Characteristic differences between full-term and premature infants with intermittent exotropia.

Strabismus is prevalent among preterm infants of low gestational age and birth weight in Southeast Asian countries, with intermittent exotropia (IXT) being the most common type in South Korea. In this retrospective, cross-sectional study, we investigated the differences between full-term and premature infants with IXT. IXT patients with available childbirth history were divided into two groups: preterm vs. full-term and low birth weight (LBW) vs. normal birth weight (NBW). Parameters related to exotropia including parental heredity, surgical history, and treatment options were investigated. In univariate regression for gestational age, a result of ≥ 100 s in the Titmus test was 1.352 times more frequent in preterm than in full-term infants. When birth weight was considered instead, a result of ≥ 100 s in the Titmus test was 1.412 times more frequent in the LBW compared to the NBW group. In multivariate regression for birth weight, the frequency of a result of ≥ 100 s in the Titmus test for the LBW group was 2.032 times higher than that for the NBW group. It is particularly important to examine stereopsis in preterm and LBW patients affected by IXT to ensure timely surgical planning and avoid potential recurrence after surgery.

Beyond complete remission: A comparative analysis of long-term laryngeal function in patients with hypopharyngeal and laryngeal cancer following radiotherapy and concurrent chemoradiation.

BACKGROUND: This study evaluates functional larynx preservation in patients with hypopharyngeal cancer (HPC) and laryngeal cancer (LC) who achieved complete remission following radiotherapy (RT) or concurrent chemoradiation (CCRT). METHODS: HPC and LC patients treated with RT/CCRT from 1999 to 2017 were retrospectively analyzed. Severe late dysphagia and tracheostomy cases were assessed to determine laryngeal function. Long-term preservation rate of functional larynx and associated factors were evaluated. RESULTS: Of 152 patients (55 HPC, 97 LC), nine developed severe dysphagia, occurring on average 58.2 months post-treatment. HPC and cervical node metastasis significantly increased the risk of laryngeal function impairment (p < 0.001 and p = 0.014, respectively), presenting a continued decline in functional larynx preservation rate beyond 10 years. CONCLUSIONS: Patients with HPC and cervical node metastasis demonstrate an increased risk for long-term laryngeal function impairment despite successful oncologic outcomes. This risk extends beyond 10 years, underscoring the need for prolonged monitoring and comprehensive support.

Three-dimensional computed tomography evaluation of the ulnocarpal joint under stress loading.

LEVEL OF EVIDENCE: IV.

Choosing Wisely Between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment for Elderly Glioblastoma Patients.

Purpose: This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics for elderly patients with glioblastoma (eGBM), and to compare the efficacy of different radiotherapy schedules. Materials and Methods: This multi-institutional retrospective study included patients aged ≥65 years who underwent surgical resection followed by radiotherapy with or without temozolomide (TMZ) for newly diagnosed eGBM. Based on the significant factors identified in the multivariate analysis for overall survival (OS), the molecular GPA for eGBM (eGBM-molGPA) was established. Results: A total of 334 and 239 patients who underwent conventionally fractionated radiotherapy (CFRT) and hypofractionated radiotherapy (HFRT) were included, respectively, with 86% of patients receiving TMZ-based chemoradiation. With a median follow-up of 17.4 months (range, 3.3-149.9), the median OS was 18.7 months for CFRT+TMZ group, 15.1 months for HFRT+TMZ group, and 10.4 months for radiotherapy alone group (CFRT+TMZ vs. HFRT+TMZ: HR 1.52, p<0.001; CFRT+TMZ vs. radiotherapy alone: HR 2.52, p<0.001). In a combined analysis with the NOA-08 and NORDIC trials, CFRT+TMZ group exhibited the highest survival rates among all treatment groups. The eGBM-molGPA, which integrated four clinical and three molecular parameters, stratified patients into low-, intermediate-, and high-risk groups. CFRT+TMZ significantly improved OS compared to HFRT+TMZ or radiotherapy alone in the low-risk (p=0.023) and intermediate-risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p=0.770). Conclusion: CFRT+TMZ may be more effective than HFRT+TMZ or radiotherapy alone for selected eGBM patients. The novel eGBM-molGPA model can guide treatment selection for this patient population.

Randomized controlled trial on the efficacy of a custom-made, fully guided implant system for flapless crestal sinus floor elevation: Accuracy and patient-reported outcomes.

