Establishment of a minimally invasive distal traumatic optic neuropathy model in mice to investigate cascade reactions of retinal glial cells.

Traumatic optic neuropathy (TON) is a complication of craniocerebral, orbital and facial injuries, leading to irreversible vision loss. At present, there is no reliable, widely used animal model, although it has been confirmed that TON can cause the loss of retinal ganglion cells (RGC). However, the cascade reaction of retinal glial cells underlying TON is unclear. Therefore, the establishment of an animal model to explore the pathological mechanism of TON would be of great interest to the scientific community. In this study, we propose a novel mouse model utilizing a 3D stereotaxic apparatus combined with a 27G needle to evaluate damage to the optic nerve by micro-CT, anatomy, SD-OCT and F-VEP. Immunofluorescence, western blotting, qPCR experiments were conducted to investigate the loss of RGCs and activation or inactivation of microglia, astrocytes and Müller glial cells in the retina from the first week to the fourth week after modeling. The results showed that this minimally invasive method caused damage to the distal optic nerve and loss of RGC after optic nerve injury. Microglia cells were found to be activated from the first week to the third week; however, they were inactivated at the fourth week; astrocytes were activated at the second week of injury, while Müller glial cells were gradually inactivated following injury. In conclusion, this method can be used as a novel animal model of distal TON, that results in a series of cascade reactions of retinal glial cells, which will provide a basis for future studies aimed at exploring the mechanism of TON and the search for effective treatment methods.

Demographic and prognostic factors of optic nerve astrocytoma: a retrospective study of surveillance, epidemiology, and end results (SEER).

BACKGROUND: Optic nerve astrocytomas (ONAs) are neurological neoplasms in the central nervous system (CNS), and they have the highest incidence rate among all the tumor types in the visual pathway. In this study, we conducted a Surveillance, Epidemiology, and End Results (SEER) -based research to explore the demographic, survival, and prognostic factors of patients diagnosed with ONAs. METHODS: Utilizing the SEER database, we retrospectively evaluated data of patients diagnosed with ONAs of all ages from 1984 to 2016. We used the Student's t distribution to test variables of patients and various characteristics, and Kaplan-Meier curve to illustrate overall survival (OS) with 95.0% confidence intervals (CIs). We also performed univariate and multivariate analyses to evaluate various variables' validity on overall survival. RESULTS: A total of 1004 cases were analyzed, and revealed that age (P<0.001, hazard ratio (HR) = 8.830, 95% CI: 4.088-19.073), tumor grade (P<0.001, HR = 1.927, 95% CI: 1.516-2.450), diagnostic confirmation (P<0.001, HR = 2.444, 95% CI: 1.632-3.660), and histology type (P = 0.046, HR = 1.563, 95% CI: 1.008-2.424) of the tumor were associated with decreased survival. CONCLUSIONS: From this large, comparative study of ONAs, we found that younger age may be considered as a protective indicator, while high-grade astrocytic tumors have a worse prognosis. We also found that diagnostic confirmation and tumor grade were independent prognostic factors in this patient population.

Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma.

Microglia activation and release of pro-inflammatory cytokines have been closely linked to glaucoma. However, the mechanisms that initiate these pathways remain unclear. Here, we investigated the role of a pro-inflammatory cytokine--osteopontin (OPN), in retinal microglia activation process along with the underlying mechanisms in glaucoma. A rat chronic ocular hypertension (COH) model was established presenting an increase in retinal OPN level and activation of microglia. Primary microglia cells were isolated and cultured under a pressure culture system showing heightened expressions of microglia-derived OPN with changes in inflammatory factors (TNF-α, IL-1ß, and IL-6). OPN and OPN neutralizing antibody (Anti-OPN) interventions were both applied systems for comparison, and cross-referenced with OPN knockdown in vitro. JAK/STAT, NF-κB, ERK1/2, and p38 MAPK, recognized as the primary signaling pathways related to microglia activation, were then screened on whether they can facilitate OPN to act on microglia and their impact on specific inhibitors. Thereafter, retrograde labeling of retinal ganglion cells (RGCs) and flash visual evoked potentials (F-VEP) were used to investigate neuron protection in context of each blockade. Results suggest that OPN is able to enhance the proliferation and activation of retinal microglia in experimental glaucoma which may play a role in the glaucomatous optic neuropathy, and contribute to the eventual RGCs loss and vision function impairment. Such effect may be mediated through the regulation of p38 MAPK signaling pathway.

