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Purpose: The purpose of this study was to examine the differences in immunopathogenesis based on the cytokine/chemokine profiles in myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-positive and -negative groups. Methods: We measured the levels of T-helper cell 17 (Th17) cell-related cytokines/chemokines in 74 serum samples, which were divided into four groups: healthy control (HC) group (n = 15), idiopathic demyelinating optic neuritis (IDON) group (n = 20), aquaporin 4 (AQP4)-IgG-positive optic neuritis (ON) group (n = 18), and MOG-IgG positive-ON group (n = 21). Serum IL17, IL21, IL28, IL31, CXCL1, CXCL2, CCL2, CCL11, CCL20, and LT-α were detected. Results: The serum of the MOG-IgG-positive ON patients showed an obvious elevation of Th17 cell-related cytokines/chemokines compared with that of all the MOG-IgG-negative ON patients. Serum IL17 and IL21 were significantly higher in the ON patients with MOG-IgG positive than in all the other three groups. The serum levels of IL28, IL31, CXCL1, and CCL11 were higher in the ON patients with MOG-IgG positive than in the HC group and the IDON group. The serum concentration of CCL2, CXCL2, and CCL20 in the MOG-IgG-positive and AQP4-IgG-positive group is higher than that of the HC group. No difference in serum LT-α level was found among the four groups. Adjusted multiple regression analyses showed a positive association of IL17 and IL21 levels with the serum concentration of MOG-IgG in the ON patients. Conclusion: The elevated serum level of Th17 cell-related cytokine/chemokines may play an important role in the pathogenesis of MOG-IgG-positive demyelinating ON.

PURPOSE To analyse the clinical characteristics of simultaneous bilateral ON patients in China. METHODS This retrospective study was done on 51 primary bilateral ON patients between April 2008 and July 2016 at the Chinese People's Liberation Army General Hospital. Fifty eight primary unilateral ON patients formed the control group. Demographic data, clinical course, serum autoantibody status, connective tissue disorders, magnetic resonance imaging and visual functions were compared. RESULTS The mean age at disease onset in the bilateral group was younger than that of the unilateral group (p = 0.001). Cerebrospinal fluid (CSF) total cell count and CSF total protein were significantly higher in the bilateral group (p = 0.001, p = 0.025). Aquaporin-4 (AQP4) antibodies were detected in 39% and 21% of the bilateral and unilateral patients, respectively (p = 0.03). Twenty two percent of the bilateral patients fulfilled the diagnosis of neuromyelitis optica (NMO); 7% in the unilateral group did so (p = 0.03). Serum autoantibodies (ANA, SSA, SSB, etc.) were found in 49% of the bilateral patients and 29% of the unilateral patients (p = 0.035). After treatment, the bilateral patients were significantly more prone to severe visual disability eventually than their unilateral counterparts (p = 0.002). Patients with MOG-IgG (myelin oligodendrocyte glycoprotein-IgG) represented 26% of the patients negative for AQP4-IgG. Myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) sero-positive patients were more likely to recover than the other patients (p

Objective. This study aims to describe the clinical manifestations and outcomes in a cohort of older Chinese patients.Method. A retrospective study of patients aged ≥ 45 years who had a first episode of optic neuritis (ON) between May 2008 and November 2012. Clinical features at onset and last follow-up were analyzed within subgroups (age 45–65 years and age ≥ 65 years).Results. 76 patients (99 eyes) were included, of which 58% were females. The mean age at presentation was 55.53 ± 8.29 years (range: 45–83 years). Vision loss was severe at presentation, with initial best corrected vision activity (BCVA) Conclusion. Chinese patients in the age group ≥ 65 years with ON are less likely to develop NMOSD or MS. Notwithstanding, they had more severe visual loss at onset and poor recovery.

To evaluate the clinical features and prognosis of atypical optic neuritis (ON) with seronegative aquaporin-4 (AQP4) antibody in Chinese patients.All patients with first or relapsing ON were recruited from the Neuro-ophthalmology Department of the Chinese People's Liberation Army General Hospital from January 2013 to December 2014 and assigned to one of three groups based on diagnosis: atypical ON, typical ON and neuromyelitis optica spectrum disorder (NMOSD)-ON.A total of 173 patients were included in the cohort. Fifty patients (28.9%) were AQP4-Ab-positive and diagnosed with NMOSD-ON. Of 123 patients with seronegative AQP4-Ab, 37 (30.1%) patients had atypical ON, with male predominance (25, 67.6%). The atypical ON group (compared with the typical ON and NMOSD-ON groups) had a significantly lower female:male ratio (1:2.1 vs 1.8:1 and 9:1, respectively, p=0.001 and p0.001), an older mean age of onset (44.8, 13-71 years vs 36.9, 13-73 years and 36.2, 13-66 years, p=0.003 and p=0.004), a lower rate of good (≥0.5) visual recovery (6.7% vs 79.8% and 30.9%, p0.001 and p0.001) and (compared with the NMOSD-ON group) a lower recurrence rate during a 2-year follow-up (29.3% vs 60%, p=0.009). However, none developed to multiple sclerosis or neuromyelitis optica in the atypical ON group.Atypical ON with seronegative AQP4-Ab had unique clinical features in this Chinese cohort, including male predominance, an older age of onset, worse visual acuity recovery and resistance to corticosteroid therapy. This condition may be a distinct nosological entity with an unusual clinical and therapeutic profile.

Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis. In NMOSD patients, NMO-IgG evokes astrocytopathy that in turn causes demyelination. While measurement of NMO-IgG titer will help neurologists make the diagnosis of NMOSDs, it is not sufficient to evaluate the severity of astrocytopathy. In this study, we compared the different levels of an astrocyte biomarker in cerebrospinal fluid of NMOSD patients with good or poor recovery, and then linked their differences to the changes in remyelinating promoter (CXCL12) levels. Our results indicate that NMO-IgG down-regulated CXCL12 and impaired the remyelinating process, this may be a mechanism contributing to the poor recovery of NMOSDs.

Metastasis is responsible for over 90% of cancer deaths. However, biochemical and molecular mechanisms that regulate tumor progression to metastatic phenotype are still poorly understood, especially the control of survival and proliferation of metastatic cells. Kinases play key roles in regulation of many cellular processes. Here we employed an unbiased RNAi in vitro screen against human kinases and a focused cDNA in vivo screen to identify kinases that have novel roles in metastasis. Beta adrenergic receptor kinase 2 (BARK2, ADRBK2, GRK3) was one of the kinases we discovered to have a novel role in cancer progression through this work. It was essential for survival and proliferation of metastatic cells in vitro and in vivo. Moreover, it was also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 functions at least in part through regulating several angiogenic factors and stimulating angiogenesis. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastasis. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis. Citation Format: Nanping Ai, Mohit Hulsurkar, Lars Akslen, Randolph Watnick, Ed Harlow, Wenliang Li. GRK3 is essential for metastatic cells and promotes prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2014-LB-189

The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by cancer cells of several cancer types. Recently, a few kinases, such as FYN and c-Met, were reported to participate in regulating EMT. However, the roles of the majority of >700 human kinases in EMT and cancer progression are still unknown. Here we carried out human kinase cDNA screens to identify novel regulators of EMT. Many unknown EMT regulators and a few known ones such as PI3K, PDGFRA, FYN and c-Met, were found to up-regulate mesenchymal marker vimentin. Some also increase expression of fibronectin and N-cadherin, as well as EMT transcriptional regulators, such as ZEB1/2, Snail and Slug. At the same time, the cells acquired mesenchymal phenotypes, such as increased migration/invasion activity, enhanced capability to survive and proliferate in growth factor deprivation condition or under drug treatments. Interestingly, FACS analysis also showed a substantial increase in CD44hiCD24low population in kinase-transducted mammary gland epithelial cells. The increase of CD44hi population could be attributed to increase of a CD44 mesenchymal variant — the standard form CD44s and decrease of the epithelial variant CD44 v8-10. And this alternation was associated with down-regulation of ESRP1 and ESRP2, two splicing factors that regulate CD44 splicing and EMT. Furthermore, the mammary gland epithelial cells undergoing EMT showed increase capability of forming mammosphere and differentiating into other lineage, such as osteoblast and adipocyte. Importantly, some of these novel EMT regulators are associated with tumor progression and stemness of human cancers. Further study of these novel EMT regulators promises to provide new mechanisms of cancer progression, and may also lead to development of new prognostic markers and therapeutics for metastasis. Citation Format: Linna Li, Nanping Ai, Mohit Hulsurkar, Wenliang Li. Characterization of novel regulators of epithelial-mesenchymal transition in human cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A57.

Kinases play key roles in the regulation of many cellular processes and are postulated to participate in the development of metastatic capability. To test the role of kinases in tumor progression, we compared pairs of non-metastatic and metastatic tumor cells, a commonly used model, to study the cellular changes that accompany metastasis. As such, we performed arrayed shRNA screens to determine how kinase requirements for survival and proliferation varied between the matched cell lines. These screens revealed patterns of kinase requirements among 4 pairs of cell lines. Of particular interest, we identified a set of kinases that were essential predominately for metastatic cells, including c-Met. In vivo metastasis experiments are underway to evaluate which kinases can promote metastasis when ectopically expressed in otherwise non-metastatic cells. Since inhibition of these kinases phenocopied c-Met inhibition, we also sought to test if any of these kinases are functionally linked to c-Met signaling. Indeed, several of the identified kinases, including PRKCZ, became essential when immortalized melanocytes were made tumorigenic and metastatic by introduction of activated c-Met. Biochemical and genetic rescue experiments are currently ongoing to further examine the links between these genes and c-Met. These studies offer new insights into the cellular signaling pathways operating in metastatic cancer cells and also suggest potential targets to treat metastatic cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-90. doi:1538-7445.AM2012-LB-90