Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.

Clinicopathological and immunohistochemical characteristics of bullous pilomatricoma: a retrospective, single-center study, and comparison with ordinary pilomatricoma.

BACKGROUND: Bullous pilomatricoma is a rare variant of pilomatricoma. As it has been published in sporadic case reports, a limited understanding of its clinicopathological characteristics restricts its effective diagnosis and treatment. OBJECTIVES: This study aimed to analyze the clinicopathological and immunohistochemical characteristics of bullous pilomatricoma to better understand the bullous transformation of pilomatricoma. METHODS: The authors conducted a retrospective study of 12 patients with bullous pilomatricoma and compared their clinical, histopathological, and immunohistochemical data with those of patients with ordinary pilomatricoma. RESULTS: Bullous pilomatricoma showed no sex preference, with a mean onset age of 31.2 years. The common sites were the upper extremities and trunk. Bullous pilomatricoma had a shorter disease duration, a larger diameter, and a greater tendency to increase in size than those of ordinary pilomatricoma. Histopathologically, bullous pilomatricoma had a shorter duration, lesser calcification, more mitotic figures, and distinct dermal features from those of ordinary pilomatricoma. Immunohistochemically, the expression of Matrix Metalloprotease (MMP)-2, MMP-9, vascular endothelial growth factor receptor-3 (VEGFR-3), and VEGF-C was elevated. STUDY LIMITATIONS: The study was retrospective, and the sample size was small. CONCLUSION: The distinctive features of bullous pilomatricoma potentially result from dermal changes associated with the release of angiogenic factors and proteolytic enzymes. This comprehensive analysis provides novel insights into the clinical features and pathogenesis of bullous pilomatricoma.

Tumor-specific cytolysis by peptide-conjugated echogenic polymer micelles.

Interest in multifunctional polymer nanoparticles for targeted delivery of anti-cancer drugs has grown significantly in recent years. In this study, tumor-targeting echogenic polymer micelles were prepared from poly(ethylene glycol) methyl ether-alkyl carbonate (mPEG-AC) derivatives, and their potential in cancer therapy was assessed. Various mPEG derivatives with carbonate linkages were synthesized via an alkyl halide reaction between mPEG and alkyl chloroformate. Micelle formation using polymer amphiphiles in aqueous media and the subsequent carbon dioxide (CO2) gas generation from the micelles was confirmed. Their ability to target neuroblastoma was substantially enhanced by incorporating the rabies virus glycoprotein (RVG) peptide. RVG-modified gas-generating micelles significantly inhibited tumor growth in a tumor-bearing mouse model owing to CO2 gas generation within tumor cells and resultant cytolytic effects, showing minimal side effects. The development of multifunctional polymer micelles may offer a promising therapeutic approach for various diseases, including cancer.

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia.

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface-a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia.

Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia.

Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood-brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.

Multi-Functional Polymer Nanoparticles with Enhanced Adipocyte Uptake and Adipocytolytic Efficacy.

Multi-functional polymer nanoparticles have been widely utilized to improve cellular uptake and enhance therapeutic efficacy. In this study, it is hypothesized that the cellular uptake of poly(D,L-lactide-co-glycolide) (PLG) nanoparticles loaded with calcium carbonate minerals into adipocytes can be improved by covalent modification with nona-arginine (R9 ) peptide. It is further hypothesized that the internalization mechanism of R9 -modified PLG nanoparticles by adipocytes may be contingent on the concentration of R9 peptide present in the nanoparticles. R9 -modified PLG nanoparticles followed the direct penetration mechanism when the concentration of R9 peptide in the nanoparticles reached 38 µM. Notably, macropinocytosis is the major endocytic mechanism when the R9 peptide concentration is ≤ 26 µM. The endocytic uptake of the nanoparticles effectively generated carbon dioxide gas at an endosomal pH, resulting in significant adipocytolytic effects in vitro, which are further supported by the findings in an obese mouse model induced by high-fat diet. Gas-generating PLG nanoparticles, modified with R9 peptide, demonstrated localized reduction of adipose tissue (reduction of 13.1%) after subcutaneous injection without significant side effects. These findings highlight the potential of multi-functional polymer nanoparticles for the development of effective and targeted fat reduction techniques, addressing both health and cosmetic considerations.

Three Cases of Recalcitrant Pediatric Tinea Capitis Successfully Treated with Griseofulvin.