OBJECTIVE: To compare fully guided flapless implant surgery using a light-cured surgical guide (FG group) with partially guided open flap surgery (PG group) in the posterior maxilla when performing simultaneous sinus floor elevation in terms of the accuracy, time requirements, and patient/clinician-reported outcomes (PROMs and CROMs). MATERIALS AND METHODS: In this study, 56 tissue-level implants were placed with crestal sinus floor elevation in 56 patients at single-tooth sites, with 28 implants allocated to the PG group and 28 to the FG group. The deviations of the placed implants from the virtually planned positions were measured at the implant platform and apex and for the angular deviation. The presurgical preparation time and the duration of surgery were measured. PROMs and CROMs were made by administering questionnaires at multiple time points. RESULTS: Horizontal deviations at the platform and apex and the angular deviation were significantly smaller in the FG group than the PG group (p < .05). Presurgical preparation and surgery times were significantly shorter in the FG group (p < .001). Patient satisfaction and willingness to receive repeat treatment were significantly better in the FG group than in the PG group (p < .005 and .025, respectively). Clinicians were more satisfied in the FG group than the PG group (p < .05). CONCLUSION: When placing an implant with sinus floor elevation, the flapless approach using a fully guided surgical system can be more accurate, faster, and increase the satisfaction of both the clinician and patient compared to the partially guided surgery.

Identification of intracellular bacteria from multiple single-cell RNA-seq platforms using CSI-Microbes.

The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data and for analyzing differential abundance of taxa. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial unique molecular identifiers by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3' v3 and 5') as the best suited approach. We analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that up-regulate proinflammatory cytokines like IL1Β and CXCL8, while infected tumor cells up-regulate antigen processing and presentation pathways. These results show that myeloid cells with bacteria engulfed are a major source of bacterial RNA within the tumor microenvironment (TME) and may inflame the TME and influence immunotherapy response.

Aging limits stemness and tumorigenesis in the lung by reprogramming iron homeostasis.

Aging is associated with a decline in the number and fitness of adult stem cells 1-4 . Aging-associated loss of stemness is posited to suppress tumorigenesis 5,6 , but this hypothesis has not been tested in vivo . Here, using physiologically aged autochthonous genetically engineered mouse models and primary cells 7,8 , we demonstrate aging suppresses lung cancer initiation and progression by degrading stemness of the alveolar cell of origin. This phenotype is underpinned by aging-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, leading to a functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescue stemness and promote tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1- lipocalin-2 axis is detrimental to young alveolar cells via induction of ferroptosis. We find that aging-associated DNA hypomethylation at specific enhancer sites associates with elevated NUPR1 expression, which is recapitulated in young alveolar cells by inhibition of DNA methylation. We uncover that aging drives a functional iron insufficiency, which leads to loss of stemness and tumorigenesis, but promotes resistance to ferroptosis. These findings have significant implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate in young individuals, revealing a critical window for such cancer prevention efforts.

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors.

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

Isolation, Culture, and Phenotypic Analysis of Murine Lung Organoids.

Three-dimensional (3D) organoid cultures retain self-renewing stem cells that differentiate into multiple cell types that display spatial organization and functional key features, providing a highly physiological relevant system. Here we describe a strategy for the generation of 3D murine lung organoids derived from freshly isolated primary tracheal and distal lung epithelial stem cells. Isolated tracheas are subjected to enzymatic digestion to release the epithelial layer that is then dissociated into a single cell suspension for organoid culture. Lung epithelial cells are obtained from dissected lobes, which are applied to mechanical and enzymatic dissociation. After flow sorting, organoids are established from tracheal basal, secretory club, and alveolar type 2 cells in the defined conditioned medium that is required to sustain organoid growth and generate the differentiated cells. Multi-cell-type organoid co-culture replicates niches for distal epithelial stem cells to differentiate into bronchiolar and alveolar cell types. Established organoids can be fixed for wholemount staining and paraffin embedding, or passaged for further culture. Taken together, this protocol provides an efficient and validated approach to generate murine lung organoids, as well as a platform for further analysis.

Using 3-Dimensional Cultures to Propagate Genetically Modified Lung Organoids.

