Effect of prostaglandin analogs: Latanoprost, bimatoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human trabecular meshwork endothelial cells.

Bimatoprost, latanoprost, and unoprostone are prostaglandin F2α analogs (PGAs) and are used to lower intraocular pressure. We investigated the free acid effects of these three prostaglandin analogs: bimatoprost, latanoprost, and unoprostone on human matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in the trabecular meshwork (TM) cells. Immunoblot results show that all three PGAs generally increased MMPs-1,9 and TIMPs-4. Additionally, bimatoprost and latanoprost both increased MMP-3 and TIMP-2, while unoprostone had an indeterminate effect on both. Zymography results show that all three PGAs except unoprostone increased intermediate MMP-1 activity while bimatoprost and latanoprost increased MMP-9 activity. Together, these data suggest that the balance between MMPs and TIMPs correlate to the relative intraocular pressure lowering effectiveness observed in clinical studies of these PGAs.

Scleral Buckle Removal: Long-Term Patient Outcomes.

PURPOSE: Scleral buckling has been a reliable treatment option in the repair of primary rhegmatogenous retinal detachments. Occasionally, patients require scleral buckles (SBs) to be removed for various reasons. While outcomes of SB removal have been investigated in this subset of patients, there has not been any large patient series to reach any conclusions. Long-term sequelae of SB removal are debated in the literature, specifically around the risk of redetachment. DESIGN: We performed a retrospective, observational study to evaluate the clinical indications for, and outcomes of, SB removal. PARTICIPANTS: No control patients in this retrospective, observational study. METHODS: Eighty-six individuals with a history of SB removal from June 1, 2000, to January 1, 2021, were followed from a large academic center and a private, retina-only practice in Chicago. Exclusion criteria were age of < 18 years and unplanned or self-explanted SB removal. MAIN OUTCOME MEASURES: Data extracted included patient symptoms before SB removal, indications for removal, resolution of symptoms following removal, rate of redetachment, and rate of additional ocular surgery. Secondary outcomes included identifying factors associated with poorer outcomes. RESULTS: Eighty-six eyes with history of SB removal were included with an average follow-up of 4 years. Approximately 60% were males and the mean age at the time of SB removal was 59 years. Leading indications for removal were exposure (61.63%), infection (20.93%), and diplopia/strabismus (19.77%). The average time from SB placement to removal was 12.28 ± 11.16 years. Most patients requiring SB removal presented with symptoms, specifically of pain and discomfort (65.12%), diplopia (22.09%), and drainage/discharge (18.60%). Of these patients, 86.59% experienced symptom resolution following SB removal. Notably, 6.56% (4 eyes) of all eyes with at least 1 year of follow-up experienced a redetachment requiring surgery. Within this subset, the average time from SB placement to removal was 2.05 ± 2.01 years and time to redetachment following removal was 15.95 ± 25.71 months. Nine percent of all eyes required additional strabismus or oculoplastic surgery. CONCLUSIONS: Scleral buckle removal provides a high rate of symptomatic relief and low risk of subsequent detachment. Nevertheless, close monitoring is warranted to monitor for recurrent retinal detachments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Curcumin Enhances the Anticancer Effects of Binimetinib on Melanoma Cells by Inducing Mitochondrial Dysfunction and Cell Apoptosis with Necroptosis.

BACKGROUND: Recent studies suggest that MEK1/2 inhibitors, including binimetinib, significantly improve malignant melanoma (MM) patient survival. Growing evidence suggests that phytochemicals, especially curcumin, can overcome drug resistance in cancer cells through a variety of mechanisms. OBJECTIVE: This study aims to examine curcumin's efficacy in vitro combined with binimetinib in human MM cells. METHODS: We used 2D monolayer and 3D spheroid human epidermal melanocyte culture models, HEMn-MP (human epidermal melanocytes, neonatal, moderately pigmented), and two human MM cell lines, G361 and SK-MEL-2, to evaluate cell viability, proliferation, migration, death, and reactive oxygen species (ROS) production following single therapy treatment, with either curcumin or binimetinib, or a combination of both. RESULTS: Compared to MM cells treated with single therapy, those with combination therapy showed significantly decreased cell viability and increased ROS production. We observed apoptosis following both single and combination therapies. However only those who had had combination therapy had necroptosis. CONCLUSION: Collectively, our data demonstrates that curcumin exerts significant synergistic anticancer effects on MM cells by inducing ROS and necroptosis when combined with binimetinib. Therefore, a strategy of adding curcumin to conventional anticancer agents holds promise for treating MM.

