A novel indole derivative, 2-{3-[1-(benzylsulfonyl)piperidin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone, suppresses hedgehog signaling and drug-resistant tumor growth.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.

Wogonin inhibits tight junction disruption via suppression of inflammatory response and phosphorylation of AKT/NF-κB and ERK1/2 in rhinovirus-infected human nasal epithelial cells.

OBJECTIVE: The maintenance of tight junction integrity contributes significantly to epithelial barrier function. If barrier function is destroyed, cell permeability increases and the movement of pathogens is promoted, further increasing the susceptibility to secondary infection. Here, we examined the protective effects of wogonin on rhinovirus (RV)-induced tight junction disruption. Additionally, we examined the signaling molecules responsible for anti-inflammatory activities in human nasal epithelial (HNE) cells. METHODS AND RESULTS: Primary HNE cells grown at an air-liquid interface and RPMI 2650 cells were infected apically with RV. Incubation with RV resulted in disruption of tight junction proteins (ZO-1, E-cadherin, claudin-1, and occludin) in the HNE cells. Cell viability of wogonin-treated HNE cells was measured using the MTT assay. Pretreatment with wogonin decreased RV-induced disruption of tight junctions in HNE cells. Furthermore, wogonin significantly decreased RV-induced phosphorylation of Akt/NF-κB and ERK1/2. Additionally, RV-induced generation of reactive oxygen species and RV-induced up-regulation of the production of inflammatory cytokines IL-8 and IL-6 were diminished by wogonin in HNE cells. CONCLUSION: Wogonin inhibits HRV-induced tight junction disruption via the suppression of inflammatory responses and phosphorylation of Akt/NF-κB and ERK1/2 in HNE cells. These finds will facilitate the development of novel therapeutic strategies.

Intralymphatic immunotherapy with tyrosine-adsorbed allergens: a double-blind, placebo-controlled trial.

BACKGROUND: Most previous studies used aluminum hydroxide-absorbed allergen extracts in evaluating the potential therapeutic roles of intralymphatic allergen-specific immunotherapy (ILAIT). In this study, we evaluated the therapeutic efficacy and safety of ILAIT with L-tyrosine-adsorbed allergen extracts of Dermatophagoides farinae, D. pteronyssinus, cat, dog, or mixtures thereof, in patients with allergic rhinitis induced by these allergens. METHODS: In this randomized, double-blind, placebo-controlled trial, study subjects received three intralymphatic injections of L-tyrosine-adsorbed allergen extracts (active group) or saline (placebo group) at 4-week intervals. RESULTS: Although ILAIT reduced daily medication use and skin reactivity to HDM and cat allergens at 4 months after treatment, overall symptom score on a visual analog scale (VAS), sinonasal outcome test-20 (SNOT-20), rhinoconjunctivitis quality of life questionnaire (RQLQ), daily symptom score (dSS), daily medication score (dMS), daily symptom medication score (dSMS), nasal reactivity to HDM allergen, and basophil activity to HDM, cat, and dog allergens at 4 months and 1 year after treatment were similar between the treatment and control groups. Intralymphatic injection was more painful than a venous puncture, and pain at the injection site was the most frequent local adverse event (12.8%); dyspnea and wheezing were the most common systemic adverse events (5.3%). CONCLUSIONS: ILAIT with L-tyrosine-adsorbed allergen extracts does not exhibit profound therapeutic efficacy in allergic rhinitis and can provoke moderate-to-severe systemic reactions and cause pain at the injection site. TRIAL REGISTRATION: clinicaltrials.gov: NCT02665754; date of registration: 28 January 2016.

Epicutaneous Allergen Administration with Microneedles as a Novel Method of Immunotherapy for House Dust Mite (HDM) Allergic Rhinitis.

PURPOSE: Epicutaneous immunotherapy (EPIT) is being studied as a method for treating allergic rhinitis because of skin immunology, user convenience and enhanced patient compliance. However, the use of EPIT is limited because of the very low skin permeability of the allergen. In this study, the limitations of EPIT were overcome by using sophisticated delivery with microneedles. The immunological efficacy of this method was studied in a murine model of house dust mite (HDM) allergic rhinitis. METHODS: The length of the microneedles was 400 µm, and the coating formulation containing HDM was locally distributed near the end of the microneedle tips. The change of distribution of FITC-dextran in porcine skin in vitro was observed over time using a confocal microscope. The effect of immunotherapy in the allergic rhinitis model, sensitized by HDM-coated microneedles (HDM MNs), was observed according to the amount of HDM applied. RESULTS: The microneedles delivered the coating formulation with precision into the porcine skin layer, and the coated formulation on the microneedles was all dissolved in the porcine skin in vitro within 20 min of administration and then gradually diffused into the skin layer. When HDM MNs were administered to mice, a 0.1-µg dose of HDM provided the most effective immunization, and improved efficacy was shown between 0.1- and 0.5- µg doses of HDM. CONCLUSIONS: Effective immunotherapy can be achieved by precision delivery of the allergen into the skin layer, and microneedles can provide effective immunological therapy by delivering the appropriate amount of allergen.

