Lgr4 in Ocular Development and Glaucoma

The leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4, also called GPR48) plays a key role in multiple developmental processes, and mice lacking Lgr4 display anterior segment dysgenesis leading to early-onset glaucomatous retinal ganglion cell loss as well as defective eyelid formation. This paper will review Lgr4 signaling and its regulation of the Axenfeld-Rieger syndrome gene Pitx2, a crucial developmental transcription factor. In addition, Wnt signaling plays an important role in eye development, with Norrin functioning to activate the Wnt receptor Frizzled 4 required for proper retinal vascularization. Recent discoveries identifying Lgr4 as a receptor for Norrin highlight the potential for Lgr4 function in retinal vascularization. Finally, several unanswered questions impeding a full understanding of Lgr4 in glaucoma are considered as avenues for further research

Review Article Lgr4 in Ocular Development and Glaucoma

The leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4, also called GPR48) plays a key role in multiple developmental processes, and mice lacking Lgr4 display anterior segment dysgenesis leading to early-onset glaucomatous retinal ganglion cell loss as well as defective eyelid formation. This paper will review Lgr4 signaling and its regulation of the AxenfeldRieger syndrome gene Pitx2, a crucial developmental transcription factor. In addition, Wnt signaling plays an important role in eye development, with Norrin functioning to activate the Wnt receptor Frizzled 4 required for proper retinal vascularization. Recent discoveries identifying Lgr4 as a receptor for Norrin highlight the potential for Lgr4 function in retinal vascularization. Finally, several unanswered questions impeding a full understanding of Lgr4 in glaucoma are considered as avenues for further research

Efficacy and safety of combined immunotherapy and stereotactic radiosurgery in NSCLCBM patients and a novel prognostic nomogram: A real-world study

ObjectiveTo explore the effectiveness of combined immunotherapy (IT) and stereotactic radiosurgery (SRS) and address the gap between evidence-based clinical practice and academic knowledge of optimal timing of IT relative to SRS. In addition, to meet the unmet need for an up-to-date prognostic assessment model in the era of IT.MethodsThe data of 86 non-small cell lung cancer brain metastasis (NSCLCBM) patients treated with SRS to 268 brain metastases (BMs) were retrospectively extracted from our hospital database. The Kaplan–Meier analysis was employed for overall survival (OS) and a log-rank test for comparison between groups. Cox proportional hazards regression models were used to identify the significant prognostic factors. The prognostic nomogram was established utilizing the rms package of R software.ResultsIT was found to be associated with improved OS (from BM diagnosis: HR 0.363, 95% CI 0.199 - 0.661, P < 0.001; from SRS: HR 0.472, 95% CI 0.260 - 0.857, P = 0.014). Individuals who received IT in combination with SRS had better OS than those who didn’t (from the day of BM diagnosis: 16.8 vs. 8.4 months, P = 0.006; from the day of SRS: 12 vs. 7 months, P = 0.037). Peri-SRS timing of IT administration was a significant prognostic factor for OS (from BM diagnosis: HR 0.132, 95% CI 0.034 - 0.517, P = 0.004; from SRS: HR 0.14, 95% CI 0.044 - 0.450, P = 0.001). Initiating IT after SRS led to superior OS than concurrent or before (from BM diagnosis: 26.5 vs. 14.1 vs. 7.1 months; from SRS: 21.4 vs. 9.9 vs. 4.1 months, respectively). Additionally, we build a nomogram incorporating IT, cumulative intracranial tumor volume (CITV), and recursive partitioning analysis (RPA), demonstrating a remarkable prognosis prediction performance for SRS-treated NSCLCBM patients.ConclusionPeri-SRS IT is a promising approach in treating NSCLCBM, as improved OS was observed without significantly increasing adverse events. Receipt of IT post-SRS was associated with superior OS than those who received IT concurrently or before. Incorporating IT and CITV into the RPA index could augment its prognosis assessment value for SRS-treated NSCLCBM patients, predominantly in the wild-type

A Natural Small Molecule Harmine Inhibits Angiogenesis and Suppresses Tumour Growth through Activation of p53 in Endothelial Cells

<div><p>Activation of p53 effectively inhibits tumor angiogenesis that is necessary for tumor growth and metastasis. Reactivation of the p53 by small molecules has emerged as a promising new strategy for cancer therapy. Several classes of small-molecules that activate the p53 pathway have been discovered using various approaches. Here, we identified harmine (β-carboline alkaloid) as a novel activator of p53 signaling involved in inhibition of angiogenesis and tumor growth. Harmine induced p53 phosphorylation and disrupted the p53-MDM2 interaction. Harmine also prevented p53 degradation in the presence of cycloheximide and activated nuclear accumulation of p53 followed by increasing its transcriptional activity in endothelial cells. Moreover, harmine not only induced endothelial cell cycle arrest and apoptosis, but also suppressed endothelial cell migration and tube formation as well as induction of neovascularity in a mouse corneal micropocket assay. Finally, harmine inhibited tumor growth by reducing tumor angiogenesis, as demonstrated by a xenograft tumor model. Our results suggested a novel mechanism and bioactivity of harmine, which inhibited tumor growth by activating the p53 signaling pathway and blocking angiogenesis in endothelial cells.</p> </div

Rhythmic expression of circadian clock genes in the preovulatory ovarian follicles of the laying hen

<div><p>The circadian clock is reported to play a role in the ovaries in a variety of vertebrate species, including the domestic hen. However, the ovary is an organ that changes daily, and the laying hen maintains a strict follicular hierarchy. The aim of this study was to examine the spatial-temporal expression of several known canonical clock genes in the granulosa and theca layers of six hierarchy follicles. We demonstrated that the granulosa cells (GCs) of the F1-F3 follicles harbored intrinsic oscillatory mechanisms <i>in vivo</i>. In addition, cultured granulosa cells (GCs) from F1 follicles exposed to luteinizing hormone (LH) synchronization displayed <i>Per2</i> mRNA oscillations, whereas, the less mature GCs (F5 plus F6) displayed no circadian change in <i>Per2</i> mRNA levels. Cultures containing follicle-stimulating hormone (FSH) combined with LH expressed levels of <i>Per2</i> mRNA that were 2.5-fold higher than those in cultures with LH or FSH alone. These results show that there is spatial specificity in the localization of clock cells in hen preovulatory follicles. In addition, our results support the hypothesis that gonadotropins provide a cue for the development of the functional cellular clock in immature GCs.</p></div

Circadian rhythm characteristics of clock genes in GCs and the TCs.

<p>Circadian rhythm characteristics of clock genes in GCs and the TCs.</p

A: Differences in the expression of <i>Lhcgr</i> and <i>StAR</i> between F1 and F5/F6 GCs. B: <i>Per2</i> transcript profile in F1 and F5/F6 GCs synchronized by LH.

<p>GCs were synchronized for 2 h with 100 ng/ml ovine LH and then washed two times with serum-free medium.</p