Stretchable and Lithography-Compatible Interconnects Enabled by Self-Assembled Nanofilms with Interlocking Interfaces.

Stretchable interconnects with miniature widths are vital for the high-density integration of deformable electronic components on a single substrate for targeted data logic or storage functions. However, it is still challenging to attain high-resolution patternability of stretchable conductors with robust circuit fabrication capability. Here, we report a self-assembled silver nanofilm firmly interlocked by an elastomeric nanodielectric that can be photolithographically patterned into microscale features while preserving high stretchability and conductivity. Both silver and dielectric nanofilms are fabricated by layer-by-layer assembly, ensuring wafer-scale uniformity and meticulous control of thicknesses. Without any thermal annealing, the as-fabricated nanofilms from silver nanoparticles (AgNPs) exhibit conductivity of 1.54 × 106 S m-1 and stretchability of ∼200%, which is due to the impeded crack propagation by the underlying PU nanodielectrics. Furthermore, it is revealed that AgNP microstrips defined by photolithography show higher stretchability when their widths are downscaled to 100 µm owing to confined cracks. However, further scaling restricts the stretchability, following the early development of cracks cutting across the strip. In addition, the resistance change of these silver interconnects can be decreased using serpentine architectures. As a demonstration, these self-assembled interconnects are used as stretchable circuit boards to power LEDs.

Overexpression of Dock180 and Elmo1 in Melanoma is Associated with Cell Survival and Migration.

BACKGROUND: Melanoma is one of the most aggressive and metastatic skin cancers. Although overexpression of Dock180 and Elmo1 has been identified in various cancers, including glioma, ovarian cancer, and breast cancer, their expression and functions in melanoma remain unknown. OBJECTIVE: This study aims to confirm the expression of Dock180 and Elmo1, their underlying mechanisms, and roles in melanoma. METHODS: Both immunohistochemical staining and Western blotting were used to confirm expression of Dock180 and Elmo1 in human melanoma. To identify roles of Dock180 and Elmo1 in cell survival, apoptosis and migration, downregulation of Dock180 or Elmo1 in melanoma cells with small interfering RNA (siRNA) was performed. RESULTS: We identified overexpression of Dock180 and Elmo1 in human melanoma compared to normal skin ex vivo. Inhibition of Dock180 or Elmo1 following siRNA in melanoma cells reduced cell viability and increased apoptosis as supported by increased proportion of cells with Annexin V-PE (+) staining and sub-G0/G1 peak in cell cycle analysis. Moreover, inhibition of Dock180 or Elmo1 regulated apoptosis-related proteins, showing downregulation of Bcl-2, caspase-3, and PARP and upregulation of Bax, PUMA, cleaved caspase-3, and cleaved PARP. Furthermore, knockdown of Dock180 and Elmo1 in melanoma cells reduced cell migration and changed cellular signaling pathways including ERK and AKT. Vemurafenib decreased cell viability in concentration-dependent manner, while transfection with Dock180- or Elmo1-specific siRNA in melanoma cells significantly reduced cell viability. CONCLUSION: Our results suggest that both Dock180 and Elmo1 may be associated with cancer progression, and can be potential targets for treatment of melanoma.

Data mining for detecting signals of adverse drug reaction of doxycycline using the Korea adverse event reporting system database.

BACKGROUND: Doxycycline is one of the most prescribed antibiotics by dermatologists. However, the concern regarding adverse events of doxycyline has been rising. OBJECTIVE: To detect the adverse events of doxycycline using the Korea Adverse Events Reporting System (KAERS) database from January 2014 to December 2018 through a data mining method. METHODS: A signal was defined as one satisfying all three indices; a proportional reporting ratio, a reporting odds ratio, and an information component. We further checked whether the detected signals exist in drug labels in Korea and five developed countries, the United States, the United Kingdom, Germany, Canada, and Japan. RESULTS: A total of 3,365,186 adverse event-drug pairs were reported and of which 3,075 were associated with doxycycline. Among the thirty-seven signals, nineteen (malaise, ileus, confusion, malignant neoplasm, ectopic pregnancy, ovarian hyperstimulation, vaginal hemorrhage, bone necrosis, acne, rosacea, seborrheic dermatitis, folliculitis, skin ulceration, crusting, dry skin, paronychia, mottled skin, application site reaction, and application site edema) were not included on any of the drug labels of the six countries. CONCLUSION: We identified nineteen new doxycycline signals that did not appear on drug labels in six countries. Further studies are warranted to evaluate the causality of the adverse events with doxycycline.

