Associations of Near Work, Time Outdoors, and Sleep Duration With Myopic Regression 5 Years After SMILE and FS-LASIK: A Cross-sectional Study.

PURPOSE: To investigate the association of near work, time outdoors, and sleep duration with myopic regression 5 years after small incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (FS-LASIK) . METHODS: This cross-sectional study included patients who received SMILE or FS-LASIK at Beijing Tongren Hospital 5 years ago. The patients underwent ophthalmic examinations including visual acuity, intraocular pressure, subjective refraction, slit-lamp examination, keratometry, corneal topography, optical coherence tomography, and fundus examination from January 2020 to March 2023. Fluorescein break-up time was measured and the Ocular Surface Disease Index questionnaire was completed to exclude dry eye. A self-administered questionnaire was used to collect data on near work exposure, physical activities, and sleep duration. RESULTS: A total of 323 eyes were included in the analysis, with a 5-year incidence rate of myopic regression after SMILE or FSLASIK of 16.1%. After adjusted for all confounders, total near work more than 8 hours/day revealed a significant association with myopic regression (odds ratio: 2.461; 95% CI: 1.143 to 5.298, P = .021), particularly in younger adults, women, and patients with high myopia and FS-LASIK treatment. The significant association between sleep duration 8 hours/day or more and myopic regression was restricted to women and patients with FS-LASIK (near significant). However, no significant associations were observed between continuous near work or time outdoors and myopic regression. CONCLUSIONS: Excessive near work exposure was associated with greater myopic regression 5 years after SMILE or FS-LASIK. It is crucial to maintain good visual behavior and care for preventing regression after SMILE or FS-LASIK, especially for younger patients and eyes with high myopia. [J Refract Surg. 2024;40(1):e10-e19.].

Association between Fundus Tessellation and Contrast Sensitivity in Myopic Eyes.

PURPOSE: To assess the association of fundus tessellation with contrast sensitivity, Quality of Vision questionnaire, and other factors at five years postcorneal refractive surgery. METHODS: This is a cross-sectional study. Both eyes of 98 subjects (196 eyes) who received femtosecond laser in situ keratomileusis (FS-LASIK) or small incision lenticular extraction (SMILE) five years prior were enrolled in this study. Fundus tessellation was imaged using wide-angle fundus photographs and graded into four categories with the assistance of the ETDRS grid. Photopic and mesopic contrast sensitivity were measured under the best correction. The Quality of Vision (QoV) questionnaire was used to assess visual symptoms. RESULTS: Fundus tessellation was classified as follows: 19 eyes were grade 0 (9.7%), 28 eyes were grade 1 (14.3%), 59 eyes were grade 2 (30.1%), and 90 eyes were grade 3 (45.9%). Higher degrees of fundus tessellation were associated with lower photopic contrast sensitivity, a significant difference was observed at spatial frequencies of 6cpd (p = 0.030, grade 1 >grade 3 p = 0.011). Higher degrees of fundus tessellation were also associated with lower mesopic contrast sensitivity, a significant difference was observed at spatial frequencies of 18cpd (p = 0.011, grade 0 >grade 3 p = 0.012). The preoperative degree of myopia was positively associated with fundus tessellation grade (p < 0.001). However, in linear mixed-effect model analysis, no significant influence of parameters (contrast sensitivity, preoperative myopia, and QoV scores) upon different tessellation grades was found (p > 0.05). CONCLUSIONS: Patients with moderate and high myopia were more likely to have higher grades of fundus tessellation. Higher degree of fundus tessellation associates with lower contrast sensitivity. Patients with moderate and high myopia should be concerned with retinal-choroidal changes. Contrast sensitivity could be a clinical sign for progression of tessellation and used to screen for early retinal-choroidal changes to prevent pathologic myopia.

Deficiency in NDH-cyclic electron transport retards heat acclimation of photosynthesis in tobacco over day and night shift.

In order to cope with the impact of global warming and frequent extreme weather, thermal acclimation ability is particularly important for plant development and growth, but the mechanism behind is still not fully understood. To investigate the role of NADH dehydrogenase-like complex (NDH) mediated cyclic electron flow (CEF) contributing to heat acclimation, wild type (WT) tobacco (Nicotiana tabacum) and its NDH-B or NDH-C, J, K subunits deficient mutants (ΔB or ΔCJK) were grown at 25/20°C before being shifted to a moderate heat stress environment (35/30°C). The photosynthetic performance of WT and ndh mutants could all eventually acclimate to the increased temperature, but the acclimation process of ndh mutants took longer. Transcriptome profiles revealed that ΔB mutant exhibited distinct photosynthetic-response patterns and stress-response genes compared to WT. Metabolite analysis suggested over-accumulated reducing power and production of more reactive oxygen species in ΔB mutant, which were likely associated with the non-parallel recovery of CO2 assimilation and light reactions shown in ΔB mutant during heat acclimation. Notably, in the warm night periods that could happen in the field, NDH pathway may link to the re-balance of excess reducing power accumulated during daytime. Thus, understanding the diurnal cycle contribution of NDH-mediated CEF for thermal acclimation is expected to facilitate efforts toward enhanced crop fitness and survival under future climates.