Oral Commissure Lift: A Retrospective Analysis of Complication Rates and Overall Outcomes.

BACKGROUND: Downward-turning oral commissures and sagging mouth corners can present an unfavorable impression. We introduced a new oral commissure lift procedure and investigated its effectiveness and complication rates. METHODS: Patients who underwent oral commissure lift in the plastic surgery clinic between January 2010 and December 2017 were enrolled retrospectively. Pre-and postoperative photographs were evaluated to measure oral commissure angles and analyze surgical complications, including visible scarring, unnatural appearance, and asymmetry. Many patients underwent a oral commissure lift with a simultaneous facelift. To exclude potential bias, we compared angular changes between patients receiving both oral commissure lift and facelift, with those receiving only oral commissure lift. Moreover, oral commissure angles of patients only receiving facelift were also measured. Statistical significance was set at p < 0.05. RESULTS: Oral commissure lift was performed in 51 patients. The mean ages and follow-up periods were 46.7 ± 11.9 years, and 25.2 ± 22.9 months, respectively. The preoperative mean angles of the right and left oral commissures measured - 3.1 ± 4.0° and - 3.4 ± 3.7°, respectively, and postoperative mean angles measured 3.6 ± 3.2° and 3.3 ± 3.5°, respectively. Postoperative changes in oral commissure angles were statistically significant (p < 0.05). The low complication rate included undercorrection in one patient, asymmetry in one patient, and visible scarring in three patients. We found no statistically significant differences in the studies excluding bias. CONCLUSIONS: The new oral commissure lift procedure for correcting sagging oral commissures was simple, safe, and effective with a low complication rate. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Autologous Fat Injection for the Correction of Facial Depression Resulting From Silent Sinus Syndrome.

The case of a 59-year-old woman who underwent endoscopic sinus surgery for right maxillary sinusitis 5 years before visiting our otorhinolaryngologic department complaining of right-sided facial depression was described in this study. Computed tomography (CT) scans revealed right facial depression and retraction of the orbital floor due to a hypoplastic right maxillary sinus. Symptoms and CT findings corresponded with silent sinus syndrome. Facial depression is a rare symptom in silent sinus syndrome and is well corrected by autologous fat transfer.

Nasal Stenosis Treated With a Composite Skin Graft.

A 58-year-old female patient was presented, who complained about breathing and aesthetic difficulties due to external nasal valve obstruction and nasal deformity that developed after nasal trauma surgery. Nasal stenosis recurs easily after surgery, especially if internal nasal stenosis is not adequately managed. Nasal stenosis in this case was well treated using a composite skin graft.

Height Changes of Tutoplast-Processed Fascia Lata Over Time After Dorsal Augmentation During Rhinoplasty.

PURPOSE: Tutoplast (Tutogen Medical, Neunkirchen am Brand, Germany)-processed fascia lata (TPFL) has been used for dorsal augmentation in rhinoplasty in the Republic of Korea for approximately 10 years, but few studies have described changes in TPFL in terms of dorsal height over time. We investigated changes in dorsal height after TPFL use as a dorsal implant material during rhinoplasty. MATERIALS AND METHODS: The records of 18 rhinoplasty patients who had undergone dorsal augmentation with TPFL were examined retrospectively. The patients had undergone rhinoplasty from March 2008 to June 2012. Two different ear, nose, and throat doctors analyzed the first follow-up photographs (2 lateral views and 2 oblique views) taken at approximately 1 month postoperatively and the last follow-up photographs taken from 18 to 75 months after surgery. The last follow-up photographs were classified as showing no nasal dorsal height change, slight change, and marked change compared with the first follow-up photographs. RESULTS: Of the 18 patients enrolled, 50% (n = 9) showed no change in the nasal dorsum whereas 33% (n = 6) showed mild depression and 17% (n = 3) showed marked depression of the nasal dorsum at last follow-up. CONCLUSIONS: About half of the patients who had undergone dorsal augmentation using TPFL during rhinoplasty showed mild or marked dorsal depression over time. It is recommended that TPFL be used with another implant during augmentation rhinoplasty or TPFL be used only for a slightly depressed nose. In addition, patients should be informed that TPFL could be resorbed over time.