The efficacy and safety of topical 10% potassium hydroxide for molluscum contagiosum: a systematic review and meta-analysis.

BACKGROUND: Molluscum contagiosum (MC) is a self-limited cutaneous viral infection. Topical 10% potassium hydroxide (KOH) has been used for treating MC. However, it remains unclear whether it is beneficial or not to apply topical 10% KOH for treating MC. METHODS: To confirm the efficacy and safety of topical 10% KOH compared with placebo as well as other treatments for MC, meta-analysis was used. Up to September 2020, we performed a comprehensive search of literature based on three databases with following keywords including 'molluscum contagiosum' and 'potassium hydroxide'. RESULTS: Our meta-analyses demonstrated a significant difference between topical 10% KOH and placebo for complete clearance of MC (RR: 2.96, 95% CI: 1.69 - 5.17, p = .0001), while there were no statistical differences between them in the number of patients with adverse events (RR: 1.73, 95% CI: 0.67 - 4.45, p = .2562). Also, topical 10% KOH was as effective as mechanical treatments for MC (RR: 0.95, 95% CI: 0.84 - 1.07, p = .3833). CONCLUSION: We demonstrate that application of topical 10% KOH may be one of effective and appropriate methods for the treatment of MC compared with awaiting spontaneous resolution due to its safety and effectiveness.

Morphologic and Cellular Changes Induced by Selective Laser Trabeculoplasty.

Purpose: Selective laser trabeculoplasty is a safe and effective procedure for reducing IOP, but its mechanism of action is not fully elucidated. We evaluated the morphologic and cellular changes as well as DNA synthesis after SLT treatment of human trabecular meshwork (TM) tissue explants. Methods: Corneoscleral rim tissues that underwent SLT treatment were compared to control segments that had no laser treatment. Light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were used to assess cell morphology. The Click-iT 5-ethynyl-2'-deoxyuridine (EdU) imaging kit was used to compare DNA synthesis/cell proliferation with a confocal microscope. All tissues were assessed for vitality. Results: SLT treatment does not reveal notable cell damage in the juxtacanalicular (JCT) region, but mildly disrupts superficial trabecular beams and uveal TM, ablates TM endothelial cells from the undamaged beams as detected by both LM and TEM. This superficial destruction was not observed in some SLT treatment spots on higher magnification by SEM. SLT treatment increased mitotic activity and DNA synthesis near the lining of Schlemm's canal after several days. Conclusion: SLT treatment disrupts endothelial cells in the corneoscleral TM and causes superficial ultrastructural changes to the uveal TM. SLT treatment also shows a trend towards dynamic time-dependent changes in (DNA synthesis) with an increase in mitotic activity at 7 days cell proliferation.

Effect of SPARC Suppression in Mice, Perfused Human Anterior Segments, and Trabecular Meshwork Cells.

Purpose: Secreted protein, acidic and rich in cysteine (SPARC) elevates intraocular pressure (IOP), increases certain structural extracellular matrix (ECM) proteins in the juxtacanalicular trabecular meshwork (JCT), and decreases matrix metalloproteinase (MMP) protein levels in trabecular meshwork (TM) endothelial cells. We investigated SPARC as a potential target for lowering IOP. We hypothesized that suppressing SPARC will decrease IOP, decrease structural JCT ECM proteins, and alter the levels of MMPs and/or their inhibitors. Methods: A lentivirus containing short hairpin RNA of human SPARC suppressed SPARC in mouse eyes and perfused cadaveric human anterior segments with subsequent IOP measurements. Immunohistochemistry determined structural correlates. Human TM cell cultures were treated with SPARC suppressing lentivirus. Quantitative reverse transcriptase polymerase chain reaction (PCR), immunoblotting, and zymography determined total RNA, relative protein levels, and MMP enzymatic activity, respectively. Results: Suppressing SPARC decreased IOP in mouse eyes and perfused human anterior segments by approximately 20%. Histologically, this correlated to a decrease in collagen I, IV, and VI in both the mouse TM and human JCT regions; in the mouse, fibronectin was also decreased but not in the human. In TM cells, collagen I and IV, fibronectin, MMP-2, and tissue inhibitor of MMP-1 were decreased. Messenger RNA of the aforementioned genes was not changed. Plasminogen activator inhibitor 1 (PAI-1) was upregulated in vitro by quantitative PCR and immunoblotting. MMP-1 activity was reduced in vitro by zymography. Conclusions: Suppressing SPARC decreased IOP in mice and perfused cadaveric human anterior segments corresponding to qualitative structural changes in the JCT ECM, which do not appear to be the result of transcription regulation.