Effect of 3% Diquafosol Sodium on Dry Eye After Femtosecond Laser-Assisted In Situ Keratomileusis and Small Incision Lenticule Extraction Surgery in High-Myopic Eyes.

PURPOSE: To evaluate the effect of 3% diquafosol sodium eye drop on dry eye after femtosecond laser-assisted in situ keratomileusis (FS-LASIK) and small incision lenticule extraction (SMILE) in high-myopic eyes. METHODS: Eighty-one cases with high myopia (162 eyes) who received FS-LASIK or SMILE were divided into four groups by surgical design and tear film stability: D-FS-LASIK (5s

Effects of riboflavin/ultraviolet-A(UVA) scleral crosslinking on the mechanical behavior of the scleral fibroblasts of lens-induced myopia Guinea pigs.

Myopia is becoming increasingly severe, and studies have shown that the cellular mechanics of scleral fibroblasts are altered following myopia. Scleral UVA-Riboflavin Collagen Crosslinking（sCXL） is a promising treatment for myopia prevention and control of axial growth. Understanding the mechanical properties of scleral fibroblasts is crucial, as it influences the cellular response and limits the extent of molecular deformation triggered. Thus, our study aimed to investigate the effect of mechanical properties of scleral fibroblasts in a lens-induced myopic guinea pig model following sCXL. For this purpose, we performed the 0.1% riboflavin/UVA scleral crosslinking (365 nm,3 mW/cm2,30 min) in the right eyes of guinea pigs in Group CXL. In Group LIM, the right eyes were only administrated negative lens for 6 weeks. No treatment was performed in both eyes of the guinea pigs in group Control. The scleral fibroblasts were isolated and cultured from the scleral tissue at the cross-linking area in Group CXL and the corresponding area in Group LIM and control. The curve of the length of microtubules inhaled by cells under negative pressure was measured by a microaspiration-based isolation technique, and the equilibrium Young's modulus and apparent viscosity of scleral fibroblasts were calculated by formula fitting. The equilibrium Young's modulus of scleral fibroblasts in group CXL was significantly lower than that in the LIM group (P < 0.01, two-sample t-test between pairs）, and there was no significant difference between groups CXL and control. The results show that sCXL can effectively moderate the phenomenon that scleral fibroblasts are not easy to deform after myopia. The apparent viscosity modulus in the CXL group was higher than the groups' control and LIM. Taken together, our data demonstrate the biomechanics of the scleral fibroblasts altered after Riboflavin/UVA scleral collagen cross-linking in a lens-induced myopia model.

Corneal biomechanical characteristics following small incision lenticule extraction for myopia and astigmatism with 3 different cap thicknesses.

BACKGROUND: The design of cap thickness for small incision lenticule extraction (SMILE) plays a role in post-laser vision correction (post-LVC) corneal biomechanics. This study aimed to compare the corneal biomechanical characteristics following SMILE with different cap thicknesses of 110 µm, 120 µm, and 130 µm for myopia and myopic astigmatism correction. METHODS: Seventy-five patients (146 eyes) who underwent SMILE with designed cap thickness of 110 µm, 120 µm, and 130 µm were recruited at the Eye Center of Beijing Tongren Hospital between August 2020 and November 2021. Visual acuity, refraction, and corneal biomechanical parameters were measured preoperatively, 1 week and 1, 3, 6 months postoperatively. One-way analysis of variances (ANOVA) with Bonferroni correction or Kruskal-Wallis test was performed to compare the parameters among different groups. Repeated-measures analysis of variance with Bonferroni correction or Friedman test was applied for comparing the parameters within different follow-up times. RESULTS: Uncorrected distance visual acuity of 110-µm group was better only at 1-week and 1-month postoperatively (P = 0.012, 0.037). There were no significant differences in spherical equivalent, nor in Corvis biomechanical index-laser vision correction (CBI-LVC). All the parameters reached stability at 3-month postoperatively. Integrated radius (IR) and deformation amplitude ratio 2 mm (DA ratio 2 mm) in 120-µm and 130-µm groups were higher than 110-µm group at 1-month postoperatively (P = 0.019, 0.002). So was Ambrósio relational thickness (ARTh) at 6-month postoperatively (P = 0.011). Stiffness parameter at applanation A1 (SP-A1), stress-strain index (SSI), biomechanically corrected intraocular pressure (bIOP) and central corneal thickness (CCT) were highest in 130-µm group, followed by 120-µm group, then 110-µm group at 3-month (P<0.001, P = 0.030, P = 0.027, P = 0.008) and 6-month (P<0.001, P = 0.002, P = 0.0023, P = 0.001) postoperatively. CONCLUSIONS: The corneal stiffness following SMILE was greatest with 130-µm cap, followed by 120-µm cap, then 110-µm cap. 130-µm cap might have advantages in terms of corneal biomechanics and retreatment option. The SMILE-designed protocol should be customized in practice.