Retained Eyeglasses in the Orbital Cavity After Penetrating Facial Trauma.

This study describes a 68-year-old man who was presented to the emergency department with left orbital cavity penetration by his eyeglasses. The eyeglasses had entered the orbit and at presentation his eyesight could not be measured. The foreign body was extracted carefully and panfacial bone fractures were then reduced through lateral rhinotomy combined with a lip-splitting incision. When planning removal of an unusual foreign body from the orbital cavity, care should be taken not to injure the optic nerve, periorbital musculatures, or the eyeball.

Frontal Sinus Osteoplastic Flap Surgery Using a Surgical Navigation System.

OBJECTIVE: To report the case of a 38-year-old woman who underwent osteoplastic flap surgery for recurrent frontal sinus mucocele. During surgery, the exact shape of the frontal sinus was duplicated using a surgical navigation system. METHODS: In this case report, the authors suggest intraoperative surgical navigation systems are useful for accurately determining the dimensions of the frontal sinus for osteoplastic flap surgery. RESULTS: The patient underwent successful and safe osteoplastic flap surgery using a surgical navigation system. CONCLUSION: Surgical navigation is useful and safe for frontal sinus osteoplastic flap surgery.

Is Surgical Navigation Useful During Closed Reduction of Nasal Bone Fractures?

OBJECTIVE: To report the case of a 42-year-old woman with a nasal bone fracture that was easily treated using a surgical navigation system. METHODS: In this clinical report, the authors suggest that intraoperative surgical navigation systems are useful diagnostically and for localizing sites of nasal bone fractures exactly. RESULTS: The patient underwent successful closed reduction of the nasal bone fracture. CONCLUSIONS: Surgical navigation is a useful tool for identifying nasal bone fracture locations and for guiding closed reduction. Surgical navigation is recommended when nasal bone fractures are complicated or not well reduced using the ordinary method.

A Case of Organizing Hematoma in a Maxillary Sinus After Reconstruction of a Blow-Out Fracture.

A 36-year-old man presented because of nasal obstruction, rhinorrhea, and postnasal drip. The patient had undergone reconstruction of a blow-out fracture of the orbital floor 12 years before and had sinusitis that likely had resulted from implant migration into the maxillary sinus. The inflammation was successfully resolved, and the implant was removed through a minimally invasive endoscopic sinus surgery technique. On pathologic examination, an organizing hematoma was identified as the cause of the lesion. Pre- and postoperational paranasal sinus computed tomography images were taken to compare the anatomy of the sinus before and following surgery.

Is Surgical Navigation Useful for Treating Zygomatic Arch Fractures?

OBJECTIVE: To report the case of a 58-year-old man with a zygomatic arch fracture, which was well localized and reduced using a surgical navigation system. METHODS: In this clinical report, the authors suggest intraoperative surgical navigation systems are useful diagnostically and for localizing sites of zygomatic arch fractures. RESULTS: The patient underwent successful closed reduction of zygomatic arch fractures using a surgical navigation system. CONCLUSIONS: Surgical navigation is a useful tool for identifying the locations of zygomatic arch fractures and for guiding closed reduction. Surgical navigation is recommended for localizing the sites of zygomatic fractures.

Salvage of a Necrotic Flap.

OBJECTIVE: To report the case of a 68-year-old woman with a skin basal cell carcinoma on the nasal dorsum. After excision, the soft tissue defect was reconstructed using a rectangular advancement flap. However, 2 days later skin necrosis was observed. This report was issued to advise how to avoid and manage skin necrosis after regional flap placement. METHODS: This is a retrospective study. RESULTS: Superficial skin necrosis recovered completely after proper medical management. CONCLUSIONS: When planning an advancement flap, care should be taken to design the flap properly and not to injure flap blood supply to avoid skin necrosis. In addition, surgeons should be aware of the difference between superficial and total flap necrosis.

Comparison of titanium and biodegradable plates for treating midfacial fractures.

