Purpose The aim was to compare the impact of rigid gas‐permeable (RGP) contact lenses on vision‐related quality of life (VR‐QOL) in keratoconic patients with different grades of severity. Methods This comparative study was conducted from December 2012 to September 2013 on 46 patients with bilateral keratoconus. Patients were divided into three groups according to the average of the steep keratometry (K) readings in the two eyes of each patient. Main outcome measures included binocular visual acuity (VA), lens wearing time, the 25‐item National Eye Institute Visual Function Questionnaire (NEI‐VFQ‐25), foreign body (FB) sensation, comfort and overall satisfaction. Results Patients with severe keratoconus showed significantly reduced wearing time compared with the other two groups (4.8 ± 2.5 hours per day). Regarding the subjective criteria, there was no significant difference on NEI‐VFQ‐25 scores, foreign body sensation, comfort and overall satisfaction between mild and moderate keratoconus groups but scores in the group with severe keratoconus were significantly lower than the other two groups. Binocular VA strongly correlated with NEI‐VFQ‐25 scores; however, NEI‐VFQ‐25 scores had no significant correlations with different disease severities. Conclusions Appropriate correction with RGP lenses contributes to good VR‐QOL for keratoconic patients; however, as the disease progresses to a steep keratometric value of more than 52 dioptres (6.50 mm), RGP lenses did not guarantee a relatively good VR‐QOL. Other lens options with new designs might bring better life quality for these patients with severe keratoconus.

Pasteurella multocida (PM) can invade the upper respiratory tract of the body and cause death and high morbidity. Tildipirosin, a new 16-membered-ring macrolide antimicrobial, has been recommended for the treatment of respiratory diseases. The objective of this research was to improve the dose regimes of tildipirosin to PM for reducing the macrolides resistance development with the pharmacokinetic/pharmacodynamic (PK/PD) modeling approach and to establish an alternate cutoff for tildipirosin against PM. A single dose (4 mg/kg body weight) of tildipirosin was administered via intramuscular (i.m.) and intravenous (i.v.) injection to the pigs. The minimum inhibitory concentration (MIC) values of clinical isolates (112) were measured in the range of 0.0625–32 μg/ml, and the MIC50 and MIC90 values were 0.5 and 2 μg/ml, respectively. The MIC of the selected PM04 was 2 and 0.5 μg/ml in the tryptic soy broth (TSB) and serum, respectively. The main pharmacokinetic (PK) parameters including the area under the curve at 24 h (AUC24 h), AUC, terminal half-life (T1/2), the time to peak concentration (Tmax), peak concentration (Cmax), relative total systemic clearance (CLb), and the last mean residence time (MRTlast) were calculated to be 7.10, 7.94 μg∗h/ml, 24.02, NA h, NA μg/ml, 0.46 L/h∗kg, 8.06 h and 3.94, 6.79 μg∗h/ml, 44.04, 0.25 h, 0.98 μg/ml, 0.43 L/h∗kg, 22.85 h after i.v. and i.m. induction, respectively. Moreover, the bioavailability of i.m. route was 85.5%, and the unbinding of tildipirosin to serum protein was 78%. The parameters AUC24 h/MIC in serum for bacteriostatic, bactericidal, and elimination activities were calculated as 18.91, 29.13, and 34.03 h based on the inhibitory sigmoid Emax modeling. According to the Monte Carlo simulation, the optimum doses for bacteriostatic, bactericidal, and elimination activities were 6.10, 9.41, and 10.96 mg/kg for 50% target and 7.86, 12.17, and 14.57 mg/kg for 90% target, respectively. The epidemiological cutoff value (ECV) was calculated to be 4 μg/ml which could cover 95% wild-type clinical isolates distribution. The PK-PD cutoff (COPD) was analyzed to be 0.25 μg/ml in vitro for tildipirosin against PM based on the Monte Carlo simulation. Compared with these two cutoff values, the finial susceptible breakpoint was defined as 4 μg/ml. The data presented now provides the optimal regimens (12.17 mg/kg) and susceptible breakpoint (4 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.

Activated natural killer (NK) cells can kill malignant tumor cells via granule exocytosis and secretion of IFN-γ, a key regulator of the TH1 response. Thus, mobilization of NK cells can augment cancer immunotherapy, particularly when mediated through antibody-dependent cellular cytotoxicity (ADCC). Stimulation of toll-like receptor (TLR)­7/8 activity in dendritic cells promotes pro-inflammatory cytokine secretion and costimulatory molecule upregulation, both of which can potentiate NK cell activation. However, currently available TLR7/8 agonists exhibit unfavorable pharmacokinetics, limiting their in vivo efficacy. To enable efficient delivery to antigen-presenting cells, we encapsulated a novel imidazoquinoline-based TLR7/8 agonist in pH-responsive polymeric NPs. Enhanced costimulatory molecule expression on dendritic cells and a stronger pro-inflammatory cytokine response were observed with a NP-encapsulated agonist, compared to that with the soluble form. Treatment with NP-encapsulated agonists resulted in stronger in vivo cytotoxicity and prolonged activation of NK cells compared to that with a soluble agonist. In addition, TLR7/8 agonist-loaded NPs potentiated stronger NK cell degranulation, which resulted in enhanced in vitro and in vivo ADCC mediated by the epidermal growth factor receptor-targeting antibody cetuximab. TLR7/8 agonist-loaded NP treatment significantly enhanced the antitumor efficacy of cetuximab and an anti-HER2/neu antibody in mouse tumor models. Collectively, our data show that a pH-responsive NP-encapsulating TLR7/8 agonist could be used as a potent immunostimulatory adjuvant for antibody-based cancer immunotherapy by promoting NK cell activation.

