Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus

PubMed Central

2011-01-01

Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9. Methods Flow cytometry, confocal microscopy and real-time PCR of flow cytometry-sorted cells were used to measure cell surface S100A8/A9, intracellular S100A8/A9 and mRNA levels of S100A8 and S100A9, respectively. Results Cell surface S100A8/A9 was detected on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and stimulation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex stimulation, pDCs up-regulated the cell surface S100A8/A9. SLE patients had also increased serum levels of S100A8/A9. Conclusions Patients with SLE had increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE. PMID:21492422

Serum S100A8 and S100A9 Enhance Innate Immune Responses in the Pathogenesis of Baker's Asthma.

PubMed

Pham, Duy Le; Yoon, Moon-Guyng; Ban, Ga-Young; Kim, Seung-Hyun; Kim, Mi-Ae; Ye, Young-Min; Shin, Yoo Seob; Park, Hae-Sim

2015-01-01

S100A8 and S100A9 can be produced by lipopolysaccharide-stimulated granulocytes and provoke an innate immune-mediated airway inflammation. Involvement of S100A8 and S100A9 has been implicated in asthma. To further understand the role of S100A8 and S100A9 during innate immune responses in baker's asthma, we investigated the associations of serum S100A8 and S100A9 with exposure to bakery allergens and polymorphisms of the Toll-like receptor 4 (TLR4) gene. Totally, 381 bakery workers and 100 unexposed healthy controls were recruited. Skin prick tests for bakery allergens were performed. Serum levels of S100A8, S100A9, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, and interleukin (IL)-8 were measured using ELISA. Predictive values of serum S100A8 and S100A9 in bakery workers were evaluated by receiver-operating characteristic (ROC) curves. Polymorphisms of TLR4 -2027Ax2192;G and -1608Tx2192;C were genotyped. Higher serum levels of S100A8 and S100A9 were noted in bakery workers compared to the normal controls (p < 0.001); however, no significant differences were noted according to work-related symptoms. The area under the ROC curve of serum S100A8 was 0.886 for occupational exposure (p < 0.001). The TLR4 -1608CC genotype was significantly associated with a higher serum S100A8 level (p = 0.025). Serum S100A8 and S100A9 levels were correlated with serum levels of MPO (r = 0.396 and 0.189, respectively), TNF-α (r = 0.536 and 0.280, respectively), and IL-8 (r = 0.540 and 0.205, respectively; p < 0.001 for all). S100A8 and S100A9 are involved in innate immune responses under the regulation of TLR4 polymorphisms in baker's asthma pathogenesis. Serum S100A8 could be a potential biomarker for predicting occupational exposure to wheat flour in bakery workers. © 2016 S. Karger AG, Basel.

Autocrine pathways involving S100A8 and/or S100A9 that are postulated to regulate the immunological functions of macrophages in rats.

PubMed

Okada, Kohki; Arai, Satoshi; Nakase, Hiroshi; Kohno, Hisashi; Nakamura, Fumihiko; Takeda, Mayu; Toda, Yoshinobu; Itoh, Hiroshi; Adachi, Souichi; Ikemoto, Masaki

2015-01-02

The development of ulcerative colitis (UC) is closely associated with abnormally functioning macrophages. Rat S100A8 (r-S100A8) and r-S100A9 (S100 proteins) is abundantly expressed in immune cells of myeloid origin, macrophages; however, it remains unclear why r-S100A9 is dominantly expressed in the macrophages of UC rats (UCR). The purpose of this study was to verify the immunological roles of S100 proteins in UCR. We observed the distribution of S100 protein-positive macrophages in the large colons of UCR using a fluorescent immunological staining method, so that S100 protein-positive macrophages were restricted to the rectal tissues of the UCR, and that the mRNA levels of r-S100A8 and r-S100A9 were up-regulated by stimulation with recombinant rat S100A8 (rr-S100A8) alone and rr-S100A9 alone, respectively. When the changes in the mRNA levels of r-S100A8 and r-S100A9 in macrophages were examined in in vitro study by PCR and real-time PCR, the mRNA levels of anti-inflammatory and inflammatory cytokines increased selectively after stimulation with rr-S100A8 alone and rr-S100A9 alone, respectively. These results suggest that autocrine signal transduction pathways involving S100 proteins regulate the immunological functions of macrophages to maintain homeostasis in the gastrointestinal tract. This may be depended on expression balance of S100 proteins in macrophages. It is strongly suggested that in UCR the immune functions of macrophages are regulated in a complex manner by r-S100A8 and/or r-S100A9 through undefined autocrine pathways on the cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of mRNA, Protein, and Urinary Nucleic Acid Levels of S100A8 and S100A9 between Prostate Cancer and BPH.

PubMed

Yun, Seok Joong; Yan, Chunri; Jeong, Pildu; Kang, Ho Won; Kim, Ye-Hwan; Kim, Eun-Ah; Lee, Ok-Jun; Kim, Won Tae; Moon, Sung-Kwon; Kim, Isaac Yi; Choi, Yung-Hyun; Kim, Wun-Jae

2015-07-01

Infections and inflammation in the prostate play a critical role in carcinogenesis, and S100A8 and S100A9 are key mediators in acute and chronic inflammation. Therefore, we investigated the differences of S100A8/A9 expression between prostate cancer (CaP) and benign prostatic hyperplasia (BPH) tissues, and we evaluated the possibilities of urinary nucleic acids of S100A8/A9 as diagnostic and prognostic markers. Tissues from 132 CaP patients who underwent prostatectomy or transurethral resection and 90 BPH patients who underwent transurethral prostatectomy were assessed.sd In addition, S100A8 and S100A9 nucleic acid levels were measured in the urine of 283 CaP patients and 363 BPH controls. S100A8 and S100A9 mRNA levels were lower in CaP than BPH tissues (P < 0.001). S100A8 and S100A9 expression was increased in cancer tissues with poorer prognosis. In 69 specimens from prostatectomy patients, S100A8/A9 were the independent predictor of biochemical recurrence (hazard ratio 5.22, 95 % confidence interval 1.800-15.155, P = 0.002). Immunohistochemical staining revealed that BPH tissues stained more strongly for both S100A8 and S100A9 than CaP tissues (P < 0.001). S100A8 and S100A9 urinary nucleic acid levels were lower in CaP than in BPH (P = 0.001 and <0.001, respectively). S100A8/A9 levels are lower in CaP than in BPH. Both were more highly expressed in patients with aggressive disease and shorter biochemical recurrence-free time. S100A8/A9 urinary cell-free nucleic acid levels correlated positively with expression levels obtained from tissue staining. Therefore, S100A8/A9 measurement in tissues and urine may have diagnostic and prognostic value in CaP.

Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells.

PubMed

Lim, S Y; Yuzhalin, A E; Gordon-Weeks, A N; Muschel, R J

2016-11-03

Myeloid cells promote the development of distant metastases, but little is known about the molecular mechanisms underlying this process. Here we have begun to uncover the effects of myeloid cells on cancer cells in a mouse model of liver metastasis. Monocytes/macrophages, but not granulocytes, isolated from experimental liver metastases stimulated migration and invasion of MC38 colon and Lewis lung carcinoma cells. In response to conditioned media from tumor-infiltrating monocytes/macrophages, cancer cells upregulated S100a8 and S100a9 messenger RNA expression through an extracellular signal-related kinase-dependent mechanism. Suppression of S100A8 and S100A9 in cancer cells using short hairpin RNA significantly diminished migration and invasion in culture. Downregulation of S100A8 and S100A9 had no effect on subcutaneous tumor growth. However, colony size was greatly reduced in liver metastases with decreased invasion into adjacent tissue. In tissue culture and in the liver colonies derived from cancer cells with knockdown of S100A8 and S100A9, MMP2 and MMP9 expression was decreased, consistent with the reduction in migration and invasion. Our findings demonstrate that monocytes/macrophages in the metastatic liver microenvironment induce S100A8 and S100A9 in cancer cells, and that these proteins are essential for tumor cell migration and invasion. S100A8 and S100A9, however, are not responsible for stimulation of proliferation. This study implicates S100A8 and S100A9 as important mediators of tumor cell aggressiveness, and highlights the therapeutic potential of S100A8 and S100A9 for interference of metastasis.

Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells

PubMed Central

Lim, S Y; Yuzhalin, A E; Gordon-Weeks, A N; Muschel, R J

2016-01-01

Myeloid cells promote the development of distant metastases, but little is known about the molecular mechanisms underlying this process. Here we have begun to uncover the effects of myeloid cells on cancer cells in a mouse model of liver metastasis. Monocytes/macrophages, but not granulocytes, isolated from experimental liver metastases stimulated migration and invasion of MC38 colon and Lewis lung carcinoma cells. In response to conditioned media from tumor-infiltrating monocytes/macrophages, cancer cells upregulated S100a8 and S100a9 messenger RNA expression through an extracellular signal-related kinase-dependent mechanism. Suppression of S100A8 and S100A9 in cancer cells using short hairpin RNA significantly diminished migration and invasion in culture. Downregulation of S100A8 and S100A9 had no effect on subcutaneous tumor growth. However, colony size was greatly reduced in liver metastases with decreased invasion into adjacent tissue. In tissue culture and in the liver colonies derived from cancer cells with knockdown of S100A8 and S100A9, MMP2 and MMP9 expression was decreased, consistent with the reduction in migration and invasion. Our findings demonstrate that monocytes/macrophages in the metastatic liver microenvironment induce S100A8 and S100A9 in cancer cells, and that these proteins are essential for tumor cell migration and invasion. S100A8 and S100A9, however, are not responsible for stimulation of proliferation. This study implicates S100A8 and S100A9 as important mediators of tumor cell aggressiveness, and highlights the therapeutic potential of S100A8 and S100A9 for interference of metastasis. PMID:27086923

Calcium-Binding Proteins S100A8 and S100A9: Investigation of Their Immune Regulatory Effect in Myeloid Cells.

PubMed

Yang, Jianxin; Anholts, Jacqueline; Kolbe, Ulrike; Stegehuis-Kamp, Janine A; Claas, Frans H J; Eikmans, Michael

2018-06-21

High expression levels of the calcium-binding proteins S100A8 and S100A9 in myeloid cells in kidney transplant rejections are associated with a favorable outcome. Here we investigated the myeloid cell subset expressing these molecules, and their function in inflammatory reactions. Different monocyte subsets were sorted from buffy coats of healthy donors and investigated for S100A8 and S100A9 expression. To characterize S100A9high and S100A9low subsets within the CD14+ classical monocyte subset, intracellular S100A9 staining was combined with flow cytometry (FACS) and qPCR profiling. Furthermore, S100A8 and S100A9 were overexpressed by transfection in primary monocyte-derived macrophages and the THP-1 macrophage cell line to investigate the functional relevance. Expression of S100A8 and S100A9 was primarily found in classical monocytes and to a much lower extent in intermediate and non-classical monocytes. All S100A9+ cells expressed human leukocyte antigen—antigen D related (HLA-DR) on their surface. A small population (<3%) of CD14+ CD11b+ CD33+ HLA-DR− cells, characterized as myeloid derived suppressor cells (MDSCs), also expressed S100A9 to high extent. Overexpression of S100A8 and S00A9 in macrophages led to enhanced extracellular reactive oxygen species (ROS) production, as well as elevated mRNA expression of anti-inflammatory IL-10 . The results suggest that the calcium-binding proteins S100A8 and S100A9 in myeloid cells have an immune regulatory effect.

S100A8/A9 increases the mobilization of pro-inflammatory Ly6Chigh monocytes to the synovium during experimental osteoarthritis.

PubMed

Cremers, Niels A J; van den Bosch, Martijn H J; van Dalen, Stephanie; Di Ceglie, Irene; Ascone, Giuliana; van de Loo, Fons; Koenders, Marije; van der Kraan, Peter; Sloetjes, Annet; Vogl, Thomas; Roth, Johannes; Geven, Edwin J W; Blom, Arjen B; van Lent, Peter L E M

2017-09-29

Monocytes are dominant cells present within the inflamed synovium during osteoarthritis (OA). In mice, two functionally distinct monocyte subsets are described: pro-inflammatory Ly6C high and patrolling Ly6C low monocytes. Alarmins S100A8/A9 locally released by the synovium during inflammatory OA for prolonged periods may be dominant proteins involved in stimulating recruitment of Ly6C high monocytes from the circulation to the joint. Our objective was to investigate the role of S100A8/A9 in the mobilization of Ly6C high and Ly6C low monocytic populations to the inflamed joint in collagenase-induced OA (CiOA). S100A8 was injected intra-articularly to investigate monocyte influx. CiOA was induced by injection of collagenase into knee joints of wild-type C57BL/6 (WT), and S100a9 -/- mice. Mice were sacrificed together with age-matched saline-injected control mice (n = 6/group), and expression of monocyte markers, pro-inflammatory cytokines, and chemokines was determined in the synovium using ELISA and RT-qPCR. Cells were isolated from the bone marrow (BM), spleen, blood, and synovium and monocytes were identified using FACS. S100A8/A9 was highly expressed during CiOA. Intra-articular injection of S100A8 leads to elevated expression of monocyte markers and the monocyte-attracting chemokines CCL2 and CX3CL1 in the synovium. At day 7 (d7) after CiOA induction in WT mice, numbers of Ly6C high , but not Ly6C low monocytes, were strongly increased (7.6-fold) in the synovium compared to saline-injected controls. This coincided with strong upregulation of CCL2, which preferentially attracts Ly6C high monocytes. In contrast, S100a9 -/- mice showed a significant increase in Ly6C low monocytes (twofold) within the synovium at CiOA d7, whereas the number of Ly6C high monocytes remained unaffected. In agreement with this finding, the Ly6C low mobilization marker CX3CL1 was significantly higher within the synovium of S100a9 -/- mice. Next, we studied the effect of S100A8/A9 on release of Ly6C high monocytes from the BM into the circulation. A 14% decrease in myeloid cells was found in WT BM at CiOA d7. No decrease in myeloid cells in S100a9 -/- BM was found, suggesting that S100A8/A9 promotes the release of myeloid populations from the BM. Induction of OA locally leads to strongly elevated S100A8/A9 expression and an elevated influx of Ly6C high monocytes from the BM to the synovium.

CD68 on rat macrophages binds tightly to S100A8 and S100A9 and helps to regulate the cells' immune functions.

PubMed

Okada, Kohki; Arai, Satoshi; Itoh, Hiroshi; Adachi, Souichi; Hayashida, Masahiko; Nakase, Hiroshi; Ikemoto, Masaki

2016-11-01

S100A8 and S100A9 (S100 proteins) are regulators of immune cells of myeloid origin. Whereas S100 proteins are found at high concentrations in such cells, their immunologic roles remain unclear. We focused on cluster of differentiation 68 (CD68). The aim of this study is to investigate whether CD68 binds to extracellular S100A8 and/or S100A9 and subsequently participates in the regulation of the cells' immune functions. ELISA and affinity chromatography showed that both recombinant rat S100A8 (r-S100A8) and r-S100A9 bound to r-CD68, but not to r-CD14. Flow cytometry clearly showed evidences supporting above the 2 results. As analyzed by flow cytometry, a less amount of r-S100A8 or r-S100A9 bound to the macrophages treated with some deglycosylation enzymes. In an in vitro assay, the expression levels of S100A8 and S100A9 were significantly suppressed after the macrophages had been treated with an anti-CD68 antibody (ED1). As stimulated macrophages with r-S100A9, the expression of IL-1β mRNA in macrophages, which were treated with anti-TLR4 or -RAGE antibodies, was significantly suppressed. r-S100A8 up-regulated IL-6 and IL-10 mRNAs, while r-S100A9 did TNF-α and IL-6 mRNAs, although these regulations were not statistically significant. Small interfering CD68 also significantly suppressed activation of macrophages through an autocrine pathway by r-S100A8 or r-S100A9. In macrophages stimulated with LPS, fluorescent immunologic staining showed that most CD68 colocalized with S100A8 or S100A9 and that the levels of all 3 molecules were markedly increased. In conclusion, CD68 on macrophages binds to S100A8 and S100A9 and thereby, plays a role in the regulation of the cells' immune functions. © Society for Leukocyte Biology.

Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux.

