. Moderating variables included kinematic variables of balance, static and dynamic balance, and type of insole. RESULTS: The overall effect size of insoles was medium (d = 0.618), which suggests that insoles are beneficial for older adults for improving balance. More specifically, this study revealed that textured and vibration insoles were the most effective types of insoles. SIGNIFICANCE: This finding supports the idea that augmented tactile and mechanical sensory input from insoles can enhance the postural control mechanisms in older adults with age-related deterioration of sensory mechanisms. The use of insoles may lead to a reduction in the rate of falls which are related to decreased quality of life in older adults.

Nitric oxide attenuated transforming growth factor-ß induced myofibroblast differentiation of human keratocytes.

Nitric oxide (NO) has the potential to modulate myofibroblast differentiation. In this study, we investigated the effect of exogenous NO on the myofibroblast differentiation of human keratocytes using sodium nitrite as a NO donor. Myofibroblasts were induced by exposing resting keratocytes to transforming growth factor (TGF)-ß1. N-cadherin and α-smooth muscle actin (αSMA) were used as myofibroblast markers. Both resting keratocytes and -stimulated keratocytes were exposed to various concentrations of sodium nitrite (1 µM to 1000 mM) for 24 to 72 h. Exposure to sodium nitrite did not alter keratocytes' viability up to a 10 mM concentration for 72 h. However, significant cytotoxicity was observed in higher concentrations of sodium nitrite (over 100 mM). The expression of αSMA and N-cadherin was significantly increased in keratocytes by TGF-ß1 stimulation after 72 h incubation. The addition of sodium nitrite (1 mM) to TGF-ß1-stimulated keratocytes significantly decreased αSMA and N cadherin expression. Smad3 phosphorylation decreased after sodium nitrite (1 mM) exposure in TGF-ß1-stimulated keratocytes. The effect of NO was reversed when NO scavenger, 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) was added in the culture medium. Application of sodium nitrite resulted in significant decrease of corneal opacity when measured at 2 weeks after the chemical burn in the mouse. These results verified the potential therapeutic effect of NO to decrease myofibroblast differentiation of human keratocytes and corneal opacity after injury.

Evaluation of moxifloxacin-induced cytotoxicity on human corneal endothelial cells.

Moxifloxacin hydrochloride (MXF) is widely used for the prevention of bacterial endophthalmitis after intraocular surgeries. However, the safety issue of intracameral injection of MXF for human corneal endothelial cells (HCECs) is still debatable. In this study, we investigated concentration-dependent cytotoxicity (0.05-1 mg/ml) of MXF for immortalized HCECs (B4G12 cell) and the underlying mechanism. Reactive oxygen generation (ROS) and cell viability after MXF exposure was measured. Flow cytometric analysis and TUNEL assay was used to detect apoptotic HCECs after MXF exposure. Ultrastructure of damaged HCECs by MXF was imaged by transmission electron microscope. Western blot analysis and caspase 2, 3 and 8 analysis were used to reveal the underlying mechanism of MXF induced damage in HCECs. We found that MXF induced dose-dependent cytotoxicity in HCECs. MXF exposure increased ROS generation and induced autophagy in HCECs. Increased LDH release represented the cellular membrane damage by MXF. In addition, caspases activation, Bax/Bcl-xL-dependent apoptosis pathway and apoptosis inducing factor nuclear translocation were all involved in MXF induced HCECs' damage, especially after exposure to high dose of MXF (0.5 and 1.0 mg/ml). These findings suggest that MXF toxicity on HCECs should be thoroughly considered by ophthalmologists when intracameral injection of MXF is planned.

Development of a novel hyaluronic acid membrane for the treatment of ocular surface diseases.