Preoperative serum CA125 levels predict the prognosis in hyperbilirubinemia patients with resectable pancreatic ductal adenocarcinoma.

Serum carbohydrate antigen 19-9 (CA19-9) is widely used to predict the prognosis for pancreatic ductal adenocarcinoma (PDAC). However, hyperbilirubinemia and the CA19-9 nonsecretor phenotype restrict the usage of serum CA19-9 alone. The goal of this study was to confirm the prognostic role of preoperative serum CA125 in PDAC, especially in patients with jaundice.A total of 211 patients with resected PDAC were eligible for this retrospective study, and were classified into 2 groups based on serum bilirubin levels. The prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses, and the performance of each factor in predicting overall survival (OS) and recurrence-free survival (RFS) was compared.High preoperative CA125, high TNM stage, and lymph node metastasis were independent risk predictors for OS and RFS in all patients and the 2 subgroups, but high CA19-9 was only significant when considering all patients and those with nonelevated bilirubin. Using time-dependent receiver-operating characteristic analysis, better predictive performance for OS and RFS was observed for serum CA19-9 as compared to serum CA125 in these patients.High serum CA125 can independently predict poor prognosis. Importantly, in PDAC patients with hyperbilirubinemia, preoperative serum CA125 can predict the prognosis, whereas CA19-9 cannot. Preoperative CA19-9 had better predictive performance for survival than CA125, and the performance of CA19-9 did not decline between all patients and those with nonelevated bilirubin, but was significantly affected by hyperbilirubinemia.

Normalization of CA19-9 following resection for pancreatic ductal adenocarcinoma is not tantamount to being cured?

BACKGROUND: Postoperative carbohydrate antigen 19-9 (CA19-9) is an independent predictor of survival for pancreatic ductal adenocarcinoma (PDAC), and more powerful than preoperative CA19-9. However, making decisions just dependent on postoperative CA19-9 may result in necessary treatments not being performed. MATERIALS AND METHODS: A total of 178 patients with resected PDAC were eligible for this retrospective study, classified into two corresponding subgroups according to postoperative CA19-9. Prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses. RESULTS: Postoperative CA19-9, preoperative CA125 and lymph node status were independent predictors. Better predictive performances for overall survival (OS) and recurrence-free survival (RFS) were achieved by postoperative CA19-9 compared to preoperative CA125 and lymph node status. Particularly, preoperative CA125 was associated with poor OS (p<0.001 for the normalized CA19-9 patients, p=0.012 for the elevated) and RFS (p=0.005 for the normalized, p=0.004 for the elevated). Moreover, preoperative CA125 levels related with survival in double- negative patients. CONCLUSIONS: Normalization of CA19-9 is not tantamount to be cured. Preoperative CA125 is a critical predictor for PDAC patients, especially in double-negative patients.

[Establishment mice model of radiation-injured lacrimal gland and pathophysiological exploration].