PubMed

Tardif, Mélanie R; Chapeton-Montes, Julie Andrea; Posvandzic, Alma; Pagé, Nathalie; Gilbert, Caroline; Tessier, Philippe A

2015-01-01

S100A8/A9 (calprotectin) and S100A12 proinflammatory mediators are found at inflammatory sites and in the serum of patients with inflammatory or autoimmune diseases. These cytoplasmic proteins are secreted by neutrophils at sites of inflammation via alternative secretion pathways of which little is known. This study examined the nature of the stimuli leading to S100A8/A9 and S100A12 secretion as well as the mechanism involved in this alternative secretion pathway. Chemotactic agents, cytokines, and particulate molecules were used to stimulate human neutrophils. MSU crystals, PMA, and H2O2 induced the release of S100A8, S100A9, and S100A12 homodimers, as well as S100A8/A9 heterodimer. High concentrations of S100A8/A9 and S100A12 were secreted in response to nanoparticles like MSU, silica, TiO2, fullerene, and single-wall carbon nanotubes as well as in response to microbe-derived molecules, such as zymosan or HKCA. However, neutrophils exposed to the chemotactic factors fMLP failed to secrete S100A8/A9 or S100A12. Secretion of S100A8/A9 was dependent on the production of reactive oxygen species and required K(+) exchanges through the ATP-sensitive K(+) channel. Altogether, these findings suggest that S100A12 and S100A8/A9 are secreted independently either via distinct mechanisms of secretion or following the activation of different signal transduction pathways.

Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux

PubMed Central

Tardif, Mélanie R.; Chapeton-Montes, Julie Andrea; Posvandzic, Alma; Pagé, Nathalie; Gilbert, Caroline; Tessier, Philippe A.

2015-01-01

S100A8/A9 (calprotectin) and S100A12 proinflammatory mediators are found at inflammatory sites and in the serum of patients with inflammatory or autoimmune diseases. These cytoplasmic proteins are secreted by neutrophils at sites of inflammation via alternative secretion pathways of which little is known. This study examined the nature of the stimuli leading to S100A8/A9 and S100A12 secretion as well as the mechanism involved in this alternative secretion pathway. Chemotactic agents, cytokines, and particulate molecules were used to stimulate human neutrophils. MSU crystals, PMA, and H2O2 induced the release of S100A8, S100A9, and S100A12 homodimers, as well as S100A8/A9 heterodimer. High concentrations of S100A8/A9 and S100A12 were secreted in response to nanoparticles like MSU, silica, TiO2, fullerene, and single-wall carbon nanotubes as well as in response to microbe-derived molecules, such as zymosan or HKCA. However, neutrophils exposed to the chemotactic factors fMLP failed to secrete S100A8/A9 or S100A12. Secretion of S100A8/A9 was dependent on the production of reactive oxygen species and required K+ exchanges through the ATP-sensitive K+ channel. Altogether, these findings suggest that S100A12 and S100A8/A9 are secreted independently either via distinct mechanisms of secretion or following the activation of different signal transduction pathways. PMID:27057553

Expression of calcium-binding proteins S100A8, S100A9 and S100A12 in otitis media.

PubMed

Hong, Wenzhou; Khampang, Pawjai; Samuels, Tina L; Kerschner, Joseph E; Yan, Ke; Simpson, Pippa

2017-10-01

Calgranulins (calcium-binding proteins S100A8, S100A9 and S100A12) are predominant cytoplasmic proteins of neutrophils and produced by various cells, playing multiple functions in innate immunity and the inflammatory process. Although up-regulated expression of S100A8 and S100A9 genes were observed in an animal model of otitis media (OM), their expressions have not been studied in human middle ear epithelial cells in response to the OM pathogen or in patients with recurrent or chronic OM (recurrent OM/RecOM or chronic OM with effusion/COME). Gene expressions were compared between Streptococcus pneumoniae (SP)-infected and non-infected human middle ear epithelial cells (HMEECs) as well as between chronic OM patients and control patients (CI). Gene expressions were profiled by quantitative real time PCR (qPCR). S100 proteins in OM patient and CI middle ear biopsies were detected by immunostaining. S100A8, S100A9 and S100A12 gene expressions were elevated in SP-infected HMEECs in time-dependent manner. S100A8 and S100A9 but not S100A12 gene expression was significantly elevated in the middle ear mucosa of OM patients. S100A8 and S100A9 protein were observed in middle ear mucosa of OM, but not CI patients. Minimal co-localization was observed between S100A8 and S100A9 with neutrophil elastase and cytokeratin in ME sections of OM patients. Elevated S100A8 and S100A9 gene expression in SP-infected HMEECs and in the middle ear mucosa of OM, minor co-localized with neutrophil markers suggests that middle ear epithelial cell secretion of S100A8 and S100A9 may play a role in the pathogenesis of recurrent and chronic OM. Copyright © 2017 Elsevier B.V. All rights reserved.

S100A8 and S100A9 Promotes Invasion and Migration through p38 Mitogen-Activated Protein Kinase-Dependent NF-κB Activation in Gastric Cancer Cells

PubMed Central

Kwon, Chae Hwa; Moon, Hyun Jung; Park, Hye Ji; Choi, Jin Hwa; Park, Do Youn

2013-01-01

S100A8 and S100A9 (S100A8/A9) are low-molecular weight members of the S100 family of calcium-binding proteins. Recent studies have reported S100A8/A9 promote tumorigenesis. We have previously reported that S100A8/A9 is mostly expressed in stromal cells and inflammatory cells between gastric tumor cells. However, the role of environmental S100A8/A9 in gastric cancer has not been defined. We observed in the present study the effect of S100A8/A9 on migration and invasion of gastric cancer cells. S100A8/A9 treatment increased migration and invasionat lower concentrations that did not affect cell proliferation and cell viability. S100A8/A9 caused activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The phosphorylation of p38 MAPK was not affected by the NF-κB inhibitor Bay whereas activation of NF-κB was blocked by p38 MAPK inhibitor SB203580, indicating that S100A8/A9-induced NF-κB activation is mediated by phosphorylation of p38 MAPK. S100A8/A9-induced cell migration and invasion was inhibited by SB203580 and Bay, suggesting that activation of p38 MAPK and NF-κB is involved in the S100A8/A9 induced cell migration and invasion. S100A8/A9 caused an increase in matrix metalloproteinase 2 (MMP2) and MMP12 expression, which were inhibited by SB203580 and Bay. S100A8/A9-induced cell migration and invasion was inhibited by MMP2 siRNA and MMP12 siRNA, indicating that MMP2 and MMP12 is related to the S100A8/A9 induced cell migration and invasion. Taken together, these results suggest that S100A8/A9 promotes cell migration and invasion through p38 MAPK-dependent NF-κB activation leading to an increase of MMP2 and MMP12 in gastric cancer. PMID:23456298

DAMP molecules S100A9 and S100A8 activated by IL-17A and house-dust mites are increased in atopic dermatitis.

PubMed

Jin, Shan; Park, Chang Ook; Shin, Jung U; Noh, Ji Yeon; Lee, Yun Sun; Lee, Na Ra; Kim, Hye Ran; Noh, Seongmin; Lee, Young; Lee, Jeung-Hoon; Lee, Kwang Hoon

2014-12-01

S100A9 and S100A8 are called damage-associated molecular pattern (DAMP) molecules because of their pro-inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house-dust mites affect S100A9 and S100A8 expression in Th2 cytokine- and Th17 cytokine-treated keratinocytes, and how secretion of these molecules affects keratinocyte-derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL-17A- and Dermatophagoides (D.) farinae-treated keratinocytes, respectively. Furthermore, co-treatment with D. farinae and IL-17A strongly increased expression of S100A9 and S100A8 compared with D. farinae-Th2 cytokine co-treatment. The IL-33 mRNA level increased in a dose-dependent manner in S100A9-treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP-mediated inflammation in AD triggered by IL-17A and house-dust mites. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

S100A8 and S100A9: DAMPs at the Crossroads between Innate Immunity, Traditional Risk Factors, and Cardiovascular Disease

PubMed Central

Schiopu, Alexandru; Cotoi, Ovidiu S.

2013-01-01

Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs) promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14) preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin) and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4) and of the receptor for advanced glycation end products (RAGE) and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing. PMID:24453429

S100A8/A9 in psoriatic plaques from patients with psoriatic arthritis.

