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Purpose: This study evaluated the effect of the excision of redundant skin and pretarsal orbicularis muscle, without vertical or horizontal tarsal fixation, on the correction of involutional entropion.Methods: This retrospective interventional case series recruited patients with involutional entropion who underwent excision of redundant skin and pretarsal orbicularis muscle, without vertical or horizontal tarsal fixation, from May 2018 to December 2021. Preoperative clinical characteristics and surgical outcomes, including recurrence at 1, 3, and 6 months, were determined by reviewing the medical charts. Surgical treatment included the excision of redundant skin and pretarsal orbicularis muscle, without any tarsal fixation, and simple skin suture.Results: All 52 patients (58 eyelids) attended every follow-up visit and were thus included in the analysis. Among 58 eyelids, 55 (94.8%) had satisfactory results. The recurrence rate was 3.45% (two eyelids) and the overcorrection rate was 1.7% (one eyelid).Conclusions: Excision of only redundant skin and the pretarsal orbicularis muscle, without capsulopalpebral fascia reattachment or horizontal lid laxity correction, is a simple surgery for correcting involutional entropion.

Augmented space can be usefully applied to cultural heritage experience, because it is possible to experience physical space and acquire information at the same time. Experiencers can expand their experiences through virtual content while feeling the presence of relics or historic sites. The cultural heritage experiences currently implemented show simple forms in terms of their content and delivery method. Many cases repeatedly provide the same content regardless of the experience in a specific location. The present research, titled “the spatial-experience model of architectural heritage,” derived a methodology for construction of spatial experiences augmented by digital technology. Specifically, it deals with the problem of content curation and the limitations of the information system, which can be seen in the spatial-experience composition methods in the current digital heritage field. The information structure of the model was improved to enable spatial-oriented explanation of the expression of architectural heritage, which was insufficient in the existing metadata and ontology structures. The model has inference rules for creating an experience sequence and composes various combinations of experience content based on historical knowledge relationships. The model and reasoning rules were tested by applying them to real architectural heritage cases. Based on the test results, the role of the information structure in the spatial expression of its combination with content, as well as the possibility of diversification of sequence derivation, were considered. This research presents a syntax for construction of a semantic-rich environment while extending historical knowledge and spatial expression to the existing cultural heritage information system. In addition, by means of the content generator, which is a model for producing content using the extended descriptive language system, it is possible to create experience content in response to the increasing amount and demands of data. By applying the proposed model, it will be possible to quickly and easily derive various experience contents from the cultural heritage space, thereby reducing cost and time for content producers and providing an evolved spatial experience for consumers.

Recent developments in experience technologies such as augmented reality (AR)/virtual reality (VR) have facilitated receiving content about the audience on site and experiencing architectural heritage in a virtual space. Despite the development of experience devices, if the quantity and quality of content are not sufficiently supported, immersive user experiences are bound to be limited. Considerable amounts of money, manpower, and time are required to make a building into experience content. Tasks such as building a database create experiential content that occupies a large proportion of the overall process. Therefore, it is necessary to devise an automated method for building data, which is the basis for content creation. This study extracted data on architectural heritage automatically and structured it around spatial expression so that it can function as base work for mass content creation. Specifically, this study devised a method to link and structure text and spatial data centering on the architectural spatial data model. Text and spatial data were extracted automatically using deep learning, and each derived result was mapped to Indoor Affordance Spaces—an indoor spatial data model—to test whether information inference is possible based on the interconnection relationship. The spatial experience route inferred using the data model expresses the detailed area where the viewing element exists, based on the description method of the model. It also shows the process of reconstructing an efficient movement line with topological relationships between spaces. The series of processes presented herein showed sufficient applicability to the extraction of data and the connection and utilization of data models. This is useful for extracting and classifying information used for content from massive raw data. This study also considered the specificity arising from architectural heritage and spatial information. Therefore, the research concept can be applied in exhibition and experience spaces, such as architectural heritage, museums, and art galleries, to create sources for content creation and refer to content composition.

