Search

Objective To explore the application value of breast cancer tumor markers tissue polypeptide specific antigen (TPS), carbohydrate antigen 15-3 (CA15-3), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125) detection alone or in combination for the monitoring of distant metastasis of breast cancer. Method The clinical data of 389 female breast cancer patients admitted to Tianjin Medical University Cancer Institute and Hospital from January 2016 to March 2017 were retrospectively analyzed. Serum levels of TPS, CA125, CA15-3, and CEA were compared to analyze their significance in prediction distant metastasis of breast cancer. The patients were divided into the distant metastatic group and the non-metastatic group according to whether the patients had distant metastasis. The non-metastatic group was divided into the control group and the occult metastasis group according to whether distant metastases occurred in 3 years after treatment. Result The receiver operating characteristic curve analysis revealed that all four markers had the diagnostic value in distant metastasis of breast cancer (AUCTPS = 0.754, AUC15-3 = 0.821, AUCCEA = 0.755, AUCCA125 = 0.651) and in occult metastasis in 3 years after treatment (AUCTPS = 0.751, AUC15-3 = 0.744, AUCCEA = 0.725, AUCCA125 = 0.661). To estimate whether the discrimination ability could be improved by marker panels, we established marker panels composed of TPS, CA125, CA15-3, and CEA. To discriminate distant metastasis from non-distant metastasis, the diagnostic ability of different panels composed of TPS, CA125, CA15-3 and CEA did not show significant difference compared with single CA15-3 (P > 0.05). To discriminate occult metastasis from the control group, no significant difference was shown in AUC between marker panels and single marker (P > 0.05). However, the sensitivity was improved when the marker-panels were used overall. Conclusion All tumor markers have abilities in prediction of distant metastasis of breast cancer. The combined detection of the markers is more valuable than using single tumor marker in improving sensitivity. Two markers' panels are more suitable for the prediction of distant metastasis of breast cancer than three or four makers' panels with the similar sensitivity and AUC.

Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting. Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity. Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.67–23.33] vs. 11.70 months [95% CI, 10.81–12.59], p p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Background Childhood overweight and obesity (OWO) has become a major public concern worldwide including in Shanghai, one of the most developed areas of China. Understanding perceptions and challenges of tackling childhood OWO among caregivers of children is critical to provide services in need. Methods A qualitative descriptive study including in-depth interviews with seven parents and six focus group discussions with a total of 32 parents or grandparents of children zero to 6 years of age. Participants lived in three districts of Shanghai and indexed children included both those with OWO or non-OWO children. Data were analyzed using qualitative thematic analysis. Results Caregivers tended to underestimate children’s weight status, and to regard chubby children as a sign of good parental care. Some caregivers even suggested that there were positive effects of childhood overweight. Caregivers identified a number of challenges to prevention of OWO in children, including difficulties in controlling dietary intake or increasing children’s physical activities; discordant views between parents and grandparents, and barriers to accessing professional guidance. Caregivers desired more detailed advice regarding children’s nutrition intake and physical activity, and preferred online approaches. Conclusions Misconceptions regarding childhood overweight were found in caregivers of children in Shanghai. Professional guidance on childhood weight control for caregivers is desired via digital applications such as mobile phone applications and social media.

Clinical research data show that gefitinib greatly improves the progression‐free survival of patients, so it is used in advanced non‐small cell lung cancer patients with EGFR mutation. However, some patients with EGFR sensitive mutations do not have good effects on initial gefitinib treatment, and this mechanism is rarely studied. METTL3, a part of N6‐adenosine‐methyltransferase, has been reported to play an important role in a variety of tumours. In this study, we found that METTL3 is up‐regulated in gefitinib‐resistant tissues compared to gefitinib‐sensitive tissues. Cell function experiments have proved that under the treatment of gefitinib, METTL3 knockdown promotes apoptosis and inhibits proliferation of lung cancer cells. Mechanistic studies have shown that METTL3 combines with MET and causes the PI3K/AKT signalling pathway to be manipulated, which affects the sensitivity of lung cancer cells to gefitinib. Therefore, our research shows that METTL3 can be used as a molecular marker to predict the efficacy of EGFR‐TKI therapy in patients, and METTL3 may be a potential therapeutic target.