Transformed lung organoids have extensive applications in lung cancer modeling and drug screening. Traditional two-dimensional (2D) cultures fail to propagate a large subpopulation of murine primary tumors in vitro. However, three-dimensional (3D) air-liquid interface (ALI) cultures, which are employed to grow normal lung organoids, can be used to efficiently culture cancerous lung tumor cells. Here, we detail a procedure for cultivating genetically modified lung organoids in 3D-ALI cultures. This protocol contains two parts. The first part describes how to transduce lung epithelial cells, which are either freshly sorted from lungs or from actively growing murine organoids, with virus in order to modify gene expression. The target lung cells are incubated with virus for 1-2 h for transduction. Then, the transduced cells are thoroughly washed and mixed with stromal support cells and Matrigel and are loaded into transwell inserts for culture and validated for genetic modifications through downstream assays. The second part describes how to isolate tumor cells growing orthotopically in genetically engineered mouse models to produce organoid cell lines that can be used for ex vivo drug discovery assays. For this protocol, tumors are isolated from lungs of mice, finely chopped and washed. Then, tumor chunks are mixed with Matrigel for 3D-ALI culture. Finally, organoids budding from tumor chunks are trypsinized and passaged to establish an organoid line. Together these two protocols provide a promising platform to study the genesis, progression, and treatment of lung cancer.

Selective delivery of imaging probes and therapeutics to the endoplasmic reticulum or Golgi apparatus: Current strategies and beyond.

To maximize therapeutic effects and minimize unwanted effects, the interest in drug targeting to the endoplasmic reticulum (ER) or Golgi apparatus (GA) has been recently growing because two organelles are distributing hubs of cellular building/signaling components (e.g., proteins, lipids, Ca2+) to other organelles and the plasma membrane. Their structural or functional damages induce organelle stress (i.e., ER or GA stress), and their aggravation is strongly related to diseases (e.g., cancers, liver diseases, brain diseases). Many efforts have been developed to image (patho)physiological functions (e.g., oxidative stress, protein/lipid-related processing) and characteristics (e.g., pH, temperature, biothiols, reactive oxygen species) in the target organelles and to deliver drugs for organelle disruption using organelle-targeting moieties. Therefore, this review will overview the structure, (patho)physiological functions/characteristics, and related diseases of the organelles of interest. Future direction on ER or GA targeting will be discussed by understanding current strategies and investigations on targeting, imaging/sensing, and therapeutic systems.

Bidirectional activation of stem-like programs between metastatic cancer and alveolar type 2 cells within the niche.

A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.

Red2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice.

Image-based lineage tracing enables tissue turnover kinetics and lineage potentials of different adult cell populations to be investigated. Previously, we reported a genetic mouse model system, Red2Onco, which ectopically expressed mutated oncogenes together with red fluorescent proteins (RFP). This system enabled the expansion kinetics and neighboring effects of oncogenic clones to be dissected. We now report Red2Flpe-SCON: a mosaic knockout system that uses multicolor reporters to label both mutant and wild-type cells. We develop the Red2Flpe mouse line for red clone-specific Flpe expression, as well as the FRT-based SCON (Short Conditional IntrON) method to facilitate tunable conditional mosaic knockouts in mice. We use the Red2Flpe-SCON method to study Sox2 mutant clonal analysis in the esophageal epithelium of adult mice which reveal that the stem cell gene, Sox2, is less essential for adult stem cell maintenance itself, but rather for stem cell proliferation and differentiation.

Safety assessment of cocamidopropyl betaine, a cosmetic ingredient.

Cocamidopropyl betaine (CAPB) is a surfactant derived from coconut oil that is widely used in cosmetics and personal products for several purposes, such as a surfactant, foam booster, mildness, and viscosity control. Cocamidopropyl betaine is used at concentrations up to 30% in cosmetics. The acute toxicity, skin irritation, eye irritation, skin sensitization, repeated dose toxicity, genotoxicity, carcinogenicity, and phototoxicity of cocamidopropyl betaine were evaluated. Cocamidopropyl betaine was observed to induce mild skin irritation, eye irritation and skin sensitization. The NOAEL of cocamidopropyl betaine was determined to be 250 mg/kg/day based on the results of a 92-day repeated-dose oral toxicity study in rats. The systemic exposure dose of cocamidopropyl betaine was estimated to range from 0.00120 to 0.93195 mg/kg/day when used in cosmetic products. The margin of safety of cocamidopropyl betaine was calculated to be greater than 100 when used at a maximum concentration of 6% in leave-on products and 30% in rinse-off products, suggesting that its use in cosmetic products is safe under current usage conditions.