Purpose: Cosmetic procedures for lower eyelids are popular in the field of plastic surgery for patients who want to make their eyes look bigger in Korea. We have experienced patients who developed entropion after the lower eyelid cosmetic procedure and treated it surgically, and therefore we would like to report on these cases.Methods: From 2015 to 2021, among all patients diagnosed as having entropion at Woori Yonsei eye clinic, 34 patients with a history of lower eyelid plastic procedure were included in this study.Results: All patients were female and their mean age was 30.6 years. We classified subjects from grade I to grade IV according to the degree of resistance to the lower eyelid retraction and lower eyelid upward movement restriction. The Hotz operation was performed in all patients. Filler removal, lower eyelid retraction recession, or palate mucosal transplantation were additionally performed depending on the severity of entropion.Conclusions: After the cosmetic procedure of lower eyelid, some patients had entropion as a complication and required surgery. To prevent these complications, sufficient pre-examination of eye conditions such as the degree of relaxation of the lower eyelid, size of eyelid fissure, morphological problems, and reevaluation of surgical technique are required before the procedure starts. In addition, it seems the patients need to provide with sufficient explanation about the necessity of the procedure and its side effects.

Purpose: To study the relationship between the levels of serum thyroid-stimulating hormone (TSH)-receptor autoantibodies (TRAbs) and thyroid eye disease (TED) activity and severity scores.Methods: A cross-sectional study was performed. The medical records of 315 patients diagnosed with TED between March 2014 and December 2019 were reviewed. The clinical activity score (CAS) was used to assess TED activity and a modified NOSPECS score was used for severity grading. The serum TRAb level was measured using two assays: a TSHR binding inhibitory immunoglobulin (TBII) assay and thyroid stimulating immunoglobulin (TSI) bioassay.Results: The TBII and TSI assay results were significantly positively correlated with the CAS (R = 0.113 and 0.211, respectively; p < 0.05), modified NOSPECS score (R = 0.173 and 0.316, respectively; p < 0.05), and proptosis (R = 0.136 and 0.167, respectively; p < 0.05). Both assays demonstrated significant differences in the level of TRAb between patients with and without compressive optic neuropathy or corneal epithelial defects.Conclusions: The levels of TRAbs according to both TBII and TSI assays showed significant correlations with clinical signs of corneal involvement, optic neuropathy, and TED activity and severity.

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

To compare matrix metalloproteinase-9 (MMP-9) point-of-care immunoassay (InflammaDry) results before and after dacryocystorhinostomy (DCR) in patients with nasolacrimal duct (NLD) obstruction.Thirty-eight eyes of 38 patients who were diagnosed with unilateral NLD obstruction were treated with endoscopic DCR. Treatment response was monitored using InflammaDry test, tear meniscus height was measured by slit-lamp microscopy, and tear meniscus parameters (tear meniscus height, depth, and area) were measured by anterior segment optical coherence tomography at baseline and at 1 month after surgery.In 38 patients, the positive percentage of MMP-9 in diseased eyes was 100% (38 eyes), much higher than that in healthy fellow eyes (13.2%, 5 of 38 eyes) at baseline (The concentration of MMP-9 increased in the tears of patients' eyes with NLD obstruction compared to the contralateral healthy eyes. These abnormal findings showed a significant improvement after DCR. The improvement of postoperative MMP-9 expression might be because of the improvement of tear retention.

In this article, the authors prove some bi-additive $$\sigma$$ -random operators inequalities and apply these inequalities, together with the fixed-point technique, to get an approximation of the additive $$\sigma$$ -random operators in Menger–Banach (MB) spaces. An approximation of random quasi- $$*$$ -multipliers on MB- $$*$$ -algebras, associated with the bi-additive $$\sigma$$ -random operator inequalities, is also considered.

Background/Aim: Using a rat model of collagen-induced arthritis (CIA), we evaluated the therapeutic effects of HM71224 (BTKi), as well as the drug-drug interactions in combined therapy with methotrexate (MTX) based on both drugs’ pharmacological role in immune regulation and antiinflammation. Materials and Methods: Arthritis in rats was induced using type II collagen and incomplete Freund’s adjuvant. The therapeutic effects of HM71224 (alone or in combination with MTX) were evaluated by arthritis score, paw volume, body weight, and histopathological examination (H&E and Safranin-O staining). The drug-drug interactions between HM71224 and MTX were investigated by measuring plasma, liver enzyme and creatinine levels and blood cell counts. Results: HM71224 reduced the clinical signs of arthritis, paw volume, and body weight loss in CIA rats. ED(50) and ED(90 )were 1.0 and 2.5 mg/kg, respectively. HM71224 combined with MTX decreased the arthritis score, bone erosion, synovitis, and cartilage degradation without apparent interaction. Conclusion: The combination of HM71224 and MTX improved the therapeutic effect with no drug-drug interactions in RA.