BRD4 Targets the KEAP1-Nrf2-G6PD Axis and Suppresses Redox Metabolism in Small Cell Lung Cancer.

Accumulating evidence has witnessed the Kelch-like ECH-associated protein 1(KEAP1)- nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis is the main regulatory factor of cell resistance to endogenous and exogenous oxidative assaults. However, there are few studies addressing the upstream regulatory factors of KEAP1. Herein, bioinformatic analysis suggests bromodomain-containing protein 4 (BRD4) as a potential top transcriptional regulator of KEAP1 in lung cancer. Using molecular and pharmacological approaches, we then discovered that BRD4 can directly bind to the promoter of KEAP1 to activate its transcription and down-regulate the stability of Nrf2 which in turn transcriptionally suppresses glucose-6-phosphate dehydrogenase (G6PD) in small cell lung cancer (SCLC), a highly proliferative and aggressive disease with limited treatment options. In addition, BRD4 could associate with the Nrf2 protein in a non-KEAP1-dependent manner to inhibit Nrf2 activity. Furthermore, simultaneous application of JQ1 and ATRA or RRx-001 yielded synergistic inhibition both in vitro and in vivo. These data suggest metabolic reprogramming by JQ1 treatment improves cell resistance to oxidative stress and might be a resistance mechanism to bromodomain and extra-terminal domain (BET) inhibition therapy. Altogether, our findings provide novel insight into the transcriptional regulatory network of BRD4 and KEAP1 and transcriptional regulation of the pentose phosphate pathway in SCLC.

FK228 potentiates topotecan activity against small cell lung cancer cells via induction of SLFN11.

The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.

Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice.

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 µmol/g tissue in WT mice vs. 0.85 ± 0.14 µmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.

NIR-II Responsive Hollow Magnetite Nanoclusters for Targeted Magnetic Resonance Imaging-Guided Photothermal/Chemo-Therapy and Chemodynamic Therapy.

Phototherapy in the second near-IR (1000-1700 nm, NIR-II) window has achieved much progress because of its high efficiency and relatively minor side effects. In this paper, a new NIR-II responsive hollow magnetite nanocluster (HMNC) for targeted and imaging-guided cancer therapy is reported. The HMNC not only provides a hollow cavity for drug loading but also serves as a contrast agent for tumor-targeted magnetic resonance imaging. The acid-induced dissolution of the HMNCs can trigger a pH-responsive drug release for chemotherapy and catalyze the hydroxyl radical (·OH) formation from the decomposition of hydrogen peroxide for chemodynamic therapy. Moreover, the HMNCs can adsorb and convert NIR-II light into local heat (photothermal conversion efficacy: 36.3%), which can accelerate drug release and enhance the synergistic effect of chemo-photothermal therapy. The HMNCs show great potential as a versatile nanoplatform for targeted imaging-guided trimodal cancer therapy.

Safety and Long-term Scleral Biomechanical Stability of Rhesus Eyes after Scleral Cross-linking by Blue Light.

Purpose: To assess the safety and long-term scleral biomechanical stability of rhesus eyes after blue light scleral CXL by investigating the biomechanical and microstructural changes.Methods: Seven rhesus monkeys (14 eyes) were observed in this study. All right eyes received blue light scleral CXL at the superior temporal equatorial sclera, and the left eyes served as controls. Biological ocular parameters were followed up to 1 year after scleral CXL. Stress-strain measurements of three rhesus sclera were measured, three rhesus retinas were examined histologically by H&E and TUNEL staining. And the microstructure of both the sclera and retina were observed by transmission electron microscopy at 1 year.Results: As for the retinal thickness, choroidal thickness, flow density of retinal superficial vascular networks and flash electroretinography (f-ERG) results, no significant differences were observed between the paired eyes at 1 year (P >.05). At the same time, the scleral collagen fibril distribution was much tighter, and the scleral biomechanical properties were significantly increased in the experimental eyes. However, apoptotic cells and retinal ultrastructural changes could still be found in the retina of the experimental eyes.Conclusion: This study demonstrates that blue light scleral CXL could effectively increase the scleral stiffness of the rhesus eye for at least 1 year, but ultrastructural change was still observed in the retina of scleral CXL eye. Therefore, the long-term intraocular safety of the blue light scleral CXL technique for preventing myopia progression should be investigated further.

Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer.

Proteasome inhibitors, bortezomib (BTZ), and carfilzomib (CFZ) are approved drugs for hematological malignancies, but lack anticancer activities against most solid tumors. Small cell lung cancer (SCLC) is a very aggressive neuroendocrine carcinoma of the lungs demanding effective therapy. In this study we investigated whether BTZ or CFZ combined with obatoclax (OBX), an antagonist for MCL-1 and a pan-BCL family inhibitor, could cause synergistic growth inhibition of SCLC cells. We showed that combined application of BTZ or CFZ with OBX caused synergistic growth inhibition of human SCLC cell lines (H82, H526, DMS79, H196, H1963, and H69) than single agent alone. Both BTZ-OBX and CFZ-OBX combinations displayed marked synergism on inducing apoptosis (~50% increase vs BTZ or CFZ alone). A comprehensive proteomics analysis revealed that BTZ preferentially induced the expression of MCL-1, an antiapoptotic protein, in SCLC cells. Thus, proteasome inhibitor-OBX combinations could specifically induce massive growth inhibition and apoptosis in SCLC cells. Subsequent proteome-wide profiling analysis of activated transcription factors suggested that BTZ- or CFZ-induced MCL-1 upregulation was transcriptionally driven by FOXM1. In nude mice bearing in SCLC H82 xenografts, both BTZ-OBX, and CFZ-OBX combinations exhibited remarkable antitumor activities against SCLC tumors evidenced by significant reduction of tumor size and the proliferation marker Ki-67 signals in tumor tissues as compared with single agent alone. Thus, proteasome inhibitor-OBX combinations are worth immediate assessments for SCLC in clinical settings.

Graphitic Carbon Nitride Quantum Dots Embedded in Carbon Nanosheets for Near-Infrared Imaging-Guided Combined Photo-Chemotherapy.

Rational design of metal-free multifunctional therapeutic reagents offers great opportunities for cancer treatment in the clinic. Here, graphitic carbon nitride (g-C3N4) quantum dots embedded in carbon nanosheets (CNQD-CN) are in situ prepared via a one-pot hydrothermal approach with formamide as carbon and nitrogen source. The CNQD-CN not only serves as an excellent near-infrared (NIR) fluorescent marker but also acts as a pH-responsive nanocarrier. Moreover, the CNQD-CN possesses both light-to-heat conversion and singlet oxygen generation capabilities under a single NIR excitation wavelength. Further investigations show that systemic delivery of doxorubicin (DOX) using the multifunctional CNQD-CN nanocarrier under NIR irradiation was highly effective to cause cancer cell apoptosis in vitro and inhibit tumor growth in vivo. CNQD-CN represents a multifunctional therapeutic platform for synchronous cancer imaging and treatment through the synergistic effect of phototherapy and chemotherapy.

Ocular safety evaluation of blue light scleral cross-linking in vivo in rhesus macaques.

PURPOSE: To investigate the safety of blue light scleral cross-linking (SXL) by evaluating changes in biological parameters in the retina and choroid in the eyes of rhesus macaques (Macaca mulatta). METHODS: Fifteen 3-year-old macaques (30 eyes) were randomly divided into three groups (n = 5). SXL was performed via riboflavin (0.5%) and blue light (460 nm) at the location of the equatorial sclera. Right eyes served as experimental eyes, and left eyes as control eyes. One quadrant of each right eye was irradiated in group A, two quadrants of each right eye and one quadrant of each left eye were irradiated in group B, and two quadrants of each right eye were irradiated in group C. Optical coherence tomography, optical coherence tomography angiography, and flash electroretinography (f-ERG) examinations were performed at baseline and 1 week, 1 month, 3 months, and 6 months after SXL. Additionally, retinal tissue alterations were detected via transmission electron microscopy at 1 week postoperatively. RESULTS: There were no significant differences between experimental eyes and control eyes in retinal thickness, vessel density of retinal superficial capillary plexus, and choroid thickness in any of the groups at any of the time points investigated (p > 0.05). Significant reductions in f-ERG parameters were detected 1 week postoperatively in the experimental eyes of groups A and C (p < 0.05), but they gradually recovered, and there was no significant difference 1 month postoperatively (p > 0.05). Ultrastructural changes were evident in the retinal layers of SXL eyes. In group B, there were no significant differences between the right and left eyes at any of the follow-up time points investigated. CONCLUSIONS: Blue light SXL can cause transient retina damage. The f-ERG parameters reductions and retinal ultrastructural changes were found at early stage, even though there were not significant changes in retinal thickness, vessel density of retinal superficial capillary plexus, and choroid thickness after blue light SXL. The long-term intraocular safety of the blue light SXL technique should be investigated further.