Isatin (1H-indole-2,3-dione) was reported to possess anticancer activities through its effect on tumor proliferation, apoptosis, and metastasis in vitro and in vivo. Here, we described the synthesis of a novel series of 1,5-disubstituted isatin derivatives with 2-indolinone scaffold as antitumor agents. Most of the synthesized compounds revealed potent antiproliferative effects in mantle cell lymphoma (MCL) cell lines, among which 7l possessed promising activities with IC50 values ranging from 0.4 to 1.3 μM. Following flow cytometric analysis, compound 7l efficiently arrested the cell cycle at G2/M phase, and induced apoptosis. Thus, this study shows promise in therapeutics of 1,5-disubstituted isatin derivatives in MCL and provides novel potential and efficient antitumor agents.

Objectives Pancreatic cancer (PC) is a highly malignant tumor with poor detection sensitivity and specificity in biomarkers and diagnosis. Previous research indicated that serum Ephrin type-A receptor 2 in exosomes (Exo-EphA2) was highly expressed and might have facilitated cell migration in PC cells. However, the dynamics of clinical performance of serum Exo-EphA2 in PC patients are unknown. Thus, this study evaluated serum Exo-EphA2 as a potential diagnostic biomarker in PC. Methods The expressions of serum Exo-EphA2 were assessed by enzyme-linked immunosorbent assay for N = 353 serum samples, including from 204 PC patients, 75 patients with benign pancreatic disease, and 74 healthy control patients. Carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 242 (CA 242) were measured by automated immunoassay. Results Serum Exo-EphA2 levels were significantly higher in PC patients than in benign pancreatic disease and healthy control patients. Receiver operating characteristic curve analysis suggested that using combined diagnoses of Exo-EphA2 with CA 19-9 and CA 242 was more effective to discriminate early stage (stage I and II) in PC than in healthy controls and benign disease patients. Conclusions Novel findings suggest that serum Exo-EphA2 is a potential early diagnostic biomarker complementing CA 19-9 and CA 242 in PC.

Pancreatic cancer (PC) is the fourth most common cause of cancer‑related mortality worldwide and is characterized by high invasiveness and early metastasis. To identify novel diagnostic markers, the present study aimed to understand the mechanism underlying PC progression. The present study demonstrated that exosomes derived from the highly metastatic Panc‑1 PC cell line were internalized by a low metastatic cell line, resulting in increased migration of the latter. Proteomics analysis further revealed that the receptor tyrosine kinase Eph receptor A2 (EphA2) was overexpressed in the Panc‑1 exosomes, and these Exo_EphA2 had the ability to transfer metastatic potential to recipient cells. Consistent with this, circulating Exo_EphA2 levels were higher in patients with PC compared with healthy controls. Taken together, these results indicated that Exo_EphA2 acts an oncogene in PC and is a potential tumor maker for PC diagnosis.

Background: Postoperative cognitive dysfunction (POCD) is a general complication following cardiac and major non-cardiac surgery amongst the elderly, yet its causes and mechanisms are still unknown. The present study aimed to detect whether regional cerebral blood flow (CBF) is altered in the brain before surgery in POCD patients compared with non-POCD (NPOCD) patients, thus, CBF variation may potentially predict the occurrence of early POCD.Methods: Fifty patients scheduled for spinal stenosis surgery were enrolled in the study. All study participants completed a battery of neuropsychological tests (NPTs) by a well-trained neuropsychologist before the surgery and 1 week after the surgery. POCD was defined when the preoperative to postoperative difference of at least two of the NPTs’ |Z|-scores with reference to a control group exceeded 1.96. Pulsed arterial spin-labeling (ASL) MRI was scanned at least 1 day before surgery. The ASLtbx toolkit and SPM12 were applied to preprocess and correct the images, which were then normalized to the MNI brain template space to obtain standardized cerebral perfusion images.Results: POCD was identified in 11 out of 50 patients (22%). The CBF of the right superior temporal lobe, right and left middle cingulate gyrus, and the right hippocampus, and parahippocampal gyrus in POCD group was lower than that in NPOCD group (P < 0.001). The CBF of the pars triangularis of inferior frontal gyrus in POCD group was higher than that in NPOCD group (P < 0.001).Conclusions: These preliminary findings suggest that CBF premorbid alterations may happen in cognitively intact elderly patients that develop early POCD. Alterations of preoperative CBF might be a bio-marker for early POCD that can be detected by noninvasive MRI scans.