Tinea capitis is an infection of the scalp hair follicles and surrounding skin that primarily occurs in prepubertal children. Microsporum canis remains the most common pathogen causing tinea capitis in Asian countries, including South Korea, although the causative organism of this condition varies across geographical regions and time periods. Systemic antifungal agents are the mainstay treatments for tinea capitis; however, the therapeutic responses to antifungal drugs may vary depending on the causative species, and treatment failure may occur owing to drug resistance. Although dermatophytosis resistant to clinical treatment have been increasingly encountered, recalcitrant tinea capitis cases have rarely been reported. Herein, we report three cases of tinea capitis caused by M. canis in children. All three patients showed unsatisfactory clinical responses to prolonged courses of oral terbinafine or itraconazole without achieving mycological cure; however, they were successfully treated with oral griseofulvin. Although griseofulvin is not currently available or licensed for use in many countries, including South Korea, it is one of the most effective agents against Microsporum species and remains the most widely used first-line treatment for tinea capitis in children, based on dermatology textbooks and reliable treatment guidelines.

Facial tinea incognito: a clinical, dermoscopic and mycological study of 38 cases.

BACKGROUND: Tinea incognito (TI) is a dermatophytic infection of the skin that is modified by steroid use. As a result, it shows atypical clinical presentations that can lead to misdiagnosis. TI occurring on the face is most frequently misdiagnosed as cutaneous fungal infection, however, very limited information is available on facial TI. OBJECTIVES: This study aimed to characterize the clinical, dermoscopic and mycological features of facial TI. MATERIALS & METHODS: We retrospectively evaluated 38 patients with mycologically proven facial TI at a single institution in Korea between July, 2014 and July, 2021. RESULTS: The patients had a mean age of 59.6 ± 20.4 years and showed a slight female predominance (male-to-female ratio of 1:1.38). The most common clinical presentation was an eczema-like pattern (47.4%), followed by rosacea-like (15.8%), psoriasis-like (10.5%), lupus erythematosus-like (10.5%), cellulitis-like (7.9%), and folliculitis-like (7.9%) patterns. The mean duration from disease onset to diagnostic confirmation was 3.4 months. Overall, 78.9% of the patients had accompanying chronic systemic diseases, and 57.9% had concurrent tinea infections at other skin sites, mainly the feet and toenails. On dermoscopy, scales and dilated vascular patterns (arborizing vessels and telangiectasia) were commonly observed on glabrous skin, with follicular patterns, such as black dots, broken hairs, and empty follicles. The characteristic trichoscopic features were comma, corkscrew, Morse code-like, and translucent hairs. CONCLUSION: The clinical characteristics and distinct dermoscopic features described in this article may aid in the differential diagnosis of facial TI while reducing diagnostic delays and unnecessary treatments.

Reconfigurable Single-Layer Graphene Radio Frequency Antenna Device Capable of Changing Resonant Frequency.

A reconfigurable passive device that can manipulate its resonant frequency by controlling its quantum capacitance value without requiring complicated equipment has been experimentally investigated by modifying the Fermi level of large-area graphene using an external electric field. When the total capacitance change, caused by the gate bias in the passive graphene device, was increased to 60% compared to the initial state, a 6% shift in the resonant frequency could be achieved. While the signal characteristics of the graphene antenna are somewhat inferior compared to the conventional metal antenna, simplifying the device structure allowed reconfigurable characteristics to be implemented by using only the gate bias change.

Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer's Disease.

Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer's disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aß) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.

Association of adenotonsillar disease and adenotonsillectomy with the development of vitiligo: A nationwide population-based cohort study.

Background: Vitiligo is a common acquired skin depigmentation disorder and is associated with various other autoimmune diseases which include thyroid disease and rheumatoid arthritis. Similarly, adenotonsillar disease (ATD) may induce inflammatory or autoimmune diseases in other organs which include the skin. However, the influence of ATD on the development of vitiligo has not been studied. Objectives: To determine the association between ATD and adenotonsillectomy, and the development of vitiligo. Design and methods: Using data from the National Health Insurance Service database, patients diagnosed with ATD between 2008 and 2010 were included in the study. We performed two rounds of 1:1 propensity score matching in the ATD and adenotonsillectomy groups. The ATD and non-ATD groups both included 206,514 individuals. Among the ATD group, the adenotonsillectomy and non-adenotonsillectomy groups both included 23,354 individuals. Each individual was monitored until 2019. The primary end point was the risk of vitiligo. Using the Cox Proportional Hazards model, the incidence of vitiligo and the hazard ratio (HR) were calculated. Results: The incidence of vitiligo was 1.16-fold higher in the ATD group than in the non-ATD group [adjusted HR (aHR), 1.16; 95% confidence interval (CI), 1.09-1.24] and 0.82-fold lower in the adenotonsillectomy group than in the non-adenotonsillectomy group (aHR, 0.82; 95% CI, 0.68-0.99). Additionally, the other risk factors for developing vitiligo included thyroid disease (aHR, 1.48; 95% CI, 1.11-1.98), age younger than 30 years (aHR, 1.18; 95% CI, 1.09-1.27), and age over 60 years (aHR, 1.22; 95% CI, 1.06-1.41), whereas factors including rural residency (aHR, 0.91; 95% CI, 0.85-0.98) and low economic status (aHR 0.87; 95% CI, 0.82-0.93) were associated with decreased incidence of vitiligo. Conclusion: In this study, ATD increases the risk of vitiligo and adenotonsillectomy attenuates its development. Clinicians should consider ATD as a pathogenic factor for vitiligo and the potential effect of adenotonsillectomy in its management.