PubMed

Chimenti, Maria Sole; Triggianese, Paola; Botti, Elisabetta; Narcisi, Alessandra; Conigliaro, Paola; Giunta, Alessandro; Teoli, Miriam; Perricone, Roberto; Costanzo, Antonio

2016-09-01

To evaluate levels of the calcium-binding proteins S100A8 and S100A9 in the skin of patients with psoriatic arthritis. Skin punch biopsies were obtained from patients with psoriatic arthritis and healthy control subjects. S100A8/A9 were semiquantified via immunohistochemistry and semiquantitative polymerase chain reaction. The study included biopsies from nine patients with psoriatic arthritis and nine control subjects. S100A8 and S100A9 were present at visibly higher levels in psoriatic plaques compared with normal skin samples. S100A8 and S100A9 RNA levels were significantly higher in the peripheral region of plaques compared with the central region. Both S100A8 and S100A9 may represent good therapeutic targets in psoriasis and psoriatic arthritis. © The Author(s) 2016.

Role of inflammatory proteins S100A8 and S100A9 in pathophysiology of recurrent early pregnancy loss.

PubMed

Nair, R R; Khanna, A; Singh, K

2013-09-01

Altered expression of inflammatory molecule at the maternal fetal interface is associated with early pregnancy loss. S100A8 and S100A9 are inflammatory proteins and they exhibit cytokine like function enhancing leukocyte recruitment to the inflammatory site. Reports from mouse model suggest the role of S100A8 with the vasculature of the decidual tissue and leukocyte recruitment during early pregnancy. Hence we hypothesized that maternal overexpression of S100A8 & S100A9 might increase the recruitment of inflammatory leukocytes in maternal-fetal interface resulting in uteroplacental perfusion deficiency, development of thrombotic events, and placental hypoxia, eventually embryo abortion. In the present study we investigated altered expression of S100A8 and S100A9 in 25 recurrent early pregnancy loss (REPL) patients compared to 40 induced abortion subjects as controls. S100A8 and S100A9 mRNA were evaluated using semi-quantitative RT-PCR and quantitative real-time PCR. To determine if differential expression pattern of these transcripts is translated to protein western blot analysis was performed.S100A8 and S100A9 mRNA and protein level were significantly increased in endometrial decidua tissue (p < 0.05) of REPL patients as compared to controls. This is the first report predicting the role of inflammatory molecules S100A8 & S100A9 in REPL. It opens a new perspective for understanding significance of S100A8 and S100A9 in pregnancy maintenance and outcome. Copyright © 2013 Elsevier Ltd. All rights reserved.

Elevated S100A8/A9 and S100A12 Serum Levels Reflect Intraocular Inflammation in Juvenile Idiopathic Arthritis-Associated Uveitis: Results From a Pilot Study.

PubMed

Walscheid, Karoline; Heiligenhaus, Arnd; Holzinger, Dirk; Roth, Johannes; Heinz, Carsten; Tappeiner, Christoph; Kasper, Maren; Foell, Dirk

2015-12-01

Juvenile idiopathic arthritis-associated uveitis (JIAU) is the most common uveitis entity in childhood. As S100A8/A9 and S100A12 proteins are valuable biomarkers in childhood arthritis, we investigated the occurrence of these proteins in childhood uveitis. Serum samples from patients with JIAU (n = 79) or idiopathic anterior uveitis (IAU, n = 24), as well as from nonuveitic controls (n = 24), were collected. Furthermore, aqueous humor samples (JIAU n = 17, nonuveitic controls n = 16, IAU n = 12) were obtained. Samples were analyzed for S100A8/A9 and S100A12 protein levels by ELISA. Intergroup comparisons were performed, involving patient data, clinical data, and S100 levels. S100A8/A9 and S100A12 serum levels were elevated in IAU and JIAU patients as compared to nonuveitic controls (all P < 0.05). S100 serum levels in JIAU patients were higher in active arthritis (not significant; P = 0.289 for S100A8/A9 and P = 0.196 for S100A12) and active uveitis (P = 0.010 for S100A8/A9 and P = 0.026 for S100A12) than in controls. No significant differences in S100 levels were found in a subgroup analysis for sex, antinuclear antibody (ANA) status, disease duration, or presence of uveitis complications. In JIAU patients, S100 serum levels correlated with age and age at onset of uveitis. A longitudinal analysis in JIAU patients showed a correlation of serum S100A8/A9 and S100A12 levels with uveitis activity (both P = 0.03). S100A8/A9 levels in aqueous humor of patients with JIAU (P = 0.001) and IAU (P = 0.0002) were increased as compared to nonuveitic controls. Increased S100A8/A9 and S100A12 levels are found in the serum and aqueous humor of patients with autoimmune uveitis. Serum levels reflect activity of joint and eye disease.

Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue.

PubMed

Van Crombruggen, Koen; Vogl, Thomas; Pérez-Novo, Claudina; Holtappels, Gabriele; Bachert, Claus

2016-01-01

Intracellular Ca(2+)-binding S100A8/A9 proteins gain novel functions when released during inflammation. The exact outcome of their extracellular function depends on the local tissue environment in which they are released; both anti-inflammatory and pro-inflammatory responses are described, modulating the immune system by binding Toll-like receptor (TLR)-4 or the receptor for advanced glycation end-products (RAGE). However, the contribution of the proteins in the pathophysiology of chronic rhinosinusitis (CRS) remains unclear.Homomeric S100A8 and S100A9, and heteromeric S100A8/A9 proteins were evaluated in CRS with/without nasal polyps (CRSw/sNP) and controls. Functional responses were assessed in polyp tissue stimulated with S100 proteins in the presence of TLR-4 and RAGE blocking antibodies.S100A8, S100A9 and S100A8/A9 protein levels were significantly higher in CRSwNP patients, showing increased deposition on extracellular matrix (ECM) structures of CRSwNP tissue in contrast to CRSsNP and controls. In the presence of Staphylococcus aureus, S100A8/A9 is released from neutrophils and from the ECM. Extracellular S100A8 and S100A9 proteins induced increased levels of diverse inflammatory mediators via TLR-4 engagement.The inflammatory/remodelling characteristics of CRSwNP specifically allow increased retention of S100A8, S100A9 and S100A8/A9 proteins in the ECM of CRSwNP tissue. Upon release, homodimeric proteins act as a local danger signal inducing inflammatory mediators, predominantly via TLR-4 activation. Copyright ©ERS 2016.

S100A8/A9 and S100A9 reduce acute lung injury.

PubMed

Hiroshima, Yuka; Hsu, Kenneth; Tedla, Nicodemus; Wong, Sze Wing; Chow, Sharron; Kawaguchi, Naomi; Geczy, Carolyn L

2017-05-01

S100A8 and S100A9 are myeloid cell-derived proteins that are elevated in several types of inflammatory lung disorders. Pro- and anti-inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL-10. S100 proteins did not significantly induce proinflammatory mediators including TNF-α, interleukin-1β (IL-1β), IL-6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL-10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL-1β, SAA3 and IL-10. Novel common pathways including increased induction of an NAD + -dependent protein deacetylase sirtuin-1 that may reduce NF-κB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung.

S100A8/A9 and S100A9 reduce acute lung injury

PubMed Central

Hiroshima, Yuka; Hsu, Kenneth; Tedla, Nicodemus; Wong, Sze Wing; Chow, Sharron; Kawaguchi, Naomi; Geczy, Carolyn L

2017-01-01

S100A8 and S100A9 are myeloid cell-derived proteins that are elevated in several types of inflammatory lung disorders. Pro- and anti-inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL-10. S100 proteins did not significantly induce proinflammatory mediators including TNF-α, interleukin-1β (IL-1β), IL-6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL-10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL-1β, SAA3 and IL-10. Novel common pathways including increased induction of an NAD+-dependent protein deacetylase sirtuin-1 that may reduce NF-κB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung. PMID:28074060

Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1

PubMed Central

2014-01-01

Background In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. Results NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation). Conclusions The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT. PMID:24670043

Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1.

PubMed

Basso, Daniela; Bozzato, Dania; Padoan, Andrea; Moz, Stefania; Zambon, Carlo-Federico; Fogar, Paola; Greco, Eliana; Scorzeto, Michele; Simonato, Francesca; Navaglia, Filippo; Fassan, Matteo; Pelloso, Michela; Dupont, Sirio; Pedrazzoli, Sergio; Fassina, Ambrogio; Plebani, Mario

2014-03-26

In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation). The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.