2,3-Indolinedione derivatives have been identified as a novel class of promising agents for cancer treatment. In this study, eighteen 2,3-indolinedione derivatives were designed and synthesized, and their anticancer activities against mantle cell lymphoma (MCL) cells were evaluated. Most of them exhibited significant antiproliferative activity against the tested cell lines, and compound K5 was the most potent (MCL cellular IC50 = 0.4–0.7 μM). Further, compound K5 could induce cell apoptosis and cell cycle arrest in G2/M phase. Additionally, the results of drug-likeness analysis demonstrated that these novel 2,3-indolinedione derivatives could have potential as novel treatment strategies for MCL.

Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives, and evaluated their biological activities. AR luciferase reporter assay revealed compound 6f (59.7%) as a potent AR antagonist. Some compounds in this series showed higher anti-proliferative activity against LNCaP cells than Bicalutamide (IC50 = 35.0 μM), especially 6g with IC50 value of 13.6 μM.

Background The incidence of brain metastasis (BM) in patients suffering from lung squamous cell carcinoma (LUSC) is lower than that in patients suffering from non-squamous cell carcinoma (NSCC) and there are few studies on BM of LUSC. The purpose of this investigation was to ascertain the risk factors of LUSC, as well as to establish a nomogram prognostic model to predict the incidence of BM in patients with LUSC. Methods Patients diagnosed with LUSC between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database and the patient data were collated. All patients diagnosed from 2010-2012 were allocated into the training cohort, and the remaining patients diagnosed from 2013-2015 formed the test cohort. Using factors that were screened out through logistic regression analyses, the nomogram in the training cohort was established. It was then evaluated for discrimination and calibration using the test cohort. The performance of the nomogram was assessed by quantifying the area under the receiver operating characteristic (ROC) curve and evaluating the calibration curve. Results A total of 26,154 LUSC patients were included in the study. The training cohort consisted of 16,543 patients and there were 8611 patients in the test cohort. Age, marital status, insurance status, histological grade, tumor location, laterality, stage of the cancer, number of metastatic organs, chemotherapy, surgery, and radiotherapy were highly correlated with the incidence of BM. The area under the ROC curve (AUC) of the nomogram for the training cohort and the test cohort were 0.810 [95% confidence interval (CI): 0.796 to 0.823] and 0.805 (95% CI: 0.784 to 0.825), respectively. The slope of the calibration curve was close to 1. Conclusions The nomogram was able to accurately predict the incidence of BM. This may be beneficial for the early identification of high-risk LUSC patients and the establishment of individualized treatments.

Background We conducted a systematic review and meta-analysis on drug-resistant tuberculosis in China to provide useful data for tuberculosis (TB) surveillance and treatment. Methods Several databases, including PubMed, Embase, and the Chinese Biological Medical Database, were systematically searched between January 1, 1999, and August 31, 2015, using strict inclusion and exclusion criteria. Results The corresponding drug-resistant TB prevalence between the new and previously treated cases was significantly different in almost all of the economic regions. The Eastern coastal region is the most developed economic region with the lowest total drug-resistant TB prevalence (any drug resistance: 28%; 95% confidence interval [CI], 25%-32%; multidrug resistance: 9%; 95% CI, 8%-12%) and the lowest number of new cases (any drug resistance: 21%; 95% CI, 19%-23%; multidrug resistance: 4%; 95% CI, 3%-5%). The Northwest is the least developed area with the lowest drug-resistant TB prevalence for previously treated cases (any drug resistance: 45%; 95% CI, 36%-55%; multidrug resistance: 17%; 95% CI, 11%-26%). The prevalence (multidrug and first-line drug resistance) exhibited a downward trend from 1996-2014. The extensively drug-resistant prevalence in China was 3% (95% CI, 2%-5%) in this review. Conclusions Overall, the status of drug-resistant tuberculosis in China is notably grim and exhibits regional epidemiologic characteristics. We are in urgent need of several comprehensive and effective control efforts to reverse this situation.