We solve the additive ϱ1,ϱ2-random operator inequality ξtTω,u+v−Tω,u−Tω,v≥κMξtϱ1Tω,u+v+Tω,u−v−2Tω,u,ξtϱ22Tω,u+v/2−Tω,u−Tω,v, in which ϱ1,ϱ2∈ℂ are fixed and max2ϱ1,ϱ2<1. Finally, we get an approximation of the mentioned additive ϱ1,ϱ2-random operator inequality by direct technique.

Purpose. To evaluate the clinical efficacy of oral hyaluronic acid (HA) in patients with dry eye disease (DED). Study Design. Prospective randomized controlled trial. Methods. This trial enrolled 54 subjects and they were randomized into the study or control group. The inclusion criteria were as follows: (1) >18 years of age; (2) distance best-corrected visual acuity ≥ 20/40 Snellen equivalent in each eye; (3) IOP ≤ 21 mmHg in both eyes; (4) ocular surface disease index (OSDI) score of ≥18 and 5 corneal spots of corneal fluorescein staining (CFS); and (7) ≤ 10 mm/5 min of the Schirmer test. All subjects were treated with a topical HA, and the study group was supplemented with oral HA. OSDI, TBUT, CFS, and the Schirmer test were evaluated for ocular surface parameters. Results. 24 patients were assigned in the study group. Significant improvement of OSDI, TBUT, and CFS was observed at 1 month and 3 months after oral HA administration in the study group. At baseline and follow-up at 1 and 3 months, OSDI scores were 61.8 ± 16.2, 47.3 ± 11.6, and 42.3 ± 9.1, respectively (P<0.001). TBUT was improved after treatment for 1 month and 3 months (4.2 ± 1.1; P=0.005 and 4.7 ± 1.1; P<0.012). There were also statistically significant improvements in the CSF (1.8 ± 1.0, 0.8 ± 0.7; P<0.001) at baseline compared with those at 1 month. Conclusions. A combined supplement of both oral and topical HA more efficiently improves corneal epithelial wound healing and related symptoms than topical HA alone, in DED.

The aim of the present study was to report two cases of refractory dry eye syndrome (DES) after transconjunctival excision of the palpebral lobe of the lacrimal gland. A 25-year-old female patient with a chief complaint of a palpable mass in both upper eyelids visited our medical center. Preoperative orbital computer tomography showed high-attenuation lesions in both lacrimal glands. Incisional biopsy of the lacrimal gland palpebral lobe via transconjunctival incision was performed in January 2019. At 1 month after the biopsy, a lack of tears and persistent corneal erosions were found in both eyes. Artificial tears, punctal occlusion, autologous serum eye drops, and therapeutic contact lenses were applied in an attempt to control the dry eye symptoms. The patient continues to suffer from intractable DES at 2.5 years after the procedure. The second case involved a 52-year-old female patient who visited our medical center with a chief complaint of a palpable mass in both upper eyelids. Bilateral orbital tumors were diagnosed with preoperative magnetic resonance imaging. An incisional biopsy of the lacrimal gland was performed. Immunoglobulin G4-related dacryoadenitis was confirmed through lacrimal palpebral lobe incisional biopsy. Intractable DES and corneal erosion of her left eye persisted thereafter. A transconjunctival incision is an effective approach for minimizing postoperative scars and is suitable for the biopsy of tumors that are visible through the conjunctiva. After a biopsy of the palpebral lobe of the main lacrimal glands, the secretion of reflex tears decreases due to damage to the secreting ducts of the main lacrimal glands. However, total tear secretion can be maintained by basal tear secretion from the accessory lacrimal glands. In this report, we describe two cases of refractory DES due to decreased total tear secretion, although only the palpebral lobes of the main lacrimal glands were biopsied.