High Levels of S100A8/A9 Proteins Aggravate Ventilator-Induced Lung Injury via TLR4 Signaling

PubMed Central

Aslami, Hamid; Jongsma, Geartsje; van den Berg, Elske; Vlaar, Alexander P. J.; Roelofs, Joris J. T. H.; Juffermans, Nicole P.; Schultz, Marcus J.; van der Poll, Tom; Roth, Johannes; Wieland, Catharina W.

2013-01-01

Background Bacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury. Methods Pulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated. Results S100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation. Conclusion S100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4. PMID:23874727

Involvement of calprotectin (S100A8/A9) in molecular pathways associated with HNSCC

PubMed Central

Khammanivong, Ali; Sorenson, Brent S.; Ross, Karen F.; Dickerson, Erin B.; Hasina, Rifat; Lingen, Mark W.; Herzberg, Mark C.

2016-01-01

Calprotectin (S100A8/A9), a heterodimeric protein complex of calcium-binding proteins S100A8 and S100A9, plays key roles in cell cycle regulation and inflammation, with potential functions in squamous cell differentiation. While upregulated in many cancers, S100A8/A9 is downregulated in squamous cell carcinomas of the cervix, esophagus, and the head and neck (HNSCC). We previously reported that ectopic S100A8/A9 expression inhibits cell cycle progression in carcinoma cells. Here, we show that declining expression of S100A8/A9 in patients with HNSCC is associated with increased DNA methylation, less differentiated tumors, and reduced overall survival. Upon ectopic over-expression of S100A8/A9, the cancer phenotype of S100A8/A9-negative carcinoma cells was suppressed in vitro and tumor growth in vivo was significantly decreased. MMP1, INHBA, FST, LAMC2, CCL3, SULF1, and SLC16A1 were significantly upregulated in HNSCC but were downregulated by S100A8/A9 expression. Our findings strongly suggest that downregulation of S100A8/A9 through epigenetic mechanisms may contribute to increased proliferation, malignant transformation, and disease progression in HNSCC. PMID:26883112

Involvement of calprotectin (S100A8/A9) in molecular pathways associated with HNSCC.

PubMed

Khammanivong, Ali; Sorenson, Brent S; Ross, Karen F; Dickerson, Erin B; Hasina, Rifat; Lingen, Mark W; Herzberg, Mark C

2016-03-22

Calprotectin (S100A8/A9), a heterodimeric protein complex of calcium-binding proteins S100A8 and S100A9, plays key roles in cell cycle regulation and inflammation, with potential functions in squamous cell differentiation. While upregulated in many cancers, S100A8/A9 is downregulated in squamous cell carcinomas of the cervix, esophagus, and the head and neck (HNSCC). We previously reported that ectopic S100A8/A9 expression inhibits cell cycle progression in carcinoma cells. Here, we show that declining expression of S100A8/A9 in patients with HNSCC is associated with increased DNA methylation, less differentiated tumors, and reduced overall survival. Upon ectopic over-expression of S100A8/A9, the cancer phenotype of S100A8/A9-negative carcinoma cells was suppressed in vitro and tumor growth in vivo was significantly decreased. MMP1, INHBA, FST, LAMC2, CCL3, SULF1, and SLC16A1 were significantly upregulated in HNSCC but were downregulated by S100A8/A9 expression. Our findings strongly suggest that downregulation of S100A8/A9 through epigenetic mechanisms may contribute to increased proliferation, malignant transformation, and disease progression in HNSCC.

[Expression of S100A8 and A100A9 in giant cell tumor of bone and its relation with CT and MR imaging findings].

PubMed

Liao, Jin-sheng; Ding, Xiao-yi; Xu, Shun-liang

2015-05-01

To investigate the mRNA and protein expression levels of S100A8 and S100A9 in giant cell tumor (GCT) of bone, and its relation with radiological findings and biological behavior. Forty three patient with GCT of bone admitted in Ruijin Hospital Shanghai Jiaotong University School of Medicine from January 2009 to June 2012 were enrolled in the study. The expression levels of S100A8 and S100A9 mRNA and protein were detected by using semiquantitative RT-PCR and Western blotting in 43 specimens of GCT and 6 specimens of normal bone marrow. The CT and MRI findings of patients were retrospectively reviewed, its relation with tissue expression of S100A8 and S100A9 was analyzed. Among 43 GCT cases 40 showed positive expression of S100A8 and S100A9 mRNA and protein, and the expression levels were significantly higher than those in normal bone marrow P<0.05). The expression level of S100A8 protein was significantly different in bone GCT with different composition ratio on MRI (P<0.05).The expression level of S100A9 protein was significantly different in GCT with different degree of bone destruction on CT scan (P<0.05). The expression of S100A8 and S100A9 mRNA and protein is up-regulated in GCT of bone. The expression of S100A8 and S100A9 is associated with the real composition ratio and the degree of bone destruction, respectively, indicating that S100A8 and S100A9 may be involved in the biological behavior of bone GCT.

Phagocyte-specific S100A8/A9 is upregulated in primary Sjögren's syndrome and triggers the secretion of pro-inflammatory cytokines in vitro.

PubMed

Nicaise, Charles; Weichselbaum, Laura; Schandene, Liliane; Gangji, Valérie; Dehavay, Florence; Bouchat, Joanna; Balau, Benoît; Vogl, Thomas; Soyfoo, Muhammad S

2017-01-01

To determine the role of S100A8/A9 in the pathogenesis of primary Sjögren's syndrome (pSS). The serum levels of S100A8/A9 were determined in pSS patients and healthy controls by ELISA. The expression of S100A8/A9 in salivary glands was assessed by immunohistochemistry. The phenotype of S100A8+ and S100A9+ cells was identified using double immunofluorescence. The effects of S100A8/A9 on cytokine production by peripheral blood mononuclear cells (PBMCs) from pSS patients were determined in vitro by flow cytometry. The effects of pro-inflammatory cytokines on S100A8/A9 secretion were additionally investigated in vitro by ELISA in PBMCs from pSS patients and control subjects. Serum levels of S100A8/A9 were significantly increased in pSS patients compared to healthy controls. The tissular expression of S100A8 and S100A9, identified in professional phagocytes (neutrophils, monocytes and plasmacytoid dendritic cells), was increased in the salivary glands of pSS patients and correlated with focus score. In vitro, recombinant S100A8/A9 increased the production of IL-1β, IL-6, TNF-α, IFN-γ, IL-10, IL-17A and IL-22 by PBMCs. The S100A8/A9-induced increase in TNF-α production in pSS patients was significant relative to controls. Furthermore, IL-1β, TNF-α, IL-6, and IL-17A stimulated release of S100A8/A9 from PBMCs in pSS patients. S100A8/A9 is increased in pSS patients contributing to the in vitro increased production of pro-inflammatory cytokines. As such, S100A8/A9 in concert with other cytokines might contribute to the pathogenesis of pSS.

Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9.

PubMed

Schenten, Véronique; Plançon, Sébastien; Jung, Nicolas; Hann, Justine; Bueb, Jean-Luc; Bréchard, Sabrina; Tschirhart, Eric J; Tolle, Fabrice

2018-01-01

S100A8 and S100A9 are members of the S100 family of cytoplasmic EF-hand Ca 2+ -binding proteins and are abundantly expressed in the cytosol of neutrophils. In addition to their intracellular roles, S100A8/A9 can be secreted in the extracellular environment and are considered as alarmins able to amplify the inflammatory response. The intracellular activity of S100A8/A9 was shown to be regulated by S100A9 phosphorylation, but the importance of this phosphorylation on the extracellular activity of S100A8/A9 has not yet been extensively studied. Our work focuses on the impact of the phosphorylation state of secreted S100A9 on the proinflammatory function of neutrophils. In a first step, we characterized the secretion of S100A8/A9 in different stimulatory conditions and investigated the phosphorylation state of secreted S100A9. Our results on neutrophil-like differentiated HL-60 (dHL-60) cells and purified human neutrophils showed a time-dependent secretion of S100A8/A9 when induced by phorbol 12-myristoyl 13-acetate and this secreted S100A9 was found in a phosphorylated form. Second, we evaluated the impact of this phosphorylation on proinflammatory cytokine expression and secretion in dHL-60 cells. Time course experiments with purified unphosphorylated or phosphorylated S100A8/A9 were performed and the expression and secretion levels of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor alpha, CCL2, CCL3, CCL4, and CXCL8 were measured by real-time PCR and cytometry bead array, respectively. Our results demonstrate that only the phosphorylated form of the complex induces proinflammatory cytokine expression and secretion. For the first time, we provide evidence that S100A8/PhosphoS100A9 is inducing cytokine secretion through toll-like receptor 4 signaling.

Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9

PubMed Central

Schenten, Véronique; Plançon, Sébastien; Jung, Nicolas; Hann, Justine; Bueb, Jean-Luc; Bréchard, Sabrina; Tschirhart, Eric J.; Tolle, Fabrice

2018-01-01

S100A8 and S100A9 are members of the S100 family of cytoplasmic EF-hand Ca2+-binding proteins and are abundantly expressed in the cytosol of neutrophils. In addition to their intracellular roles, S100A8/A9 can be secreted in the extracellular environment and are considered as alarmins able to amplify the inflammatory response. The intracellular activity of S100A8/A9 was shown to be regulated by S100A9 phosphorylation, but the importance of this phosphorylation on the extracellular activity of S100A8/A9 has not yet been extensively studied. Our work focuses on the impact of the phosphorylation state of secreted S100A9 on the proinflammatory function of neutrophils. In a first step, we characterized the secretion of S100A8/A9 in different stimulatory conditions and investigated the phosphorylation state of secreted S100A9. Our results on neutrophil-like differentiated HL-60 (dHL-60) cells and purified human neutrophils showed a time-dependent secretion of S100A8/A9 when induced by phorbol 12-myristoyl 13-acetate and this secreted S100A9 was found in a phosphorylated form. Second, we evaluated the impact of this phosphorylation on proinflammatory cytokine expression and secretion in dHL-60 cells. Time course experiments with purified unphosphorylated or phosphorylated S100A8/A9 were performed and the expression and secretion levels of interleukin (IL)-1α, IL-1β, IL-6, tumor necrosis factor alpha, CCL2, CCL3, CCL4, and CXCL8 were measured by real-time PCR and cytometry bead array, respectively. Our results demonstrate that only the phosphorylated form of the complex induces proinflammatory cytokine expression and secretion. For the first time, we provide evidence that S100A8/PhosphoS100A9 is inducing cytokine secretion through toll-like receptor 4 signaling. PMID:29593718

S100A8/A9 mRNA induction in an ex vivo model of endotoxin tolerance: roles of IL-10 and IFNγ.

PubMed

Fontaine, Mathieu; Planel, Séverine; Peronnet, Estelle; Turrel-Davin, Fanny; Piriou, Vincent; Pachot, Alexandre; Monneret, Guillaume; Lepape, Alain; Venet, Fabienne

2014-01-01

Septic syndromes are the leading cause of death in intensive care units. They are characterized by the development of immune dysfunctions such as endotoxin tolerance (ET), whose intensity and duration are associated with increased risk of nosocomial infections and mortality. Alarmins S100A8 and S100A9 have been shown to be increased after septic shock. Importantly, a delayed S100A9 mRNA increase predicts hospital-acquired infection in patients. The aim of this study was to investigate the regulation of S100A8 and S100A9 mRNA expression in an ex vivo model of ET. ET was reproduced ex vivo by priming healthy peripheral blood mononuclear cells (number of donors  = 9 to 10) with low-dose endotoxin (2 ng/ml) before stimulation with high dose endotoxin (100 ng/ml). S100A8 and S100A9 mRNA levels were measured by quantitative real-time polymerase chain reactions. ET was established by observing decreased TNFα and increased IL-10 transcriptomic responses to two subsequent endotoxin challenges. Interestingly, ET was associated with increased S100A8 and S100A9 mRNA expression ex vivo. We showed that IL-10 played a role in this process, since S100A8 and S100A9 mRNA increases were significantly abrogated by IL-10 blockade in the model. Conversely, treatment with rIFN-γ, a pro-inflammatory and immunostimulating molecule known to block ET induction, was able to restore normal S100A8 and S100A9 mRNA in this model. In this ex vivo model, we observed that S100A8 and S100A9 mRNA expression was significantly increased during ET. This reproduced ex vivo the observations we had previously made in septic shock patients. Interestingly, IL-10 blockade and rIFN-γ treatment partially abrogated S100A8/A9 mRNA increases in this model. Pending confirmation in larger, independent clinical studies, these preliminary results suggest that S100A8 and S100A9 mRNA levels might be used as surrogate markers of ET and as stratification tools for personalized immunotherapy in septic shock patients.

Advanced glycation end products increase expression of S100A8 and A9 via RAGE-MAPK in rat dental pulp cells.

PubMed

Nakajima, Y; Inagaki, Y; Kido, J; Nagata, T

2015-04-01

Advanced glycation end products (AGE) are involved in the progression of diabetic complications. Although our previous reports show that AGE increased dental pulp calcification, AGE accumulation is also associated with inflammation. This study examined AGE effect on the expression of inflammation factors using rat dental pulp tissues and cell cultures. Receptor for AGE (RAGE), S100A8, S100A9, and interleukin (IL)-1β were selected as inflammation parameters. Rat dental pulp cells were cultured and treated with AGE, and the effects were determined by real-time PCR. An anti-RAGE antibody or MAPK pathway inhibitors (PD98059, SB203580, and SP60012) were used to investigate AGE signaling pathway. The mRNA levels of RAGE, S100A8, S100A9, and IL-1β were higher in diabetic pulp tissues. AGE increased mRNA expressions of S100A8, S100A9, and IL-1β in cultured dental pulp cells. In the presence of anti-RAGE antibody, AGE did not increase in S100A8 or S100A9 expressions. The AGE-induced increases in S100A8 and S100A9 were inhibited by PD98059 and SB203580, respectively. Advanced glycation end products increased mRNA expression of S100A8, S100A9, and IL-1β under diabetic pulp conditions, and AGE-induced increases in S100A8 and S100A9 expressions may be associated with the RAGE-MAPK signaling pathway. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3-Induced Myocarditis.

PubMed

Müller, Irene; Vogl, Thomas; Pappritz, Kathleen; Miteva, Kapka; Savvatis, Konstantinos; Rohde, David; Most, Patrick; Lassner, Dirk; Pieske, Burkert; Kühl, Uwe; Van Linthout, Sophie; Tschöpe, Carsten

2017-11-01

The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. S100A8 and S100A9 mRNA expression was 13.0-fold ( P =0.012) and 5.1-fold ( P =0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies. © 2017 American Heart Association, Inc.

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE.

PubMed

Narumi, Kenta; Miyakawa, Reina; Ueda, Ryosuke; Hashimoto, Hisayoshi; Yamamoto, Yuki; Yoshida, Teruhiko; Aoki, Kazunori

2015-06-01

S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-γ expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-γ production, and Pan02-S100A8/A9 cells further increased the number of IFN-γ(+) NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-γ production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02-S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9-RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity. Copyright © 2015 by The American Association of Immunologists, Inc.

Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis.

PubMed

Schelbergen, R F P; de Munter, W; van den Bosch, M H J; Lafeber, F P J G; Sloetjes, A; Vogl, T; Roth, J; van den Berg, W B; van der Kraan, P M; Blom, A B; van Lent, P L E M

2016-01-01

Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Induction of Canonical Wnt Signaling by the Alarmins S100A8/A9 in Murine Knee Joints: Implications for Osteoarthritis.