SFRP1 acts as a well-established inhibitory regulator of the Wnt signaling pathway, whose polymorphisms have been demonstrated to be associated with the risk of inflammation, infection as well as cancer. We verified the hypothesis that single nucleotide polymorphisms (SNPs) within SFRP1 gene are associated with susceptibility and clinical characteristics of tuberculosis disease in a Chinese Han population.Six candidate SNPs were genotyped using MassARRAY method in a case-control design (260 tuberculosis patients and 252 healthy controls). A comprehensive analysis of single locus including the genotypic, allelic frequencies and the genetic models, haplotypic construction as well as gene-gene interaction was conducted to investigate the relationships between SNPs and TB. Significant SNPs were further interrogated in relation to TB clinical features and host inflammatory status.Genotype frequencies of rs4736958 and rs7832767 within SFRP1 gene were significantly different (p=0.011, p=0.008, respectively) between tuberculosis group and control group. Subjects carrying C allele for rs4736958 showed a decreased tuberculosis risk (OR=0.66, 95% CI=0.51-0.87, p=0.003), whereas individuals carrying rs7832767 T allele had a significant increased risk in tuberculosis susceptibility (OR=1.32, 95% CI=1.01-1.74, p=0.046). Genetic model analysis revealed that dominant, co-dominant and recessive models of rs4736958 were associated with decreased susceptibility to tuberculosis (p all0.05), while the recessive and co-dominant models of rs7832767 were related to significantly increased risk for tuberculosis (p all0.05). There was a reduced tuberculosis risk in association with the haplotype CC (representing rs3242 and rs4736958) of SFRP1 (OR=0.73, 95% CI=0.56-0.96, p=0.026). Further stratification analysis indicated that TB patients with genotype CT for rs4736958 were associated with higher CRP concentrations, and heterozygous patients (CT genotype) of rs7832767 trended towards greater ESR levels.SNPs rs4736958 and rs7832767 of SFRP1 gene were significantly associated with tuberculosis susceptibility and might influence the expression levels of inflammatory markers of tuberculosis patients in a Chinese Han population.

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration-resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability compared with 10e in human liver microsomes.

Recent studies have implicated long non-coding RNA, AC079767.4, as a highly susceptible gene in tuberculosis. The aim of the study was to preliminarily explore the possible association of single nucleotide polymorphisms (SNPs) in AC079767.4 gene with clinical phenotypes and TB susceptibility in Western Chinese Han population. The improved multiplex ligation detection reaction (iMLDR) method was employed to genotype 4 SNPs in AC079767.4 in 554 tuberculosis patients and 561 healthy individuals. In subgroup analysis, only the C allele for rs12477677 was associated with the decreased susceptibility to pulmonary TB with a p-value of 0.026, but p-value was 0.103 after Bonferroni correction. In total samples, haplotype [ACAC], representing four AC079767.4 variants, was found to slightly decrease TB risk (p = 0.045). Furthermore, patients with the CC genotype of rs12477677 were correlated with fewer occurrences of fever (p = 0.016), while patients carrying the T allele were associated with lower levels of ESR in the dominant model of rs1055229 (p = 0.021). For the first time, we reported the potential susceptibility and clinical traits of tuberculosis with lncRNA variants in the Western Han Chinese population. Our data indicate AC079767.4 polymorphisms may potentially act as novel biomarkers for tuberculosis diagnostic and therapeutic purposes.

Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

Tuberculous meningitis continues to be a serious problem for physicians because it is difficult to make an early diagnosis and the consequences of delaying treatment are severe. The objective of this study is to provide data for the optimization of diagnostic and timely treatment of tuberculous meningitis. Of the 401 human immunodeficiency virus (HIV)-negative tuberculous meningitis patients in our study, 332 were found to have an impaired blood brain barrier (82.8%). Nearly 17.0% of patients failed to be timely diagnosed. Headache (53.6%) and fever (48.6%) were the most common features and Computed Tomography/Magnetic Resonance Imaging (CT/MRI) detected 96 patients (23.9%) with abnormal meningeal imaging. Cerebrospinal fluid real-time polymerase chain reaction was positive in 73.8% of the tuberculous meningitis patients, whereas, smears and cultures detected only 6.7% and 5.2%, respectively. Further analysis identified striking differences between drug-resistant and drug-susceptible tuberculous meningitis. Patients with drug resistance correlated with grave prognosis. Tuberculous meningitis diagnosis should overall embody clinical symptoms, laboratory and cerebral imaging findings and more sensitive diagnostic approaches are still warranted. Our data suggest cerebrospinal fluid polymerase chain reaction for mycobacterial DNA and molecular drug susceptibility testing as routine assays for suspected tuberculous meningitis patients and observation of the blood brain barrier function could be performed for individual management.

In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Conduction block in demyelinated axons underlies early neurological symptoms, but axonal transection and neuronal loss are believed to be responsible for more permanent chronic deficits. Several therapies are approved for treatment of relapsing-remitting MS, all of which are immunoregulatory and clinically proven to reduce the rate of lesion formation and exacerbation. However, existing approaches are only partially effective in preventing the onset of disability in MS patients, and novel treatments to protect myelin-producing oligodendrocytes and enhance myelin repair may improve long-term outcomes. Studies in vivo in genetically modified mice have assisted in the characterization of mechanisms underlying the generation of neuropathology in MS patients, and have identified potential avenues for oligodendrocyte protection and myelin repair. However, no treatments are yet approved that target these areas directly, and in addition, the relationship between demyelination and axonal transection in the lesions of the disease remain unclear. Here, we review translational research targeting oligodendrocyte protection and myelin repair in models of autoimmune demyelination, and their potential relevance as therapies in MS patients.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology. Conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory, and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability in MS patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes and reduce the rate of axonal transection. Studies in genetically modified animals have improved our understanding of mechanisms underlying CNS pathology in MS models, and have identified pathways that regulate oligodendrocyte viability and myelin repair. However, although clinical trials are ongoing, many have been unsuccessful and no treatments are yet approved that target these areas in MS. In this review, we examine avenues for oligodendrocyte protection and endogenous myelin repair in animal models of de- and remyelination, and their relevance as therapeutics in human patients.

While a substantial amount of data on gene mutations related to acute myeloid leukemia (AML) prognosis from western and other populations have been reported, these studies largely describe one or two genes. Additionally, in southwest China, only insufficient data exist regarding FLT3-ITD, FLT3-TKD, NPM1, C-KIT, DNMT3A, and CEBPA mutations have been widely used in clinical settings. Therefore, a comprehensive study about these mutations of clinical importance in the prognosis of AML in western China is necessary. In a cohort of 255 patients with de novo AML, we retrospectively analyzed the prevalence of the six gene mutations, and then we assessed the results in conjunction with clinical characteristics and treatment responses. As for the frequencies of these mutations, the NPM1 mutation occurred most frequently (17.7 %; 42/237), followed by the CEBPA mutation (15.0 %; 19/127) and the FLT3-ITD mutation (10.2 %; 25/244). The frequencies of the FLT3-TKD, DNMT3A, and C-KIT mutations were 3.7 % (9/234), 4.0 % (9/225) and 4.2 % (10/238), respectively. These mutations were closely related to clinical characteristics including FAB classification, gender and age, hemogram, blasts (%), fusion genes, and immunophenotypes. Additionally, a higher complete remission (CR) rate was found in NPM1-mutated patients. The occurrence of these mutations is variable among different countries and regions worldwide, which may provide clues to the etiology of AML. Besides, we identified new clinical characteristics that advance our understanding of these mutations and further clarify the involvement of these mutations in the development of leukemia.