OBJECTIVE: To establish a radiation-injured model of lacrimal gland in mice and explore its pathophysiology. METHOD: Experimental research. According to the random number table, 50 healthy mice were divided into five groups:one control group (n = 10) and four experimental groups (n = 40). The experimental mice (n = 40) were exposed to different dosages of irradiation 12, 15, 18 and 21 Gy, respectively. The sham-irradiated controls (n = 10) were anesthetized in parallel with the irradiated rats but not irradiated. The mice were placed laterally and covered with a bolus material, then the X-ray irradiation was performed under general anaesthesia from above towards the mice' orbital region. The schirmer tests, Single- photon emission computed tomography/Computed tomography (SPECT/CT), HE, immunohistological, and ultrastructural examinations were conducted prior and 3 days, 7 days as well as 30 days after irradiation.Using t test to compare the differentiation of each group at the same time point. RESULTS: In 12 Gy group, there is no statistically significant decline in tear secretion (3 days after radiation, t = 2.137, P = 0.061;7 days after radiation, t = 1.137, P = 0.243).In 15 Gy group, Schirmer I test showed significantly reduced lachrymal secretion and the difference was statistically significant(3 days after radiation:t = 3.228, P = 0.011;7 days after radiation:t = 4.781, P = 0.001;30 days after radiation:t = 3.162, P = 0.011). Immunohistochemical findings include a significant loss in the expression of α-SMA (3 days after radiation, t = 4.395, P = 0.013; 30 days after radiation, t = 3.049, P = 0.035) , aquaporin (AQP-5) (3 days after radiation, t = 3.587, P = 0.028;30 days after radiation, t = 5.598, P = 0.005) , and an excessive expression of Tenascin-C (3 days after radiation, t = 2.964, P = 0.046;30 days after radiation, t = 4.028, P = 0.017) and CK8 (3 days after radiation, t = 5.103, P = 0.008;30 days after radiation, t = 6.178, P = 0.004) , which were statistically significant. Ultrastructural changes include a retention of secretory granules and an increase of apoptotic acinar nuclei as well as macrophage phagocytosis. Disturbance in the tracer uptake as well as reduction of the lacrimal ejection fraction was assessed under SPET/CT test and the difference was statistically significant (3 days after radiation:t = 2.796, P = 0.029;30 days after radiation:t = 2.641, P = 0.038). This radiation dosage didn't cause obvious eye complications (cataract, radiation retinopathy, etc.). At the dosages of 18 and 21 Gy, the lacrimal gland inflammation and tissue apoptosis expand obviously. CONCLUSIONS: The model of radiation-injured lacrimal gland was successfully constructed. Pathophysiological manifestation include the impaired structures of lacrimal gland cells and infiltration of inflammatory cells, as well as damaged function of tear secretion. These changes may prerequisites for further study on radiological protection of lacrimal glands during radiotherapy of the periorbital region for orbital tumors.

Improvement of radiotherapy-induced lacrimal gland injury by induced pluripotent stem cell-derived conditioned medium via MDK and inhibition of the p38/JNK pathway.

Radiation therapy is the most widely used and effective treatment for orbital tumors, but it causes dry eye due to lacrimal gland damage. Induced pluripotent stem cell-derived conditioned medium (iPSC-CM) has been shown to rescue different types of tissue damage. The present study investigated the mechanism of the potential radioprotective effect of IPS cell-derived conditioned medium (iPSC-CM) on gamma-irradiation-induced lacrimal gland injury (RILI) in experimental mice. In this study, we found that iPSC-CM ameliorated RILI. iPSC-CM markedly decreased radiotherapy induced inflammatory processes, predominantly through suppressing p38/JNK signaling. Further signaling pathway analyses indicated that iPSC-CM could suppress Akt (Protein Kinase B, PKB) phosphorylation. High levels of midkine (MDK) were also found in iPSC-CM and could be involved in lacrimal gland regeneration by promoting cell migration and proliferation. Thus, our study indicates that inhibiting the p38/JNK pathway or increasing the MDK level might be a therapeutic target for radiation-induced lacrimal gland injury.

Radiotherapy­induced Gadd45a impairs lacrimal gland epithelial cell migration and proliferation.

Radiotherapy­induced lacrimal gland injury is a serious clinical problem currently lacking satisfactory therapeutic strategies. Exploring the mechanisms underlying secondary injuries caused by radiation may aid in the development of novel targeted medicine. In the current study, growth arrest and DNA damage­inducible 45 α (Gadd45a), a gene which is upregulated in irradiated skin, was observed as being overexpressed in the irradiated lacrimal gland. Moreover, overexpressed Gadd45a may impair lacrimal gland repair by inhibiting lacrimal gland epithelial cell migration and proliferation. Further signalling pathway analyses indicated that Gadd45a overexpression suppresses Akt (protein kinase B, PKB), P38 and JNK phosphorylation. Thus, the results of the current study suggested that Gadd45a may be a therapeutic target in radiation­induced lacrimal gland injury.