Chiral π-Conjugated Double Helical Aminyl Diradical with the Triplet Ground State.

We report a neutral high-spin diradical of chiral C2-symmetric bis[5]diazahelicene with ΔEST ≈ 0.4 kcal mol-1, as determined by EPR spectroscopy/SQUID magnetometry. The diradical is the most persistent among all high-spin aminyl radicals reported to date by a factor of 20, with a half-life of up to 6 days in 2-MeTHF at room temperature. Its triplet ground state and excellent persistence may be associated with the unique spin density distribution within the dihydrophenazine moiety, which characterizes two effective 3-electron C-N bonds analogous to the N-O bond of a nitroxide radical. The enantiomerically enriched (ee ≥ 94%) (MM)- and (PP)-enantiomers of the precursors to the diradicals are obtained by either preparative chiral supercritical fluid chromatography or resolution via functionalization with the chiral auxiliary of the C2-symmetric racemic tetraamine. The barrier for the racemization of the solid tetraamine is ΔG‡ = 43 ± 0.01 kcal mol-1 in the 483-523 K range. The experimentally estimated lower limit of the barrier for the racemization of a diradical, ΔG‡ ≥ 26 kcal mol-1 in 2-MeTHF at 293 K, is comparable to the DFT-determined barrier of ΔG‡ = 31 kcal mol-1 in the gas phase at 298 K. While the enantiomerically pure tetraamine displays strong chiroptical properties, with anisotropy factor |g| = |Δε|/ε = 0.036 at 376 nm, |g| ≈ 0.005 at 548 nm of the high-spin diradical is comparable to that recently reported triplet ground-state diradical dication. Notably, the radical anion intermediate in the generation of diradical exhibits a large SOMO-HOMO inversion, SHI = 35 kcal mol-1.

Changes in optical coherence tomography biomarkers in eyes with advanced idiopathic epiretinal membrane treated with dexamethasone implantation.

PURPOSE: To investigate the effects of vitrectomy and intravitreal dexamethasone (DEX) implantation on retinal biomarkers in patients with advanced idiopathic epiretinal membrane (IERM) and to evaluate this treatment's anatomical and functional outcomes. METHODS: This retrospective study included 41 patients with advanced IERM who underwent vitrectomy and were divided into a pars plana vitrectomy (PPV) group (20 eyes) and a dexamethasone (DEX) group (21 eyes) based on intravitreal DEX implantation. We collected data on best-corrected visual acuity (BCVA), central macular thickness (CMT), disorganization of the retinal inner layers (DRIL), subretinal fluid, intraretinal cystoid changes (IRC), integrity of the inner-outer segment layer, and intraocular pressure. RESULTS: BCVA improved significantly in both groups; the DEX group had a higher visual acuity gain at 1 and 6 months (P = 0.002 and 0.023, respectively). Postoperative CMT gradually decreased in both groups, with the DEX group showing a greater decrease at 1 and 6 months (P = 0.009 and 0.033, respectively). Six months after surgery, the DRIL and IRC grades in the DEX group were significantly improved compared to those in the PPV group (P = 0.037 and 0.038, respectively). Multivariate regression analyses revealed that patients with intraoperative DEX implants were more likely to have a significant CMT reduction (≥ 100 µm) from baseline (odds ratio (OR), 9.44; 95% confidence intervals (CI), 1.58-56.56; P = 0.014) at 6 months and less likely to exhibit DRIL at 6 months postoperatively (OR, 0.08; 95% CI, 0.01-0.68; P = 0.021). CONCLUSION: Vitrectomy combined with intravitreal DEX implantation facilitates the recovery of postoperative visual acuity and improvement of anatomical outcomes in patients with advanced IERM, effectively reducing CMT and improving DRIL.

OBJECTIVE QUANTIFICATION OF DEPTH-OF-FIELD ADVANTAGE IN 3D SURGICAL VIDEO SYSTEM FOR VITREORETINAL SURGERY: Safety and Efficacy in Macular Diseases.