Background and Objectives: To find the differences in ocular axial length, keratometric measurements, and intraocular lens (IOL) power in patients with Graves’ disease (GD) after treatment with a thionamide antithyroid drug (ATD), methimazole. Materials and Methods: The medical charts of 28 patients (4 males and 24 females, mean age: 47.2 ± 21.2 years) were studied. Each patient was examined twice using an IOL Master Device and keratometry at the first visit (before ATD treatment) and after 1 month of ATD treatment. The IOL power was calculated for each patient using the Hoffer Q, SRK-2, and SRK/T formulas according to axial length. Results: After 1 month, the axial length increased (right and left eyes: p &lt, 0.001 and p = 0.05, respectively). Based on keratometry, changes in the horizontal and vertical optical power [in diopters (D)] were not statistically significant. However, the IOL power changed after 1 month of ATD treatment in 64.3% of the patients. In 14 patients (50%), there was a 0.5–1.0 D IOL power decrease in single eyes, in two patients (7.1%), an IOL power decrease of 0.5–1.0 D in both eyes, and in two patients (7.1%), a 0.5 D IOL power increase in single eyes. The calculated IOL power values were lower after ATD treatment (right and left eyes, p = 0.010 and p = 0.018, respectively). Conclusions: The IOL power changed in 64.3% of GD patients after ATD treatment. Therefore, avoiding cataract surgery at the early stage of ATD treatment would be appropriate for selecting a more accurate IOL power.

Purpose In the present study, the authors investigated the effects of selenium on inflammation, hyaluronan production, and oxidative stress in primary cultured orbital fibroblasts of patients with Graves ophthalmopathy (GO). Methods Orbital adipose/connective tissue specimens were obtained during the course of orbital surgery for patients with GO (n = 7) and other noninflammatory problems (n = 5). After incubation with various concentrations of sodium selenite for 48 hours, supernatants from primary cultures were collected. Hyaluronan and cytokine levels were measured using commercially available enzyme-linked immunosorbent assay kits. To determine the effect of selenium on reactive oxygen species (ROS) production stimulated by H2O2 (100 μM) for 30 minutes, the cells were pretreated with various concentrations of sodium selenite for 60 minutes. Results Interleukin (IL)-6 and tumor necrosis factor-alpha levels were significantly higher in orbital fibroblasts of patients with GO than in orbital fibroblasts of control patients. Hyaluronan production was suppressed by selenium in cultured orbital fibroblasts of patients with GO. Inflammatory cytokines such as IL-1α, IL-8, and tumor necrosis factor-alpha were suppressed by selenium in cultured orbital fibroblasts of patients with GO. IL-1β and IL-6 were not suppressed by selenium in cultured orbital fibroblasts of patients with GO. Selenium pretreatment reduced intracellular ROS generation stimulated by H2O2 in cultured orbital fibroblasts of patients with GO. Conclusions In conclusion, hyaluronan production, inflammatory cytokines, and intracellular ROS generation were suppressed by selenium in cultured orbital fibroblasts of patients with GO. Several inflammatory cytokines may be suppressed by selenium in cultured orbital fibroblasts of patients with GO. This study provide the basis for use of selenium in the treatment of GO.

Transforming growth factor-β activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.

Morbihan disease (MD) is a rare form of rosacea that presents with chronic erythema and solid oedema on the upper half of the face. A diagnosis of MD can be made only after eliminating diseases that are similar in terms of clinical and histopathological presentation. The cause of MD remains unclear and no standardised treatment is yet available. MD often tends to be recalcitrant to therapies commonly used to treat rosacea, including systemic corticosteroids, antibiotics, isotretinoin, and topical regimens. Thus, surgical interventions have been attempted but most cases have exhibited unsatisfactory responses. We treated six patients with extreme eyelid lymphoedema without any other cutaneous manifestation. Surgical eyelid reduction was performed in all patients, because ptosis and narrowing of the visual field were the major complaints. Histopathological tests revealed various extents of perivascular and perifollicular inflammation, and dermal oedema. After surgery, patients with severe inflammatory cell infiltration (including mast cells) exhibited a tendency toward recurrence. Other patients with severe dermal oedema exhibited better responses to surgical reduction, and thus no recurrence. We propose that MD should be included in the differential diagnosis of persistent, chronic eyelid oedema even if eyelid oedema is the only manifestation; the histological features may aid in the selection of appropriate therapeutic strategies. We suggest that eyelid reduction surgery can be a useful treatment option for MD patients when there is no massive mast cell infiltration.

Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.

To investigate the characteristics of regenerated retinal pigment epithelial (RPE) cells after retinal laser photocoagulation in diabetic mice. C57BL/6J mice were used to induce diabetes using intraperitoneal injection of streptozotocin. The proliferation of RPE cells after laser photocoagulation was determined using the 5-ethynyl-2'-deoxyuridine (EdU) assay in both diabetic and wild-type mice. The morphological changes of RPE cells were evaluated by using Voronoi diagram from immunostaining for ß-catenin. Characteristics of regenerated cells were evaluated by quantifying the mRNA and protein levels of RPE and epithelial-mesenchymal transition (EMT) markers. There were significantly less EdU-positive cells in laser-treated areas in diabetic mice than wild-type mice. Hexagonality was extensively lost in diabetic mice. Many EdU-positive cells were co-localized with Otx2-positive cells in the center of the laser-treated areas in wild-type mice, but only EdU-positive cells were widely distributed in diabetic mice. Quantitative analysis of mRNA and protein levels showed that the expression levels of RPE markers, Pax6, Mitf, and Otx2, were significantly decreased in RPE of diabetic mice compared with that of wild-type mice, whereas the expression levels of EMT markers, vimentin and fibronectin, were significantly increased. The proliferation and hexagonality of regenerating RPE cells were impaired after laser photocoagulation, and the regenerated RPE cells lost their original properties in diabetic mice. Further clinical research is needed to elucidate the RPE response after laser photocoagulation in diabetic patients.

Background: The purpose of this study was to determine the potential effects of HM71224, a Bruton’s tyrosine kinase (BTK) inhibitor, as a monotherapy and in combination with methotrexate (MTX) in rats with collagen-induced arthritis (CIA) and to evaluate the effects of drug-drug interactions in combination therapy.Methods: The therapeutic effect of HM71224 and the combination effects with MTX were evaluated in CIA rats. Arthritis was induced through immunization by type II collagen in Lewis rats. The therapeutic effects were evaluated by arthritis score, paw volume, body weight changes, and histopathological examination. The effective dose levels (ED) were determined from arthritis score. Bone erosion, synovial inflammation, and cartilage degradation were assessed by staining with hematoxylin and eosin (H&E) and safranin-O in ankle joints. The drug-drug interaction between HM71224 and MTX was investigated by the comparison of plasma levels and monitoring of liver enzymes, creatinine and blood cell counts in CIA rats. Results: HM71224 dose dependently ameliorated the clinical signs, paw volume and body weight loss on the development of arthritis in CIA rats, and ED50 and ED90 values were 1.0 and 2.5 mg/kg, respectively. The combination of HM71224 with MTX decreased the arthritis score, bone erosion, synovitis and cartilage degradation compared with HM71224 and MTX alone; however, no drug-drug interactions in the plasma and no abnormalities in the liver enzymes, creatinine or blood cell counts were observed. Conclusion: BTK inhibition by HM71224 prevented the development of arthritis and the combination therapy with MTX produced additive therapeutic effects with no drug-drug interactions in CIA rats. Therefore, we suggest that HM71224 may be useful as a monotherapy and in combination with MTX for the treatment of patients with rheumatoid arthritis.

Background/AimsTo investigate the role of Wnt signalling in adipogenesis using an in vitro model of Graves’ orbitopathy (GO).MethodsOrbital fat was obtained from patients with GO and non-GO participants for primary orbital fibroblast (OF) culture. Expression levels of Wnt5a, Wnt10b, β-catenin, phospho-β-catenin and cyclin D1 were compared between GO and non-GO OFs. These expression levels were also determined during adipogenesis of GO and non-GO OFs. The effects of a stimulator and inhibitor of Wnt signalling on adipogenesis of GO and non-GO OFs were investigated.ResultsWestern blotting analysis showed significant reductions in β-catenin and cyclin D1 and significant enhancement of phospho-β-catenin in OFs from patients with GO, compared with OFs from non-GO participants (pConclusionThese results indicate that Wnt signalling inhibits adipogenesis in OFs from patients with GO and non-GO participants. Further studies are required to examine the potential of Wnt signalling as a target for therapeutic strategies.