In vitro culture of hematopoietic stem cell niche using angiopoietin-1-coupled alginate hydrogel.

Stem cells exist and maintain their quiescence and pluripotency in stem cell niche. Here, we hypothesized that regulation of cell-cell interactions using a polymeric scaffold as synthetic extracellular matrix (ECM) could be critical in creating a hematopoietic stem cell (HSC) niche in vitro. Angiopoietin-1 (Ang1) binds to the tyrosine kinase receptor (Tie2), and regulation of the Tie2/Ang1 interaction is important in maintaining the quiescence of HSCs in vivo. Alginate hydrogel was thus modified with Ang1 as a synthetic ECM to mimic the HSC niche. Long-term HSCs (CD34-, CD135-, and CD150+) were isolated from mouse femurs and cultured on Ang1-modified alginate hydrogel. The percentage of LT-HSCs in G0 phase was 46.8 ± 1.8%, which was comparable to that of LT-HSCs co-cultured with osteoblasts (46.8 ± 2.1%). Ang1-coupled alginate gels were useful to provide a niche for HSC quiescence without a co-culture system. Polymeric scaffolds containing biomimetic and cell-instructive characteristics for stem cell phenotype regulation might help create HSC niches in vitro and be useful to engineer tissues and transplant stem cells.

Operative and long-term oncologic outcomes of laparoscopic versus open major liver resection in patients with a high body mass index (> 25 kg/m2): a propensity score matching analysis.

BACKGROUND: With the recent rapid increase in the prevalence of obesity, the number of obese patients requiring liver resection, including laparoscopy, has increased. Accordingly, evaluating the outcome of laparoscopic liver resection in obese patients is increasingly important. This study aimed to compare the safety and feasibility of laparoscopic major liver resection (LMR) and open major liver resection (OMR) in patients with a high body mass index (BMI > 25.0 kg/m2). METHODS: We reviewed 521 patients with high BMI (> 25.0 kg/m2) who underwent major liver resection for various indications between January 2009 and November 2018 at Asan Medical Center. We performed 1:1 propensity score matching of the LMR and OMR groups, with 120 patients subsequently included in each group. RESULTS: LMR was associated with lower blood loss and shorter postoperative hospital stays (p < 0.001). Although there was no significant difference in overall complications (p = 0.080), non-liver-specific complications were observed less frequently after LMR (p = 0.025). American Society of Anesthesiologists class > II, BMI > 30 kg/m2, and malignancy were independent predictors of morbidity. In a subgroup analysis of patients with hepatocellular carcinoma, there was no significant difference between the two groups in overall survival (hazard ratio 0.225; 95% confidence interval 0.049-1.047; p = 0.057) and recurrence-free survival (hazard ratio 0.761; 95% confidence interval 0.394-1.417; p = 0.417). CONCLUSIONS: Obesity should not be considered a contraindication for major liver resection using a laparoscopic approach; however, when applying this approach for resecting malignancies in patients with a BMI > 30 kg/m2 and comorbid diseases, special attention should be paid to the possibility of complications.

Cutaneous Mycobacterium massiliense Infection Caused by Skin Coining 'Gua Sha' in Korean Healthy Female.

Nontuberculous mycobacteria are ubiquitous environmental organisms that are rare pathogens in immunocompetent individuals. However, cutaneous nontuberculous mycobacteria infections have been increasingly associated with invasive procedures, including surgery, liposuction, filler injection, intramuscular injection, mesotherapy, piercing, acupuncture, and cupping therapy. Herein, we report the first case of cutaneous nontuberculous mycobacteria infection caused by the East-Asian traditional treatment 'Gua Sha', also known as scraping, coining or spooning in English. A 35-year-old healthy female presented with widespread, painful skin nodules and pustules on her upper and lower extremities that had developed after Gua Sha treatment for body contouring. Histopathologic examination of the lesions revealed granulomatous inflammation in the dermis and the culture isolates were identified as Mycobacterium massiliense with molecular identification. The patient was successfully treated with intermittent incision and drainage of persistent nodules and oral clarithromycin based on antimicrobial susceptibility testing. We recommend implementation of a standard safety protocol for Gua Sha practitioners to minimize the risk of infection transmission.