PURPOSE: The objective of this study was to demonstrate, based on objective clinical indicators, the advantages of depth of field provided by the 3D surgical video system compared with the traditional microscope during vitrectomy for treating epiretinal membranes or macular holes. METHODS: A total of 38 patients were included in this study and randomly assigned to either the 3D surgical video group or the conventional microscope group. Surgical parameters, such as the focal plane adjustment frequency, membrane peeling time, and number of attempts to peel the membrane, were recorded for each patient. In addition, patients were followed up for 3 months postoperatively. RESULTS: No significant differences were observed in age, sex, operated eyes, or follow-up rates between the groups. The 3D group had significantly lower focal plane adjustment frequency in macular hole surgery and epiretinal membrane surgery. No significant differences were observed in peeling maneuvers, time, or total surgical time. Postoperative follow-up data showed no significant differences. CONCLUSION: In conclusion, the 3D surgical video system exhibits potential advantages in depth of field. The 3D surgical video system is a safe and effective technology in vitrectomy for macular diseases.

Microinvasive pars plana vitrectomy combined with internal limiting membrane peeling versus anti-VEGF intravitreal injection for treatment-naïve diabetic macular edema (VVV-DME study): study protocol for a randomized controlled trial.

BACKGROUND: Diabetic macular edema (DME) is the main cause of vision loss in diabetic patients. Currently, anti-vascular endothelial growth factor (VEGF) intravitreal injection stands as the first-line therapy for DME. However, some patients exhibit insufficient response to anti-VEGF agents and often require multiple injections, imposing psychological and economic burdens. While microinvasive pars plana vitrectomy (PPV) has been shown to be safe and effective in treating refractory DME, scant research has explored its application to treatment-naïve DME. The purpose of this study is to determine whether early PPV combined with internal limiting membrane (ILM) peeling can lessen the therapeutic burden of DME patients, prevent vision loss, and maintain long-term stabilization of diabetic retinopathy. METHODS: This is a single-center, prospective, parallel-group, non-inferiority randomized controlled trial involving 102 DME participants. Participants will be randomly assigned to either the study group (PPV combined with ILM peeling) or the control group (conbercept intravitreal injection (IVC)) at a 1:1 ratio, with a scheduled follow-up at 12 months post-operation. Comparative analysis of results between the two groups will be conducted at months 1, 3, 6, and 12 after the intervention. The primary outcomes involve evaluating the changes in central subfield thickness (CST) and best corrected visual acuity (BCVA). The secondary outcomes include assessment of optical coherence tomography (OCT) and OCT angiography (OCTA) biomarkers, re-treatment and adverse events rates, diabetic retinopathy (DR) development, cost-effectiveness analysis, and vision-related quality of life (VRQL). DISCUSSION: Some patients do not respond well to anti-VEGF drugs and repeated intravitreal injections increase the treatment burden for patients. The VVV study aims to explore whether PPV combined with ILM peeling could become an initial treatment option for treatment-naïve DME patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT05728476. Registered on 15 February 2023.

Enhancing surgical precision and efficiency: a study and comparison of a three-dimensional surgical video system in proliferative diabetic retinopathy surgery.

Purpose: This study aimed to investigate the safety and efficacy of three-dimensional (3D) surgical video systems for proliferative diabetic retinopathy (PDR). Methods: This retrospective clinical case study included 30 patients (30 eyes) with PDR. Patients were divided into two groups: one underwent surgery using a 3D surgical video system (14 cases, 14 eyes), while the other underwent traditional microscope surgery (16 cases, 16 eyes). Safety and efficacy were assessed through predetermined surgical parameters, including surgical duration, intraoperative membrane removal rate, and occurrences during intraoperative and postoperative phases. Results: Our study revealed noteworthy differences in various aspects between the 3D surgical video system group and the traditional microscope surgery group. Specifically, the mean surgical time was 30.25 ± 14.43 mins in the 3D surgical video system group, while it was 38.56 ± 18.71 mins in the traditional microscope surgery group (p = 0.051). Furthermore, the mean membrane removal time was significantly shorter in the 3D group at 2.53 ± 1.52 mins, as compared to 3.23 ± 1.76 mins in the traditional group (p = 0.042). Importantly, the membrane removal rate also displayed a significant difference, with the 3D group at 0.55 ± 0.07 and the traditional group at 0.41 ± 0.11 (p = 0.018). However, no notable differences were observed between the two groups in terms of intraoperative and postoperative incidences. Conclusion: The safety and efficacy obtained using the 3D surgical video system in PDR surgery were comparable to those obtained in traditional microscopic surgery.