PubMed

van den Bosch, Martijn H; Blom, Arjen B; Schelbergen, Rik F P; Vogl, Thomas; Roth, Johannes P; Slöetjes, Annet W; van den Berg, Wim B; van der Kraan, Peter M; van Lent, Peter L E M

2016-01-01

Both alarmins S100A8/A9 and canonical Wnt signaling have been found to play active roles in the development of experimental osteoarthritis (OA). However, what activates canonical Wnt signaling remains unknown. This study was undertaken to investigate whether S100A8 induces canonical Wnt signaling and whether S100 proteins exert their effects via activation of Wnt signaling. Expression of the genes for S100A8/A9 and Wnt signaling pathway members was measured in an experimental OA model. Selected Wnt signaling pathway members were overexpressed, and levels of S100A8/A9 were measured. Activation of canonical Wnt signaling was determined after injection of S100A8 into naive joints and induction of collagenase-induced OA in S100A9-deficient mice. Expression of Wnt signaling pathway members was tested in macrophages and fibroblasts after S100A8 stimulation. Canonical Wnt signaling was inhibited in vivo to determine if the effects of S100A8 injections were dependent on Wnt signaling. The alarmins S100A8/A9 and members of the Wnt signaling pathway showed coinciding expression in synovial tissue in an experimental OA model. Synovial overexpression of selected Wnt signaling pathway members did not result in increased expression of S100 proteins. In contrast, intraarticular injection of S100A8 increased canonical Wnt signaling, whereas canonical Wnt signaling was decreased after induction of experimental OA in S100A9-deficient mice. S100A8 stimulation of macrophages, but not fibroblasts, resulted in increased expression of canonical Wnt signaling members. Overexpression of Dkk-1 to inhibit canonical Wnt signaling decreased the induction of matrix metalloproteinase 3, interleukin-6, and macrophage inflammatory protein 1α after injection of S100A8. Our findings indicate that the alarmin S100A8 induces canonical Wnt signaling in macrophages and murine knee joints. The effects of S100A8 are partially dependent on activation of canonical Wnt signaling. © 2016, American College of Rheumatology.

Circulating S100A8 and S100A9 protein levels in plasma of patients with acquired aplastic anemia and myelodysplastic syndromes.

PubMed

Giudice, Valentina; Wu, Zhijie; Kajigaya, Sachiko; Fernandez Ibanez, Maria Del Pilar; Rios, Olga; Cheung, Foo; Ito, Sawa; Young, Neal S

2018-06-26

The alarmin family members S100A8 and S100A9 are acute phase inflammation proteins, but they also have been proposed as biomarkers in many malignant and non-malignant diseases. In this study, circulating S100A8 and S100A9 homodimers and S100A8/A9 heterodimers in plasma were systematically investigated by ELISA in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Plasma was obtained from 58 severe AA (SAA) and 30 MDS patients, and from 47 age- and sex-matched healthy donors. In 40 out of the 58 AA subjects, S100A protein levels were measured before and 6 months after immunosuppressive therapy (IST). No differences were observed in AA patients at diagnosis compared to healthy controls for circulating S100A homodimers and heterodimers. After therapy, SAA-responders showed significantly increased circulating S100A8. Non-responding patients had significantly higher levels of circulating S100A8/A9 compared to responders and healthy controls, but without variations of S100A8 and S100A9 homodimers. In MDS patients, circulating S100A8 was significantly elevated compared to those of AA and/or healthy controls. By Pearson correlation analysis of protein levels and blood counts, multiple correlations were found. However, as S100A8 and S100A9 are abundantly present in white blood cells and platelets, correlations with blood counts likely mirror the higher number of cells in the blood of some patients. In conclusion, our findings indicate that circulating S100A8 is increased in MDS but not in AA, and that may be useful to distinguish these diseases in the differential diagnosis of bone marrow failure syndromes. Clinicaltrials.gov identifiers: NCT00260689, NCT00604201, NCT01328587, NCT01623167, NCT00001620, NCT00001397. Published by Elsevier Ltd.

S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome.

PubMed

Wang, Lin; Rosé, Carlos D; Foley, Kevin P; Anton, Jordi; Bader-Meunier, Brigitte; Brissaud, Philippe; Chédeville, Gaelle; Cimaz, Rolando; Fernández-Martín, Jorge; Guly, Catherine; Hachulla, Eric; Harjacek, Miroslav; Mackensen, Friederike; Merino, Rosa; Modesto, Consuelo; Naranjo Hernández, Antonio; Pajot, Christine; Ramanan, Athimalaipet V; Thatayatikom, Akaluck; Thomée, Caroline; Vastert, Sebastiaan; Votta, Bart J; Bertin, John; Wouters, Carine H

2018-04-07

To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

S100A8 as potential salivary biomarker of oral squamous cell carcinoma using nanoLC-MS/MS.

PubMed

Jou, Yu-Jen; Hua, Chun-Hung; Lin, Chia-Der; Lai, Chih-Ho; Huang, Su-Hua; Tsai, Ming-Hsui; Kao, Jung-Yie; Lin, Cheng-Wen

2014-09-25

Oral squamous cell carcinoma (OSCC) shows low 5-year survival; early treatment greatly reduces mortality and morbidity. Saliva is a non-invasive sample, with good potential to discover biomarkers for early detection. NanoLC-MS/MS served to analyze saliva proteome from control subjects (n=35) and OSCC patients T1 (n=29), T2 (n=36), T3 (n=14) and T4 (n=21) stages. Identified biomarkers were verified by Western blot and ELISA assays. NanoLC-MS/MS analysis of salivary proteins between 10 and 15kDa identified S100A8, hemoglobin delta and gamma-G globin in T3 and T4 stage OSCC as well as S100A7 in T1 and T2 stage OSCC. Western blot and ELISA indicated positive correlation between salivary S100A8 increment and tumor size stage. High level of S100A8 appeared in 3.4, 13.9, 92.9, and 100% of saliva OSCC patients with T1, T2, T3, and T4 stages, respectively. Significant increase of salivary S100A7 was observed in 20.7% and 11.1% of those with T1 and T2, respectively. AUROC curve indicated high sensitivity, specificity and accuracy of S100A8-based ELISA as a detector. NanoLC-MS/MS, Western blot and ELISA manifested salivary S100A8 as a specific and sensitive marker for detection of OSCC patients. Salivary S100A8 protein could be applicable in developing OSCC diagnostics. Copyright © 2014 Elsevier B.V. All rights reserved.

Increased serum levels of S100A8/A9 and S100A12 are associated with cardiovascular disease in patients with inactive systemic lupus erythematosus.

PubMed

Tydén, Helena; Lood, Christian; Gullstrand, Birgitta; Jönsen, Andreas; Nived, Ola; Sturfelt, Gunnar; Truedsson, Lennart; Ivars, Fredrik; Leanderson, Tomas; Bengtsson, Anders A

2013-11-01

Patients with SLE have an increased morbidity and mortality from cardiovascular disease (CVD). The reason for this is not entirely understood, but is believed to be partly related to the long-lasting inflammatory process seen in SLE. The aim of the present study was to investigate whether there is an association between CVD and serum levels of the proinflammatory proteins S100A8/A9 and S100A12 in SLE. Serum levels of S100A8/A9 and S100A12 were measured with ELISA in 237 SLE patients with clinically inactive disease and without infections, as well as in 100 healthy individuals. Cardiovascular manifestations were defined according to the SLICC/ACR Damage Index (SLICC/ACR-DI). Serum levels of S100A8/A9 were elevated in our inactive SLE patients as compared with healthy individuals (P < 0.0001), which was not seen for S100A12 (P = 0.12). SLE patients with a history of CVD had increased serum levels of both S100A8/A9 and S100A12 compared with patients with no CVD or venous thromboembolism (P = 0.003 and P = 0.006, respectively). The presence of organ damage according to SLICC/ACR-DI was associated with an increase in both S100A8/A9 and S100A12 serum levels (P = 0.001 and P = 0.006, respectively). Elevated serum levels of S100A8/A9 and S100A12 may be used as an indicator of severe disease and CVD in SLE, suggesting that SLE patients with elevated serum S100A8/A9 and S100A12 concentrations may benefit from more intense cardiovascular primary preventive strategies and possibly also from more intense and early immunosuppressive treatment.

Calprotectin and the Initiation and Progression of Head and Neck Cancer.