Effect of 4-week preoperative prism adaptation in preventing postoperative residual esotropia.

BACKGROUND: Preoperative prism adaptation (PPA) simulates postoperative status and possibly can predict postoperative undercorrection before surgery in esotropia. The present study aimed to assess the effect of 4-week PPA in preventing postoperative residual esotropia. METHODS: Seventy-five (75) esotropes who had undergone surgery at a single strabismus center were retrospectively enrolled. They included 25 basic, 31 acute comitant, 10 partially accommodative, and 9 recurrent esotropia patients. The preoperative deviation angle, which had been determined using the alternating prism and cover test, was fully corrected with press-on prisms 4 weeks before surgery. If there was an increase of 5 PD or more of esodeviation, the prisms were changed accordingly at 2 weeks. The deviation angle measured at 4 weeks was determined as the surgical target angle. Patients were then divided into increase (≥ 5 PD increase of angle during 4-week PPA) and non-increase groups. Success was defined as either esodeviation of 8 PD or under or exodeviation of 5 PD or under at distance at postoperative 6 months. RESULTS: The increase group included 44 patients (58.7%). The mean deviation angle before PPA was 27.4 PD, and after the 4-week PPA, there was an average increase of 9.4 PD. The success rate was 90.9% in the increase group and 96.8% in the non-increase group (p = 0.316). There were no intergroup differences in preoperative clinical characteristics, esotropia types, postoperative deviation angle or postoperative near stereopsis (p > 0.05). CONCLUSIONS: The results of this study indicated a beneficial effect of 4-week PPA in esotropia of various types, specifically by uncovering the hidden esodeviation in the increase group and simulating the postoperative alignment in both the increase and the non-increase groups.

Beyond nanoparticle-based oral drug delivery: transporter-mediated absorption and disease targeting.

Various strategies at the microscale/nanoscale have been developed to improve oral absorption of therapeutics. Among them, gastrointestinal (GI)-transporter/receptor-mediated nanosized drug delivery systems (NDDSs) have drawn attention due to their many benefits, such as improved water solubility, improved chemical/physical stability, improved oral absorption, and improved targetability of their payloads. Their therapeutic potential in disease animal models (e.g., solid tumors, virus-infected lungs, metastasis, diabetes, and so on) has been investigated, and could be expanded to disease targeting after systemic/lymphatic circulation, although the detailed paths and mechanisms of endocytosis, endosomal escape, intracellular trafficking, and exocytosis through the epithelial cell lining in the GI tract are still unclear. Thus, this review summarizes and discusses potential GI transporters/receptors, their absorption and distribution, in vivo studies, and potential sequential targeting (e.g., oral absorption and disease targeting in organs/tissues).

Synchrotron Analysis of Damaged Extraction Sockets Augmented Using a Synthetic Bone Block: A Pilot Study.

This study aimed to investigate the dimensional stability and quality of the alveolar ridge augmented using a synthetic bone block (SBB) at damaged extraction sockets. Four participants were included, and socket augmentation was performed using SBB and a collagen membrane. Intraoral and CBCT scans were performed before extraction (baseline), immediately postoperative (IP), and at 6 months postoperative (6M). At 6M, a trephine biopsy sample was obtained during implant placement, and the sample was observed using synchrotron. Soft tissue profile changes were assessed using profilometric analysis of the intraoral scan data, while dimensional changes in hard tissue were evaluated based on CBCT measurements. Bone quality was analyzed using synchrotron imaging. There were minimal changes in the soft tissue profile between baseline and IP, baseline and 6M, and IP and 6M (0.11 ± 1.08 mm3, 0.02 ± 0.8 mm3, and -0.65 ± 0.82 mm3, respectively). Horizontal bone width was measured at 1-mm increments from the augmented bone crest to 5 mm apically and revealed only a slight reduction (< 1 mm) at all levels between IP and 6M. The augmented bone height was well maintained from IP until 6M (-0.21 ± 0.53 mm). Synchrotron analysis revealed low to moderate bone quality after 6M (percentage of new bone: 16.49% ± 4.91%). Socket augmentation using SBB appears to be a viable technique for regenerating damaged extraction sockets, with the augmented ridge dimensions maintained up to 6M. Further long-term randomized clinical trials are needed.