Stevens-Johnson syndrome and concurrent hand foot syndrome during treatment with capecitabine: A case report.

BACKGROUND: Capecitabine is used in combination with lapatinib as palliative treatment for human epidermal growth factor receptor 2 - positive metastatic breast cancer. The most frequently reported adverse events attributed to capecitabine include diarrhea, hyperbilirubinemia, and hand-foot syndrome (HFS). A number of cutaneous adverse events have been attributed to capecitabine, including Stevens-Johnson syndrome (SJS) as a rare and potentially life-threatening mucocutaneous condition. We report the first case involving concurrent SJS and HFS after capecitabine and lapatinib treatment. CASE SUMMARY: A 70-year-old woman with a history of breast cancer treatment visited our hospital for evaluation of painful skin lesions. Six weeks earlier, she had been prescribed capecitabine plus lapatinib as treatment for metastatic breast cancer. She subsequently developed worsening erythema and bullae on her palms and soles, as well as reddish macules on her back and chest wall. Histopathological evaluation of the chest wall lesions revealed extensive eosinophilic epidermal necrosis and separation of the epidermis from the dermis. The capecitabine plus lapatinib treatment was discontinued immediately and treatment was started using systemic steroids. This treatment resolved most lesions, although the lesions on her palms and soles required Vaseline gauze dressings, which resulted in re-epithelialization. Therefore, we determined that the patient had concurrent SJS and HFS. Although the dermatological problems resolved, the patient ultimately died because of multiple organ failure. CONCLUSION: Oral capecitabine treatment carries a risk of both HFS and also life-threatening adverse cutaneous drug reactions, such as SJS.

Video-assisted thoracoscopic surgical wedge resection using multiplanar computed tomography reconstruction-fluoroscopy after CT guided microcoil localization.

BACKGROUND: When early-stage lung cancer is diagnosed, the recommended treatment is anatomical resection using video-assisted thoracoscopic surgery (VATS) or robotic lobectomy. However, nonanatomical resection, known as wedge resection (WR), which is performed to diagnose pulmonary nodules, can be problematic for clinicians performing VATS or robotic-assisted thoracic surgery (RATS). The purpose of this study was to evaluate the safety and effectiveness of VATS WR using multiplanar computed tomography reconstruction (CT MPR)-fluoroscopy after CT guided microcoil localization to achieve complete pulmonary nodule resection. METHODS: Between January 2016 to December 2020, the medical records of patients who underwent CT-guided microcoil localization for suspicious malignant pulmonary nodules and VATS WR with CT MPR and intraoperative fluoroscopy were retrospectively reviewed. RESULTS: All 130 patients successfully underwent CT-guided localization. The success rate of VATS WR with CT MPR-intraoperative fluoroscopy was 98.5%. Mean operation time was 58 min (range 50-84 min). The postoperative complication rate was 3.1%, and no major postoperative complications were reported. The mean postoperative length of hospital stay was 4.7 days (range 4-8 days). CONCLUSIONS: VATS WR using CT MPR-fluoroscopy after CT guided microcoil localization is a safe and highly effective approach for complete pulmonary nodule resection. However, even in uniport VATS or recently performed robotic surgery, localization and resection of nonvisible, nonpalpable pulmonary nodules is a challenging problem. Consequently, satisfactory outcomes can be expected if this technique is used for suspicious malignant pulmonary nodule resection.

Charging Effect by Fluorine-Treatment and Recess Gate for Enhancement-Mode on AlGaN/GaN High Electron Mobility Transistors.

An enhancement-mode AlGaN/GaN metal-insulator-semiconductor high-electron- mobility-transistor was fabricated using a recess gate and CF4 plasma treatment to investigate its reliable applicability to high-power devices and circuits. The fluorinated-gate device showed hysteresis during the DC current-voltage measurement, and the polarity and magnitude of hysteresis depend on the drain voltage. The hysteresis phenomenon is due to the electron trapping at the Al2O3/AlGaN interface and charging times longer than milliseconds were obtained by pulse I-V measurement. In addition, the subthreshold slope of the fluorinated-gate device was increased after the positive gate bias stress because of the two-dimensional electron gas reduction by ionized fluorine. Our systematic observation revealed that the effect of fluorine ions should be considered for the design of AlGaN/GaN power circuits.