PURPOSE: The purpose of the present study was to evaluate the use of titanium plates and screws (TPSs) versus biodegradable plates and screws (BPSs) for fixation of midfacial fractures. In addition, complications related to the plates and rates of secondary surgery for plate removal were compared. PATIENTS AND METHODS: From March 2005 to March 2012, 109 patients were enrolled in this study. Fifty-six patients with TPSs implanted to fix midfacial fractures (group A) and 53 patients with BPSs to treat midfacial fractures (group B) were evaluated. Patients' histories of plate-related nonunion, infection, displacement, pain, and palpability and secondary surgery for plate removal were checked. RESULTS: None of the study participants developed nonunion issues related to the TPSs or BPSs. Six patients in group A developed complications associated with TPSs and 5 patients underwent secondary surgery for plate removal. One patient (1.8%) had a plate-related infection, 1 patient (1.8%) developed plate extrusion, 1 patient (1.8%) had plate-associated chronic pain, 2 patients (3.6%) complained of palpability, and 2 patients (3.6%) developed psychological problems (1 patient developed 2 complications). In contrast, only 1 patient in group B (2%) complained of temporary palpability, and this problem disappeared over time. None of the patients in group B complained of any other problems. CONCLUSIONS: The results indicated that BPSs and TPSs have the potential for successfully treating midfacial fractures. BPSs are suitable for treating midfacial fractures and could serve as an alternative for TPSs in selected cases.

Effect of endoscopic marsupialization of paranasal sinus mucoceles involving the orbit: a review of 27 cases.

Paranasal sinus mucoceles (PSMs) can involve the orbit because the topographic anatomies of the paranasal sinuses and orbit are interrelated. We encountered 27 patients with PSMs involving the orbit that caused orbital symptoms. In this study, we evaluated the frequent symptoms and signs of PSMs involving the orbit, and report postoperative changes of orbital symptoms including the effects on visual acuity. A retrospective chart review, radiologic evaluation, and interviews were conducted after Institutional Review Board approval was obtained. Over the past 11 years, we encountered 27 patients with PSMs involving the orbit. We classified the patients according to orbital symptoms and PSM origin, and evaluated the surgical outcomes. A total of 27 patients (17 males and 10 females) with PSMs involving the orbit were included in the present study. The mean patient age was 51.0 ± 9.7 years (range 32-90) and the mean follow-up period was 20.5 months (range 2-84). Proptosis (15/27, 56%) was the most common symptom. Other common symptoms included orbital pain (9/27, 33%), decreased visual acuity or vision loss (9/27, 33%), and diplopia (7/27, 26%). All symptoms except for vision loss were improved by endoscopic marsupialization regardless of the disease period. Four out of five patients with decreased visual acuity experienced complete recovery. The remaining patient showed partial improvement after surgery. Four patients who were blind when they initially visited the hospital did not show any improvement after surgery. For PSM patients with decreased visual acuity, we can predict that vision will improve after surgery regardless of the disease duration. However, blindness will probably not resolve after endoscopic marsupialization. Even if the orbital symptoms (except for blindness) have persisted for a long time, surgery could still produce positive outcomes.

Ginsenoside Re protects rhinovirus-induced disruption of tight junction through inhibition of ROS-mediated phosphatases inactivation in human nasal epithelial cells.

Maintaining tight junction integrity significantly contributes to epithelial barrier function. If the barrier function is destroyed, the permeability of the cells increases, and the movement of the pathogens is promoted, thereby further increasing the susceptibility to secondary infection. Ginsenoside components have multiple biological activities, including antiviral effects. In this study, we examined the protective effects of ginsenoside Re against rhinovirus-induced tight junction disruption in primary human nasal epithelial cells (HNE). Incubation with human rhinovirus resulted in marked disruption of tight junction proteins (ZO-1, E-cadherin, claudin-1, and occludin) in human nasal epithelial cells. Rhinovirus-induced disruption of tight junction proteins was strongly inhibited by the treatment of cells with ginsenoside Re. Indeed, significant amounts of reactive oxygen species (ROS) have been detected in human nasal epithelial cells co-incubated with rhinovirus. Moreover, rhinovirus-induced ROS generation was markedly reduced by the ginsenoside Re. However, ginsenosides Rb1 and Rc did not inhibit tight junction disruption or ROS generation in nasal epithelial cells following incubation with rhinovirus. Furthermore, incubation with rhinovirus resulted in a marked decrease in protein phosphatase activity and an increase in protein tyrosine phosphorylation levels in nasal epithelial cells. Treatment of cells with ginsenoside Re inhibited rhinovirus-induced inactivation of phosphatases and phosphorylation of tyrosine. Our results identified ginsenoside Re as an effective compound that prevented rhinovirus-induced tight junction disruption in human nasal epithelial cells.