Type 2 diabetes mellitus (T2DM) has been gradually considered as a micro- inflammatory disease. To explore the significance of peripheral CD4(+) regulatory T cells and CD4(+) effector T cells in T2DM, we analyzed inflammation, humoral and cellular immune state in patients with T2DM.118 patients with T2DM without complications and 116 healthy volunteers were included. Serum C-reactive protein (CRP), Complement 3 (C3), Complement 4 (C4), IgG, IgA, IgM, plasma sIL-2 R and peripheral T lymphocyte subsets (including CD4(+)CD25(high) regulatory T cells (Treg) and CD4(+)CD25(low+median) effector T cells (Teff)) were analyzed by rate nephelometry immunoassay, chemiluminescence immunoassay and flow cytometry, respectively.(1) micro-inflammation state in T2DM: Serum CRP, C3, IgA and plasma sIL-2 R were all significantly higher in T2DM than those in healthy control (HC) (all P0.05). (2) Disturbance of cellular immune in T2DM: Compared with HC, the percentage of peripheral CD3(+)CD4(+)T cells and ratio of CD3(+)CD4(+)T cells to CD3(+)CD8(+)T cells in T2DM were both significantly increased (P0.05); and the percentage of peripheral CD4(+)CD25(+)T cells, Teff cells increased (P0.05), Treg cells strikingly decreased in T2DM (P0.05). A positive correlation between sIL-2R levels and peripheral CD4(+)CD25(+)T cells or Teff cell percentages, as well as a negative correlation between plasma sIL-2 R levels and serum HDL, LDL or CHOL levels in T2DM were shown (all P0.05).Micro-inflammation state in T2DM was characterized by increased sIL-2 R, elevated CD3(+)CD4(+)T cells and the imbalance of Treg cells and Teff cells, which as one of the pathogeneses took part in inflammation reaction in T2DM.

Objective: Laquinimod is an orally administered CNS-active immunomodulator currently in phase III clinical trials for therapy of relapsing remitting multiple sclerosis (RRMS). Data show that RRMS patients show beneficial effects of laquinimod 0.6mg on clinical disease activity as evidenced by slowing of the progression of disability, reducing the rate of MRI-measured brain volume loss, and reducing relapse rate. The current work examines the mechanisms underlying these effects. Background Laquinimod crosses the blood-brain barrier and enters the CNS, thus in addition to peripheral effects it may act directly on CNS-resident lineages including oligodendrocytes, microglia and astrocytes. Increasing evidence implicates reactive astrocytes as critical regulators of CNS inflammation and repair in MS. Design/Methods: Here, we report that laquinimod profoundly impacts proinflammatory gene expression in a human in vitro model of reactive astrogliosis. Results: Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in RRMS, and in primary human astrocyte cultures it strongly induced inflammatory factors including cytokines, chemokines and reactive nitrogen species. Importantly, at therapeutic concentrations, laquinimod abrogated IL-1β-induced induction of cytokines including tumor necrosis factor-α (TNFα) and IL-6, and inducible nitric oxide synthase. Laquinimod also differentially regulated IL-1β-induced expression of CXC and CC chemokines, suggesting that it acts as an immunomodulator rather than an immunosuppressant in astrocyte cultures. IL-1β exerts its effects via the transcription factor NF-κB, and suggesting mechanism, laquinimod pretreatment of human astrocytes downregulated NF-κB activation. Conclusions: Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act centrally on resident CNS cells to restrict pathology in MS lesions. Supported by: A research grant from Teva Pharmaceuticals. Disclosure: Dr. Pham has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Hayardeny Nisimov has nothing to disclose. Dr. John has received personal compensation for activities with EMD Serono, Teva Neuroscience, and Biogen Idec. Dr. John has received research support from Teva Neuroscience, and Vaccinex Inc.

Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in multiple sclerosis (MS). LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-012-1009-1) contains supplementary material, which is available to authorized users.