Establishment and validation of a prognostic nomogram for long-term low vision after diabetic vitrectomy.

Purpose: We aimed to evaluate the risk factors and develop a prognostic nomogram of long-term low vision after diabetic vitrectomy. Methods: This retrospective study included 186 patients (250 eyes) that underwent primary vitrectomy for proliferative diabetic retinopathy with a minimum follow-up period of one year. Patients were assigned to the training cohort (200 eyes) or validation cohort (50 eyes) at a 4:1 ratio randomly. Based on a cutoff value of 0.3 in best-corrected visual acuity (BCVA) measurement, the training cohort was separated into groups with or without low vision. Univariate and multivariate logistic regression analyses were performed on preoperative systemic and ocular characteristics to develop a risk prediction model and nomogram. The calibration curve and the area under the receiver operating characteristic curves (AUC) were used to evaluate the calibration and discrimination of the model. The nomogram was internally validated using the bootstrapping method, and it was further verified in an external cohort. Results: Four independent risk factors were selected by stepwise forward regression, including tractional retinal detachment (ß=1.443, OR=4.235, P<0.001), symptom duration ≥6 months (ß=0.954, OR=2.595, P=0.004), preoperative BCVA measurement (ß=0.540, OR=1.716, P=0.033), and hypertension (ß=0.645, OR=1.905, P=0.044). AUC values of 0.764 (95% CI: 0.699-0.829) in the training cohort and 0.755 (95% CI: 0.619-0.891) in the validation cohort indicated the good predictive ability of the model. Conclusion: The prognostic nomogram established in this study is useful for predicting long-term low vision after diabetic vitrectomy.

Analysis of Risk Factors for Revitrectomy in Eyes with Diabetic Vitreous Hemorrhage.

Purpose: We aimed to investigate the risk factors associated with revitrectomy in eyes with diabetic vitreous hemorrhage and to determine the prognosis of these patients at least one year postoperatively. Patients and Methods: This retrospective case-control study had a minimum follow-up period of one year. Patients were divided into single vitrectomy group (control group, n=202) and revitrectomy group (case group, n=36) for analysis. The indications, number, and timing of revitrectomies were documented. And the revitrectomy group was further divided into two vitrectomies group (n=30) and three or more vitrectomies group (n=6). The best-corrected visual acuity (BCVA) at the last follow-up and the occurrence of neovascular glaucoma (NVG) were compared among the single vitrectomy, two vitrectomies and three or more vitrectomies groups. We conducted a thorough collection of patient data and used univariate and binary logistic regression analyses to identify the risk factors associated with revitrectomy. Results: A total of 197 patients (238 eyes) were included. Thirty-six eyes (15.1%) required revitrectomy with six eyes (2.5%) undergoing three or more vitrectomies during the follow-up period. The median duration of the second vitrectomy was 3 (2-6) months. The indications for a second vitrectomy included 28 eyes (77.8%) of postoperative vitreous hemorrhage and 7 eyes (22.2%) combined with tractional retinal detachment. Patients undergoing three or more vitrectomies had significantly worse postoperative BCVA and a higher incidence of NVG (P<0.01). Fibrinogen> 4 g/L (P<0.001) and preoperative anti-vascular endothelial growth factor intravitreal injection (P=0.015) were independent risk factors for revitrectomy, and glycated hemoglobin A1c (HbA1c)>10% (P=0.049) showed significant difference only in univariate analysis. Conclusion: Patients requiring revitrectomy tended to have higher fibrinogen levels, tightly adhered fibrovascular membranes, higher HbA1c levels, and worse prognoses.

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC50 values and achieved picomolar DC50 values and >99% of maximum degradation (Dmax) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-METY1230H and c-METD1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Correlation and significance of COX-2, Ki67, VEGF and other immune indexes with the growth of malignant pulmonary nodules.