Clinical significance of residual ischaemia in acute myocardial infarction complicated by cardiogenic shock undergoing venoarterial-extracorporeal membrane oxygenation.

AIMS: Although culprit-only revascularization during the index procedure has been recommended in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS), the reduction in residual ischaemia is also emphasized to improve clinical outcomes. However, few data are available about the significance of residual ischaemia in patients undergoing mechanical circulatory supports. This study aimed to evaluate the effects of residual ischaemia on clinical outcomes in patients with AMI undergoing venoarterial-extracorporeal membrane oxygenation (VA-ECMO). METHODS AND RESULTS: Patients with AMI with multivessel disease who underwent VA-ECMO due to refractory CS were pooled from the RESCUE and SMC-ECMO registries. The included patients were classified into three groups according to residual ischaemia evaluated using the residual Synergy between percutaneous coronary intervention with Taxus and Cardiac Surgery (SYNTAX) score (rSS): rSS = 0, 0 < rSS ≤ 8, and rSS > 8. The primary outcome was 1-year all-cause death. A total of 408 patients were classified into the rSS = 0 (n = 100, 24.5%), 0 < rSS ≤ 8 (n = 136, 33.3%), and rSS > 8 (n = 172, 42.2%) groups. The cumulative incidence of the primary outcome differed significantly according to rSS (33.9 vs. 55.4 vs. 66.1% for rSS = 0, 0 < rSS ≤ 8, and rSS > 8, respectively, overall P < 0.001). In a multivariable model, rSS was independently associated with the risk of 1-year all-cause death (adjusted hazard ratio 1.03, 95% confidence interval 1.01-1.05, P = 0.003). Conversely, the baseline SYNTAX score was not associated with the risk of the primary outcome. Furthermore, when patients were stratified by rSS, the primary outcome did not differ significantly between the high and low delta SYNTAX score groups. CONCLUSION: In patients with AMI with refractory CS who underwent VA-ECMO, residual ischaemia was associated with an increased risk of 1-year mortality. Future studies are needed to evaluate the efficacy and safety of revascularization strategies to minimize residual ischaemia in patients with CS supported with VA-ECMO. CLINICAL TRIAL REGISTRATION: REtrospective and Prospective Observational Study to Investigate Clinical oUtcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With Cardiogenic Shock (RESCUE), NCT02985008.

Ribosomal S6 kinase 2-forkhead box protein O4 signaling pathway plays an essential role in melanogenesis.

Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4's transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis.

Changes in intraocular pressure following intravitreal dexamethasone implant in patients with history of glaucoma filtration surgery.

PURPOSE: This study aimed to evaluate changes in intraocular pressure following intravitreal dexamethasone implant injection, specifically in patients undergoing glaucoma filtration surgery. METHODS: The degree of increase in intraocular pressure was compared retrospectively among three groups. Group 1 comprised patients who underwent prior glaucoma filtration surgery (54 eyes). Group 2 included patients with or suspected glaucoma without such surgical history (20 eyes). Group 3 included patients without glaucoma (33 eyes). Pressure measurements were taken before the injection and at 1, 2, 3, and 6 months post-injection. A subgroup analysis was performed for pressure > 35 mmHg, > 30 mmHg, > 25 mmHg, and a difference > 10 mmHg between the peak and baseline pressure. RESULTS: Group 1 consistently displayed lower pressures compared with Group 2, with significant difference at both 1- and 6-month post-injections (15.09 mmHg vs. 18.10 mmHg, P = 0.042 and 13.91 mg vs. 17.25 mmHg, P = 0.040). The proportion of patients in Group 1 and Group 3 with pressures > 25 mmHg, > 30 mmHg, and a difference > 10 mmHg did not significantly differ (15.6% vs. 9.5%, P = 0.231; 3.1% vs. 2.3%, P = 0.867; and 17.1% vs. 7.1%, P = 0.231). Notably, Group 2 exhibited a significantly higher proportion within each category (> 25 mmHg, 24.0%; > 30 mmHg, 20.0%; > 10 mmHg difference, 28.0%). CONCLUSION: Intravitreal dexamethasone implant did not increase the risk of elevated intraocular pressure in patients with a history of glaucoma filtration surgery compared with patients with suspected glaucoma; the risk was similar to those without glaucoma.