AimTo examine the role of microRNA-146a (miR-146a) in the regulation of fibrosis in an in vitro model of Graves’ orbitopathy (GO).MethodsOrbital fat/connective tissues were harvested from patients with GO and non-GO for primary orbital fibroblast cultures. The effects of transforming growth factor-β (TGF-β), a potent cytokine that promotes fibrosis, on miR-146a expression were analysed in GO and non-GO orbital fibroblasts using quantitative real-time PCR. The effects of overexpressed miR-146a on TGF-β-induced fibrotic markers were examined in GO orbital fibroblasts by western blot analysis. Expression ofSma and Mad related family (Smad) 4/tumour necrosis factor receptor-associated factor 6 (TRAF6) after transfection of miR-146a mimics or inhibitors were examined.ResultsTGF-β induced an increase in miR-146a expression in orbital fibroblasts from patients with GO in a time-dependent and concentration-dependent manner. miR-146a mimics further decreased the production of TGF-β-induced fibronectin, collagen Iα and α-smooth muscle actin protein. The Smad4 and TRAF6 protein levels were significantly decreased by miR-146a mimics, compared with control mimics, and significantly increased on inhibition of miR-146a production compared with a control.ConclusionsmiR-146a plays a role as a negative regulator in the production of TGF-β-induced fibrotic markers. Thus, miR-146a may be involved in the regulation of fibrosis in orbital fibroblasts from patients with GO.

Introduction: The adenosine pathways via type A2a and A2b receptors are known to suppress immunity by regulating the functions of immune cells, such as macrophages, dendritic cells, MDSC, T cells and NK cells in tumor microenvironment. Also, the adenosine pathway through an A1 receptor induces tumor growth by promoting cancer cell proliferation. On the other hand, it has been recently reported that the downregulation of A1R induces expression of tumor PD-L1. Herein, we introduce a novel antagonist of adenosine receptor, HM87277, which has potent antagonistic activity against three types of adenosine receptors A1R, A2aR and A2bR, and present preclinical results that the triple antagonist HM87277 may be more effective in treating cancer patients through appropriate combination with immune checkpoint blockers (ICBs). Materials and Methods: Receptor binding affinities were assessed using human adenosine receptors of type A1, A2a, A2b and A3. Cellular functional activity tests such as cAMP production. To identify adenosine receptor downstream signaling in cancer cells, p-ERK and p-JNK were measured by western blotting in SK-BR3 cells. PD-L1 induction by adenosine receptor antagonist was determined by flow cytometry using Canto II (BD) in PD-L1 expressing SK-MEL-28 cells. For cytotoxicity assay of T cell, isolated human CD8+ T cells were co-cultured with A1R expressing cancer cells in the presence of a high concentration of adenosine. Antitumor activity of HM87277 alone and in combination with ICBs was assessed in syngeneic mouse models using murine cancer cell lines. Results: HM87277 showed strong binding affinity toward human adenosine receptors of type A1, A2a and A2b, and potently inhibited the NECA-mediated production of intracellular cAMP in HEK293-A2aR cells. HM87277 significantly increased the proliferation of effector T cells. HM87277 potently inhibited the p-ERK and p-JNK, and induced the expression of PD-L1 in A1R-expressing cancer cells. As well, the combination of HM87277 and anti-PD-L1 mAb was observed to have synergistic inhibitory effect on tumor cell growth in co-culture with SK-MEL-28 and CD8 + T cells. Furthermore, in the mouse syngeneic model using murine cancer cell lines, HM87277 effectively inhibited tumor growth alone or in combination with anti-PD-L1 mAb. Conclusion: These results indicate that a triple antagonist HM87277, which simultaneously antagonizes type A1, A2a and A2b adenosine receptors, may not only stimulate immune cells such as cytotoxic CD8+ T cell but also inhibit the growth of cancer cells themselves through inhibition of ERK and JNK pathway. In addition, it showed a strong combination effect by enhancing the sensitivity to ICBs through the increase of PD-L1 in tumor cells. Therefore, it is considered that the triple antagonist HM87277 is worth developing as a potential anticancer agent. Citation Format: Sunyoung Jang, Seunah Jun, Hosun Lee, Yongtaek Lee, Joo-Yun Byun, Junghwa Park, Yu-Yon Kim, Young Gil Ahn, YoungHoon Kim, Kwee Hyun Suh. Discovery and characterization of a novel triple A1/A2a/A2b adenosine receptor antagonist for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1704.