OBJECTIVE: This study intends to explore the factors affecting the growth of pulmonary nodules in the natural process by immunohistochemical method. METHODS: 40 cases of pulmonary nodules followed up for more than 3 years were divided into growth group (n = 20) and stable group (n = 20). The expressions of cyclooxygenase-2 (COX-2), Ki67, vascular endothelial growth factor (VEGF), CD44V6, epidermal growth factor receptor (EGFR), double microsome 2 (MDM2) and transforming growth factor (TGF)-ß1 in pulmonary nodules were detected by immunohistochemical method so as to explore the relationship between it and the growth of pulmonary nodules. RESULTS: Compared with stable pulmonary nodules, the positive rates of COX-2, Ki67 and VEGF in the growth group were 85%, 80% and 55%, respectively. There was significant difference between the stable group and the growth group (P < 0.05). The correlation between other indexes and the growth of pulmonary nodules was not statistically significant (Pcd44v6 = 0.104;PEGFR = 0.337; PMDM2 = 0.49; PTGF-ß1 = 0.141). In the subgroup of patients with non-invasive lung cancer, there was a correlation between VEGF and the growth of pulmonary nodules (P < 0.05). CONCLUSION: The high expression of COX-2, Ki67 and VEGF proteins may be significantly related to the growth of pulmonary nodules, and VEGF may be an important factor affecting the growth of malignant pulmonary nodules. This study intends to provide a research direction for further searching for the essential causes of the growth of pulmonary nodules.

Inhibition of cannabinoid receptor type 1 sensitizes triple-negative breast cancer cells to ferroptosis via regulating fatty acid metabolism.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that displays highly aggressive with poor prognosis. Owing to the limited targets and drugs for TNBC clinical therapy, it is necessary to investigate the factors regulating cancer progression and develop novel therapies for cancer treatment. Ferroptosis, a nonapoptotic form of programmed cell death characterized by accumulation of iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating potential combinational therapeutic strategies for cancer treatment. In this study, by drug combination screen of lipid metabolism compounds with ferroptosis inducers in decreasing TNBC cell viability, we found potent synergy of the CB1 antagonist rimonabant with erastin/(1 S, 3 R)-RSL3 (RSL3) in inhibiting TNBC cell growth both in vitro and in vivo via promoting the levels of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and cytosolic reactive oxygen species (ROS) production, enhancing intracellular glutathione (GSH) depletion and inducing G1 cell cycle arrest. We identified that inhibition of CB1 promoted the effect of erastin/RSL3 on inducing ferroptosis and enhanced their inhibitory effect on tumor growth. Using RNA-Seq, fatty acid analyses and functional assays, we found that CB1 regulated stearoyl-CoA desaturase 1 (SCD1)- and fatty acyl desaturase 2 (FADS2)-dependent fatty acid metabolism via phosphatidylinositol 3 kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) signaling pathways to modulate ferroptosis sensitivity in TNBC cells. These data demonstrate that dual targeting of CB1 and ferroptosis could be a promising therapeutic strategy for TNBC.

Electrochromatographic behavior of core-shell particles: A comparison study.

Core-shell particle is a new generation high performance packing material for liquid chromatography. Through comparison with a classical totally porous silica phase of the same particle size, we studied Ascentis Express 5 µm core-shell particle's electrochromatographic behavior, in terms of voltage-current property, electroosmotic flow (EOF) and van Deemter curve. It was found, due to the nonpermeable solid core, the core-shell particle presented a diminished EOF and efficiency than the totally porous paricle. This on the other hand proved that the intra-particle pore flow extensively exists and plays an important role in electrochromatography on totally porous material. The core-shell particle's high retentivity led to an enhanced resolution for weakly retained hydrophilic peptides, which were poorly retained and co-eluted on totally porous particles. Further exploration has shown the core-shell material can achieve efficient electrochromatography of protein digests, excellent performance in terms of resolution, reproducibility and long term stability have been observed. The results indicate that the core-shell structure may suggest a reasonable design of stationary phase for bioelectrochromatography of peptides and proteins.