Jing Zhang

Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2-SLC7A11-HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.

Abstract Background Our previous work showed that the anti-TGF-β/PD-L1 bispecific antibody YM101 effectively overcame anti-PD-L1 resistance in immune-excluded tumor models. However, in immune-desert models, the efficacy of YM101 was limited. Bivalent manganese (Mn 2+ ) is identified as a natural stimulator of interferon genes (STING) agonist, which might enhance cancer antigen presentation and improve the therapeutic effect of YM101. Methods The effect of Mn 2+ on STING pathway was validated by western blotting and enzyme-linked immunosorbent assay. Dendritic cell (DC) maturation was measured by flow cytometry. The synergistic effect between Mn 2+ and YM101 in vitro was determined by one-way mixed lymphocyte reaction, CFSE dilution assay, and cytokine detection. The in vivo antitumor effect of Mn 2+ plus YM101 therapy was assessed in CT26, EMT-6, H22, and B16 tumor models. Flow cytometry, RNA-seq, and immunofluorescent staining were adopted to investigate the alterations in the tumor microenvironment. Results Mn 2+ could activate STING pathway and promote the maturation of human and murine DC. The results of one-way mixed lymphocyte reaction showed that Mn 2+ synergized YM101 in T cell activation. Moreover, in multiple syngeneic murine tumor models, Mn 2+ plus YM101 therapy exhibited a durable antitumor effect and prolonged the survival of tumor-bearing mice. Relative to YM101 monotherapy and Mn 2+ plus anti-PD-L1 therapy, Mn 2+ plus YM101 treatment had a more powerful antitumor effect and a broader antitumor spectrum. Mechanistically, Mn 2+ plus YM101 strategy simultaneously regulated multiple components in the antitumor immunity and drove the shift from immune-excluded or immune-desert to immune-inflamed tumors. The investigation in the TME indicated Mn 2+ plus YM101 strategy activated innate and adaptive immunity, enhanced cancer antigen presentation, and upregulated the density and function of tumor-infiltrating lymphocytes. This normalized TME and reinvigorated antitumor immunity contributed to the superior antitumor effect of the combination therapy. Conclusion Combining Mn 2+ with YM101 has a synergistic antitumor effect, effectively controlling tumor growth and prolonging the survival of tumor-bearing mice. This novel cocktail strategy has the potential to be a universal regimen for inflamed and non-inflamed tumors.

BACKGROUND: Deep brain stimulation has generated sustained improvement in motor function for patients with dystonia, but the long-term impact of subthalamic nucleus stimulation on dystonia has not been elucidated. METHODS: Patients with primary dystonia underwent bilateral subthalamic nucleus stimulation and were evaluated with the Burke-Fahn-Marsden dystonia rating scale and the Medical Outcomes Study 36-item Short-Form General Health Survey at baseline and 1 month, 1 year, and 3 to 10 years postoperatively. RESULTS: Improvements in motor function according to the Burke-Fahn-Marsden dystonia rating scale at 1 month, 1 year, and 3 to 10 years of stimulation were 55%, 77%, and 79%, respectively. The quality of life improved after 1 month of stimulation (P < 0.001), progressed within 1 year (P < 0.001), and then remained stable. Disease duration was negatively correlated with an improvement in motor function. CONCLUSIONS: Our results demonstrate that the subthalamus is an alternative to the globus pallidus internus as a target for deep brain stimulation to treat primary dystonia.

PURPOSE: To compare visual function after phacoemulsification with implantation of a multifocal intraocular lens (IOL) or a monofocal IOL. SETTING: Department of Ophthalmology, Affiliated Hospital of Qingdao University Medical College, Qingdao, Shandong, China. METHODS: This study comprised patients with unilateral cataract who had phacoemulsification with implantation of an AcrySof ReSTOR SA60D3 multifocal IOL (multifocal group) or an AcrySof SA60AT single-piece monofocal IOL (monofocal group). Postoperative visual function, including uncorrected (UDVA) and corrected (CDVA) distance visual acuity; uncorrected (UNVA), corrected (CNVA), and distance-corrected near visual acuity; and contrast sensitivity were evaluated 1 week, 1 month, and 6 months postoperatively. Patient-reported vision and spectacle independence in the 2 groups were also compared. RESULTS: Of the 161 eyes, 72 were in the multifocal group and 89 were in the monofocal group. The multifocal group had statistically significant better UNVA than the monofocal group from 1 week postoperatively to the final follow-up and statistically significant better CNVA at 6 months (both P<.05). There were no statistically significant differences in UDVA or CDVA between the 2 groups over the 6-month follow-up. The multifocal group had statistically significantly better pseudoaccommodation than the monofocal group; the monofocal group had significantly better contrast sensitivity (both P<.05). Patients with the multifocal IOL reported being more satisfied than those with the monofocal IOL. CONCLUSIONS: The multifocal IOL provided better near visual acuity and more spectacle independence than the monofocal IOL.

BRAFV600E mutation is highly prevalent in patients with papillary thyroid carcinoma (PTC), and TERT promoter (TERTp) mutation is strongly associated with cancer-related mortality. However, predictive power of the two mutations remains inconclusive. We aimed to verify the prognostic effects of both mutations to assess the value of mutation detection for risk stratification in terms of PTC prognosis and tumour invasion, to guide PTC diagnosis and treatment. We conducted a literature search in the MEDLINE (PubMed), EMBASE, Web of Science and CENTRAL (Cochrane library) databases, from inception to February 2020. Basic characteristics, prognoses and clinicopathological features were collected from the included studies for further analysis. Twelve studies involving 4184 PTC patients were enrolled in our analysis. In total, 2412 (57.6%) of the patients carried either BRAFV600E or TERTp mutation, and 290 (6.9%) patients had both mutations. TERTp mutation was more common in patients with BRAFV600E mutation (RR = 1.75 [95% CI 1.44-2.13]). Patients with both mutations had a worse prognosis compared with those with a single mutation (vs BRAFV600E only: RR = 5.34 [4.20-6.78] vs TERTp only: RR = 2.12 [1.41-3.19]). TERTp mutation alone independently increased the risk of a poor prognosis (RR = 2.90 [1.93-4.35]) in terms of mortality (RR = 15.09 [7.75-29.37]), disease persistence (RR = 4.00 [2.03-7.90]), recurrence (RR = 4.34 [4.20-6.78]), lymph node metastasis (RR = 1.57 [1.24-1.99]) and distant metastasis (RR = 2.94 [1.13-7.65]). We found that PTC patients with BRAFV600E mutation were more likely to have TERTp mutation. TERTp mutation was an independent predictive factor for poor prognosis of PTC patients, but the predictive value of BRAFV600E mutation remains inconclusive. Patients with both mutations have remarkably higher risks of adverse outcomes compared with those with a single mutation. PTC patients could benefit from mutation detection for aiding risk stratification (BRAF + TERT+ > BRAF - TERT+ > BRAF + TERT-).