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood–brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood–tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a “whole brain” approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.

Cancer vaccines composed of tumor-associated antigens (TAAs) and toll-like receptor (TLR) agonists have shown promising antitumor efficacy in preclinical studies by generating antigen-specific CD8 T cells, but translation of cancer vaccines to the clinic has been limited due to variables responses and development of resistance. The tumor microenvironment deploys various immune escape mechanisms that neutralize CD8 T cell-mediated tumor rejection. Therefore, we hypothesized that modulation of the tumor microenvironment can augment CD8 T cell activation and enhance therapeutic efficacy of cancer vaccines. To accomplish this, we aimed to eliminate immune suppressive cells and block their inhibitory signaling. Combination of the tyrosine kinase inhibitor (TKI) sunitinib with a nanoparticle-based cancer vaccine (nanovaccine) resulted in the reduction of immune-suppressive myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs). Blockade of programmed death-ligand 1 (PD-L1) using anti-PD-L1 antibody was used to reduce CD8 T cell exhaustion. Combination of nanovaccine+sunitinib+PD-L1 antibody treatment reduced PD-L1 high M2 macrophages and MDSCs and upregulated activation of CD8 T cells in the tumor. Nanovaccine+sunitinib+PD-L1 antibody treatment also stimulated antigen-specific CD8 T cell response, which led to improved therapeutic efficacy in MB49 and B16F10 murine tumor models. These results suggest that modulation of tumor microenvironment using sunitinib and PD-L1 blockade can significantly enhance the antitumor efficacy of cancer nanovaccine.

Brain tumours have a poor prognosis and lack effective treatments. The blood-brain barrier (BBB) represents a major hurdle to drug delivery to brain tumours. In some locations in the tumour, the BBB may be disrupted to form the blood-brain tumour barrier (BBTB). This leaky BBTB enables diagnosis of brain tumours by contrast enhanced magnetic resonance imaging; however, this disruption is heterogeneous throughout the tumour. Thus, relying on the disrupted BBTB for achieving effective drug concentrations in brain tumours has met with little clinical success. Because of this, it would be beneficial to design drugs and drug delivery strategies to overcome the 'normal' BBB to effectively treat the brain tumours. In this review, we discuss the role of BBB/BBTB in brain tumour diagnosis and treatment highlighting the heterogeneity of the BBTB. We also discuss various strategies to improve drug delivery across the BBB/BBTB to treat both primary and metastatic brain tumours. Recognizing that the BBB represents a critical determinant of drug efficacy in central nervous system tumours will allow a more rapid translation from basic science to clinical application. A more complete understanding of the factors, such as BBB-limited drug delivery, that have hindered progress in treating both primary and metastatic brain tumours, is necessary to develop more effective therapies.

Aim: We previously developed two antibodies that bind to a cell surface protein, perlecan, overexpressed in triple-negative breast cancer (TNBC). The goal of this study was to investigate these antibodies as targeting ligands for nanoparticle-mediated drug delivery. Methods: Paclitaxel-loaded poly(D,L-lactide-co-glycolide) nanoparticles were functionalized with antibodies using thiol–maleimide chemistry. Effect of antibody functionalization on therapeutic efficacy of drug-loaded nanoparticles was investigated using in vitro and in vivo models of TNBC. Results: The antibodies were covalently conjugated to nanoparticles without affecting antibody binding affinity or nanoparticle properties. Perlecan-targeted nanoparticles showed improved cell uptake, retention, cytotoxicity in vitro and enhanced tumor growth inhibition in vivo . Conclusion: The data presented here indicates that perlecan-targeted nanoparticles can improve tumor drug delivery to TNBC.

Purpose: To compare the clinical outcomes of bilateral medial rectus plication and resection for the treatment of convergence insufficiency (CI)-type intermittent exotropia (IXT). Methods: Fifty-five patients with CI-type IXT were included in this prospective study and were followed for 6 months. The patients were randomized into two groups: the bilateral medial rectus plication (BMRP) group (n = 27) and the bilateral medial rectus resection (BMRR) group (n = 28). The eye examinations of each patient were carried out before the surgery and at 1 day and 1, 3 and 6 months postoperatively. The success rate, angle of deviation, stereoacuity, operative time and postoperative conjunctival swelling and redness score were analysed. Results: The mean deviation at distance at 1 day postoperatively was +6.6 AE 5.6 prism dioptres (PD) in the BMRP group, which was lower than the value of +10.8 AE 9.3 PD observed in the BMRR group (p = 0.046). There was more overcorrection in the BMRR group at first day after surgery. However, there were no significant differences in deviations or success rates were observed between the two groups at 1, 3 and 6 months after surgery (p > 0.05). The operative time in the BMRP (12.9 AE 1.4 min) group was shorter than that in the BMRR (14.7 AE 1.4 min) group (p < 0.001). Postoperative conjunctival swelling and redness were milder in the BMRP group than in the BMRR group (p < 0.001). Conclusion: The BMRP surgery could be an alternative procedure to BMRR for the treatment of CI-type IXT with less immediate postoperative overcorrection and simpler, safer, less traumatic characteristics.