Ocular surface diseases (OSD) can cause serious visual deterioration and discomfort. Commercial artificial tear solution containing hyaluronic acid (HA) show excellent biocompatibility and unique viscoelastic characteristics. Here, we developed a novel HA membrane (HAM) by chemical crosslinking using 1,4-butanediol diglycidyl ether for the effective treatment of OSDs. The main purpose of HAMs is to provide sustained release of HA to modulate the wound healing response in OSDs. The safety and efficacy of HAMs were investigated using primary cultured human corneal epithelial cells and various OSD rabbit models. In the dry state, the HAM is firm, transparent, and easy to manipulate. When hydrated, it swells rapidly with high water retention and over 90% transmission of visible light. Human corneal epithelial cells and rabbit eyes showed no toxic response to HAM. Addition of HAMs to the culture medium enhanced human corneal epithelial cell viability and expression of cell proliferation markers. Investigation of HAM wound healing efficacy using mechanical or chemical corneal trauma and conjunctival surgery in rabbits revealed that application of HAMs to the ocular surface enhanced healing of corneal epithelium and reduced corneal limbal vascularization, opacity and conjunctival fibrosis. The therapeutic potential of HAMs in various OSDs was successfully demonstrated.

Effects of Nonporous Silica Nanoparticles on Human Trabecular Meshwork Cells.

PRECIS: Silica nanoparticles (SiNPs), which are potential drug carriers for glaucoma treatment, may induce mild dose-dependent cytotoxicity but not so severe as to compromise a mammalian target of rapamycin (mTOR) pathway in immortalized trabecular meshwork (TM) cells. PURPOSE: Nanoparticle-based ophthalmic drug delivery is a promising field of drug development. In this study, we evaluated the effect of nonporous SiNPs on human TM cells. METHODS: TM cells were exposed to different concentrations (0 to 100 µg/mL) of SiNPs (50, 100, and 150 nm) for up to 48 hours. Transmission electron microscopy confirmed the intracellular distribution of SiNPs. Cellular viability assay, reactive oxygen species generation, autophagy, and activation of the mTOR pathway were evaluated. Histologic analysis of the TM structure was performed after intracameral injection of SiNPs (0.05 mL of 200 µg/mL concentration) in rabbits. RESULTS: SiNPs were taken up by TM cells and localized in the cytoplasm. Neither nuclear entry nor mitochondrial damage was observed. SiNPs induced a mild but dose-dependent increase of lactate dehydrogenase. However, neither increase of intracellular reactive oxygen species levels nor apoptosis was observed after SiNPs exposure. Significant coactivation of autophagy and the mTOR pathway were observed with exposure to SiNPs. Aqueous plexus structure was well maintained without inflammation in rabbits after SiNPs exposure. CONCLUSIONS: SiNPs induce mild and dose-dependent cytotoxicity in TM cells. However, the toxicity level is not enough to compromise the mTOR pathway of TM cells and histologic structure of the aqueous plexus tissue.

Block and Random Practice: A Wii Fit Dynamic Balance Training in Older Adults.

Purpose: To compare the effectiveness of blocked and random practice schedules of balance training in dynamic balance abilities of older adults using Wii Fit balance game tasks. Method: Forty-one participants who were not receiving hospice care or living in a nursing home participated. Three Wii Fit balance tasks (tasks A, B, and C) were selected for training, and one task (task D) was selected as the transfer test among the nine tasks in the Wii Fit balance game software. Scores for tasks A and D were evaluated. Completion times for tasks B and C were evaluated. Moved distance for the functional reach test (FRT), completion time for the timed up and go test (TUG), and performance score for the Tinetti performance-oriented mobility assessment (POMA) were also tested as clinical balance assessment outcomes. Results: The training significantly improved the performance outcomes of clinical balance assessments and task D. There were no significant group × time interaction effects and no significant main effects by group during the acquisition and retention periods of tasks A, B, and C. However, significant main effects by time were observed for tasks A, B, and C. Conclusions: When dynamic balance training such as the Wii Fit balance system is administered to older adults in a clinical setting, either a block or a random practice schedule can be effectively used to improve the dynamic balance skills. Wii Fit-based balance training is clinically effective for improving the dynamic balance ability.