Background: Multiple sclerosis (MS) biomarker identification is important for pathogenesis research and diagnosis in routine clinical practice. Cerebrospinal fluid (CSF) and blood cytokines as potential biomarkers that can inform MS pathogenesis, diagnosis and response to treatment have been assessed in numerous studies. However, there have been no comprehensive meta-analyses to pool cytokine data and to address their diagnostic performance. We systematically reviewed literature with meta-analyses to assess the alteration levels of cytokines and chemokines in MS.Methods: We searched PubMed and Web of Science for articles published between January 1, 1990 and April 30, 2018 for this systematic review and meta-analysis. Data were extracted from 226 included studies encompassing 13,526 MS patients and 8,428 controls. Biomarker performance was rated by a random-effects meta-analysis based on the standard mean difference between cytokine concentration in patients with MS and controls, or patients before and after treatments.Results: Of the 26 CSF cytokines and 37 blood cytokines for potential differentiation between MS patients and controls, the random-effects meta-analysis showed that 13 CSF cytokines and 21 blood cytokines were significantly increased in MS patients in comparison to the controls. Interestingly, TNF-α, CXCL8, IL-15, IL-12p40, and CXCL13 were increased in both blood and CSF of MS patients. For those cytokines analyzed in at least 10 studies, differentiation between case and control was strong for CSF CXCL13, blood IL-2R, and blood IL-23; CSF CXCL8, blood IL-2, and blood IL-17 also performed well in differentiating between MS patients and controls, whereas those of CSF TNF-α and blood TNF-α, CXCL8, IL-12, IFN-γ were moderate. Furthermore, CSF IL-15, CCL19, CCL11, CCL-3, and blood CCL20, IL-12p40, IL-21, IL-17F, IL-22 had large effective sizes when differentiating between MS patients and controls but had a relatively small number of studies (three to seven studies).Conclusion: Our findings clarified the circulating cytokine profile in MS, which provide targets for disease modifying treatments, and suggest that cytokines have the potential to be used as biomarkers for MS.

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Oxidative stress has been reported to be involved in the onset and development of amyotrophic lateral sclerosis (ALS). Data from clinical studies have highlighted increased peripheral blood oxidative stress markers in patients with ALS, but results are inconsistent. Therefore, we quantitatively pooled data on levels of blood oxidative stress markers in ALS patients from the literature using a meta-analytic technique. A systematic search was performed on PubMed and Web of Science, and we included studies analyzing blood oxidative stress marker levels in patients with ALS and normal controls. We included 41 studies with 4,588 ALS patients and 6,344 control subjects, and 15 oxidative stress marker levels were subjected to random-effects meta-analysis. The results demonstrated that malondialdehyde (Hedges’ g, 1.168; 95% CI, 0.812 to 1.523; P<0.001), 8-hydroxyguanosine (Hedges’ g, 2.194; 95% CI, 0.554 to 3.835; P=0.009), and Advanced Oxidation Protein Product (Hedges’ g, 0.555; 95% CI, 0.317 to 0.792; P<0.001) levels were significantly increased in patients with ALS when compared with control subjects. Uric acid (Hedges’ g, -0.798; 95% CI, -1.117 to -0.479; P<0.001) and glutathione (Hedges’ g, -1.636; 95% CI, -3.020 to -0.252; P=0.02) levels were significantly reduced in ALS patients. In contrast, blood Cu, superoxide dismutase, glutathione peroxidase, ceruloplasmin, triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, coenzyme-Q10, and transferrin levels were not significantly different between cases and controls. Taken together, our results showed significantly increased blood levels of 8-hydroxyguanosine, malondialdehyde, and Advanced Oxidation Protein Product and decreased glutathione and uric acid levels in the peripheral blood of ALS patients. This meta-analysis helps to clarify the oxidative stress marker profile in ALS patients, supporting the hypothesis that oxidative stress is a central component underpinning ALS pathogenesis.

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In human pancreatic ductal adenocarcinoma (PDAC), the cyclophilin A (CypA) is overexpressed and promotes the development of PDAC. However, the mechanism underlying cyclophilin A expression remains elusive. Here, we reported that the citron Rho-interacting serine/threonine kinase (CIT) promotes the HIF1a-CypA signaling and growth of PDAC cells. CIT expression was higher in PDAC cells compared with the normal epithelial cells, and clinical data showed that CIT was overexpressed in PDAC tissues and high expression of CIT predicted poor overall and disease-free survival. In PDAC cells, knockdown of CIT expression repressed the rate of proliferation and capacity of colony formation, which were accomplished with an increased percentage of apoptotic cells and cell cycle arrest. The knockdown of CIT in PDAC cells reduced the expression of CypA while overexpression of CIT promoted the expression of CypA. We observed that the effects of CIT on the expression of CypA relied on the transcriptional factor HIF1a, which was previously reported to transcriptionally activate the expression of CypA in PDAC cells. Furthermore, the effects of CIT on apoptosis, cell cycle, proliferation, and colony formation of PDAC cells relied on its role in the regulation of CypA expression. Collectively, our data showed that CIT promoted the activation of HIF1-CypA signaling and enhanced the growth of PDAC cells.