Predictors of Continuous Positive Airway Pressure Adherence and Comparison of Clinical Factors and Polysomnography Findings Between Compliant and Non-Compliant Korean Adults With Obstructive Sleep Apnea.

OBJECTIVE: Continuous positive airway pressure (CPAP) is the preferred treatment for obstructive sleep apnea (OSA). However, compliance with CPAP therapy varies among studies, and studies on its predictors are insufficient in Korea. This study aimed to identify factors that predict compliance with CPAP therapy in patients with OSA. METHODS: We retrospectively reviewed medical records, polysomnography (PSG) records, and self-report questionnaires of patients w ith OSA. Criteria for compliance was the use of CPAP devices for ≥4 h per night for ≥70% of the consecutive 30 nights (i.e., 21 days) during the first 3 months of treatment initiation. The patients were classified into two groups: compliant and non-compliant. Logistic regression analyses were performed to identify the clinical factors and PSG parameters associated with CPAP compliance. RESULTS: Of the 188 participants, 80 were classified into the compliant group and 108 into the non-compliant group. The ratios of stage N1 (p=0.011) and health insurance coverage (p=0.007) were significantly associated with compliance with CPAP, with an explanatory power of 18.6% (R2=0.186, p<0.001). CONCLUSION: Stage N1 ratio and health insurance coverage were significant predictors of CPAP compliance. It is necessary to confirm whether the relationship between a high stage N1 ratio and compliance can be reproduced in a larger sample and in individuals from other countries.

Expression of autoantibodies in patients with sudden sensorineural hearing loss.

OBJECTIVES: The aim of this study was to establish the expression rate of autoimmunity in patients with sudden sensorineural hearing loss and to determine whether a positive marker is associated with a higher rate of hearing recovery after steroid treatment. METHODS: A prospective study was performed on 137 patients who experienced sudden sensorineural hearing loss and underwent immunoserologic investigations. Autoantibodies evaluated on the day of admission included anti-double-stranded DNA, rheumatoid factor, antiphospholipid immunoglobulins G and M, antinuclear antibody, and complements C3 and C4. RESULTS: Of 137 patients, 75 were male and 62 were female (mean age, 45.1 years). Hearing loss was found on the left side in 61 patients and on the right side in 76 patients. Elevation of at least 1 autoantibody or abnormal complement levels were found in 80 patients (58%), and abnormalities of 2 or more antibodies were found in 28 (20%). There were no statistically significant correlations between autoantibody abnormalities and age, initial hearing level, or positive treatment response. CONCLUSIONS: There is no clear evidence of a correlation between autoimmunity and hearing improvement in patients with autoantibody abnormalities. A high (but not significant) expression rate of autoantibody abnormality and complement level was seen in patients with sudden sensorineural hearing loss.

Effect of intralymphatic allergen-specific immunotherapy on house dust mite in a murine model of allergic rhinitis.

BACKGROUND: Intralymphatic immunotherapy (ILIT) is a promising alternative for the treatment of patients with allergic rhinitis, providing similar therapeutic efficacy to conventional allergen-specific immunotherapy (AIT). However, the allergic mechanism of ILIT is not completely known. AIM: The aim of this study was to determine the efficacy of ILIT in a house dust mite (HDM) mouse model of allergic rhinitis. METHODS: BALB/c mice were divided into four groups: G1, control without allergy; G2, allergy sensitized with HDM; G3, allergy with ILIT (starting with HDM 1.25 µg/mL); and G4, allergy with ILIT (starting with HDM 2.5 µg/mL). After the murine model of allergic rhinitis with HDM was established, mice were administered an intralymphatic injection through the inguinal lymph nodes with HDM. RESULTS: ILIT decreased serum total IgE level and eosinophil infiltration in the nasal mucosa. ILIT also decreased the expression levels of IL-13, IL-25, IL-33, IFN-γ, IL-6, and IL-17, and increased the expression of FoxP3(+) T reg cells. CONCLUSIONS AND SIGNIFICANCE: Our results suggest that ILIT regulates the specific immunotherapy immunologic mechanism by downregulating Th1, Th2, and Th17 cytokines and upregulating FoxP3(+) T reg cells in the HDM allergic mouse model.