To compare preoperative incision design markings between both eyelids in upper blepharoplasty.This retrospective study examined 22 patients who underwent bilateral upper blepharoplasty surgery resulting from senile dermatochalasis and/or blepharoptosis. The initial preoperative incision design markings were drawn with the patient sitting upright. Then, with the patient in a supine position, preoperative design photographs were taken. The authors measured medial canthal excision angle, maximal lid excision height, maximal lid excision width, peak point angle, and peak point distance and compared measurements between both upper eyelids designs using Image J software.The mean medial canthal excision angle, maximal lid excision height, and maximal lid excision width for the right side (30.68° ± 10.16°, 1.17 ± 0.24 cm, and 0.72 ± 0.19 cm) were significantly different from those for the left side (35.39° ± 13.82°; Plt; 0.001, 1.24 ± 0.25 cm; P = 0.002, and 0.77 ± 0.21 cm; P = 0.011). The mean peak point angle and peak point distance for the right side (15.67° ± 5.09°, 2.41° ± 0.31°) were significantly different from those for the left side (18.11° ± 5.49°; P = 0.001, 2.22 ± 0.28 cm; P = 0.001).In upper blepharoplasty, the preoperative incision marking design measurements of the left side were significantly greater than those of the right side. The symmetry can therefore be maximized by including the asymmetries in the preoperative design.

PURPOSE To investigate the surgical outcome of grafting acellular human dermis compared with concurrent lower eyelid retractor recession during swinging eyelid orbital decompression for correction of lower eyelid retraction in patients with Graves' orbitopathy. METHODS Institutional Review Board-approved retrospective nonrandomized study of 54 Graves' orbitopathy patients (95 eyes) from 2008 to 2012. Patients who received decompression were divided into 3 groups: Group 1 with conjunctival lengthening using 0.3-mm thickness AlloDerm (36 eyes), Group 2 with inferior retractor recession (33 eyes), and Group 3 with decompression only (26 eyes). Outcome measures included lower eyelid height, inferior sclera show, cosmetic appearance, and complications. RESULTS Baseline clinical characteristics and the degree of improvement of exophthalmos were not different between groups. Preoperative MRD2 was higher in group 1 (8.0 mm) than in groups 2 (6.9 mm, p < 0.001) and 3 (6.6 mm, p < 0.001). Mean improvement of MRD2 as well as postoperative improvement of inferior scleral show at postoperative 4 to 6 months were significantly higher in group 1 (2.7 mm) than in groups 2 (1.8 mm, p < 0.001) and 3 (1.2 mm, p < 0.001). CONCLUSION Simultaneous correction of lower eyelid retraction using thin AlloDerm during swinging eyelid orbital decompression maximizes improvement of lower eyelid retraction compared with concurrent inferior retractor recession.

Purpose A mixture of 2% lidocaine with epinephrine and bupivacaine was developed to achieve the fast-onset anesthetic effect of lidocaine and the long-lasting effect of bupivacaine. The authors compared pain scores between 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture during local anesthesia for eyelid surgeries. Methods This was a double-blind, randomized, prospective, comparative study. In total, 120 consecutive patients (43 males, 77 females, mean age = 47.2 ± 21.2) who underwent bilateral eyelid surgery under subcutaneous anesthesia were asked to report pain scores for each eye during the first injection of anesthesia. Each patient was randomly assigned to receive 1 of the 3 anesthetic agents in 1 eyelid, and 1 of the remaining 2 agents in the other. Results The pH values of the 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture were 6.23 ± 0.21, 4.21 ± 0.37, and 3.87 ± 0.19, respectively. The pain scores of each were 4.3 ± 1.8, 5.1 ± 1.8, and 5.7 ± 1.9, respectively. The 2% lidocaine with epinephrine produced a statistically significantly higher pain score than 2% lidocaine (p = 0.044, generalized estimating equation method). The mixture also showed a significantly higher pain score than 2% lidocaine (p = 0.003, generalized estimating equation method). Conclusions Epinephrine seemed to increase subjective pain scores. Compared with 2% lidocaine with epinephrine, 2% lidocaine with epinephrine-bupivicaine mixture was not significantly different in terms of subjective symptoms or pH.