PubMed

Argyris, P P; Slama, Z M; Ross, K F; Khammanivong, A; Herzberg, M C

2018-06-01

Calprotectin (S100A8/A9), a heterodimeric complex of calcium-binding proteins S100A8 and S100A9, is encoded by genes mapping to the chromosomal locus 1q21.3 of the epidermal differentiation complex. Whereas extracellular calprotectin shows proinflammatory and antimicrobial properties by signaling through RAGE and TLR4, intracytoplasmic S100A8/A9 appears to be important for cellular development, maintenance, and survival. S100A8/A9 is constitutively expressed in myeloid cells and the stratified mucosal epithelia lining the oropharyngeal and genitourinary mucosae. While upregulated in adenocarcinomas and other cancers, calprotectin mRNA and protein levels decline in head and neck squamous cell carcinoma (HNSCC). S100A8/A9 is also lost during head and neck preneoplasia (dysplasia). Calprotectin decrease does not correlate with the clinical stage (TNM) of HNSCC. When expressed in carcinoma cells, S100A8/A9 downregulates matrix metalloproteinase 2 expression and inhibits invasion and migration in vitro. S100A8/A9 regulates cell cycle progression and decelerates cancer cell proliferation by arresting at the G2/M checkpoint in a protein phosphatase 2α-dependent manner. In HNSCC, S100A8 and S100A9 coregulate with gene networks controlling cellular development and differentiation, cell-to-cell signaling, and cell morphology, while S100A8/A9 appears to downregulate expression of invasion- and tumorigenesis-associated genes. Indeed, tumor formation capacity is attenuated in S100A8/A9-expressing carcinoma cells in vivo. Hence, intracellular calprotectin appears to function as a tumor suppressor in head and neck carcinogenesis. When compared with S100A8/A9-low HNSCC based on analysis of TCGA, S100A8/A9-high HNSCC shows significant upregulation of apoptosis-related genes, including multiple caspases. Accordingly, S100A8/A9 facilitates DNA damage responses in HNSCC, promotes apoptotic cell death, and confers sensitivity to cisplatin and X-radiation in vitro. In the tumor milieu, loss of S100A8/A9 strongly associates with poor squamous differentiation and higher tumor grading, EGFR upregulation, increased DNA methylation, and, finally, poorer overall survival for patients with HNSCC. Hence, intracellular calprotectin shows a multifaceted protective role against the development of HNSCC.

Clinical significance of calcium-binding protein S100A8 and S100A9 expression in non-small cell lung cancer.

PubMed

Huang, He; Huang, Qingdong; Tang, Tingyu; Gu, Liang; Du, Jianzong; Li, Zhijun; Lu, Xiaoling; Zhou, Xiaoxi

2018-05-07

The purpose of this study was to evaluate the correlation between calcium-binding protein S100A8 and S100A9 expression in non-small cell lung cancer (NSCLC) and patients' clinical features. Fifty-two NSCLC patients who underwent surgery at Zhejiang Hospital from February 2014 to January 2016 were included in this study. Calcium-binding protein S100A8 and S100A9 expression patterns in cancer and para-cancer tissues were examined by immunohistochemistry assay. The correlation between calcium-binding protein S100A8 and S100A9 expression patterns and NSCLC patients' clinical characteristics, including age, gender, tumor node metastasis stage, and pathology type, were evaluated. S100A8 and S100A9 were generally expressed on the cytoplasm and nucleus of NSCLC cells, mainly located in the cytoplasm, stained with brown particles, and distributed evenly. The positive expression rates of S100A8 and S100A9 in cancer tissues were 71.2% and 76.9%, respectively, which were significantly higher than in para-cancer tissues at 11.5% and 19.2%, respectively, with statistical significance (P < 0.05). S100A8 and S100A9 positive expression was associated with tumor differentiation degree (P < 0.05) but were not correlated with age, gender, smoking history, tumor diameter, pathology type, tumor node metastasis stage, or pleural effusion (P all  > 0.05). S100A8 and S100A9 positive expression in cancer tissues was significantly higher than in para-cancer tissues and was correlated with tumor differentiation, which may be a potential marker for poor prognosis. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Expression and function of S100A8/A9 (calprotectin) in human typhoid fever and the murine Salmonella model.

PubMed

De Jong, Hanna K; Achouiti, Ahmed; Koh, Gavin C K W; Parry, Christopher M; Baker, Stephen; Faiz, Mohammed Abul; van Dissel, Jaap T; Vollaard, Albert M; van Leeuwen, Ester M M; Roelofs, Joris J T H; de Vos, Alex F; Roth, Johannes; van der Poll, Tom; Vogl, Thomas; Wiersinga, Willem Joost

2015-04-01

Typhoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model. S100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury. S100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice.

Expression and Function of S100A8/A9 (Calprotectin) in Human Typhoid Fever and the Murine Salmonella Model

PubMed Central

De Jong, Hanna K.; Achouiti, Ahmed; Koh, Gavin C. K. W.; Parry, Christopher M.; Baker, Stephen; Faiz, Mohammed Abul; van Dissel, Jaap T.; Vollaard, Albert M.; van Leeuwen, Ester M. M.; Roelofs, Joris J. T. H.; de Vos, Alex F.; Roth, Johannes; van der Poll, Tom; Vogl, Thomas; Wiersinga, Willem Joost

2015-01-01

Background Typhoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model. Methods and principal findings S100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury. Conclusion S100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice. PMID:25860480

S100A8 and S100A9 Induce Cytokine Expression and Regulate the NLRP3 Inflammasome via ROS-Dependent Activation of NF-κB1

PubMed Central

Simard, Jean-Christophe; Cesaro, Annabelle; Chapeton-Montes, Julie; Tardif, Mélanie; Antoine, Francis; Girard, Denis; Tessier, Philippe A.

2013-01-01

S100A8 and S100A9 are cytoplasmic proteins expressed by phagocytes. High concentrations of these proteins have been correlated with various inflammatory conditions, including autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, as well as autoinflammatory diseases. In the present study, we examined the effects of S100A8 and S100A9 on the secretion of cytokines and chemokines from PBMCs. S100A8 and S100A9 induced the secretion of cytokines such as IL-6, IL-8, and IL-1β. This secretion was associated with the activation and translocation of the transcription factor NF-κB. Inhibition studies using antisense RNA and the pharmacological agent BAY-117082 confirmed the involvement of NF-κB in IL-6, IL-8, and IL-1β secretion. S100A8- and S100A9-mediated activation of NF-κB, the NLR family, pyrin domain-containing 3 (NLRP3) protein, and pro-IL-1β expression was dependent on the generation of reactive oxygen species. This effect was synergistically enhanced by ATP, a known inflammasome activator. These results suggest that S100A8 and S100A9 enhance the inflammatory response by inducing cytokine secretion of PBMCs. PMID:23977231

TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still's Disease and Their Association with Disease Activity and Clinical Manifestations.

PubMed

Kim, Hyoun-Ah; Han, Jae Ho; Kim, Woo-Jung; Noh, Hyun Jin; An, Jeong-Mi; Yim, Hyunee; Jung, Ju-Yang; Kim, You-Sun; Suh, Chang-Hee

2016-08-16

S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still's disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD.

Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus.

PubMed

Lood, Christian; Tydén, Helena; Gullstrand, Birgitta; Jönsen, Andreas; Källberg, Eva; Mörgelin, Matthias; Kahn, Robin; Gunnarsson, Iva; Leanderson, Tomas; Ivars, Fredrik; Svenungsson, Elisabet; Bengtsson, Anders A

2016-08-01

Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins. The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity. We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell-cell communication. S100A8/A9 levels were highly regulated by interferon-α, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5-14.9, P = 0.032 [adjusted for age, sex, and smoking]). Platelets contain S100A8/A9 in membrane-enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target. © 2016, American College of Rheumatology.

S100A8/A9: From basic science to clinical application.

PubMed

Pruenster, Monika; Vogl, Thomas; Roth, Johannes; Sperandio, Markus

2016-11-01

Neutrophils and monocytes belong to the first line of immune defence cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amounts of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca 2+ binding S100 protein family and has recently gained a lot of interest as a critical alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biological function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre-clinical imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small molecule inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biological function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9. Copyright © 2016 Elsevier Inc. All rights reserved.

Vesicular Location and Transport of S100A8 and S100A9 Proteins in Monocytoid Cells

PubMed Central

Chakraborty, Paramita; Bjork, Per; Källberg, Eva; Olsson, Anders; Riva, Matteo; Mörgelin, Matthias; Liberg, David; Ivars, Fredrik; Leanderson, Tomas

2015-01-01

We show here, by using surface biotinylation, followed by Western blotting or surface plasmon resonance analysis, that very low levels of S100A8 and/or S100A9 can be detected on the surface of THP-1 cells or freshly isolated human monocytes. This was supported by immune-electron microscopy where we observed membrane-associated expression of the proteins restricted to small patches. By using confocal microscopy we could determine that S100A8 and S100A9 protein in THP-1 cells or freshly isolated human monocytes was mostly present in vesicular structures. This finding was confirmed using immune-electron microscopy. Subcellular fractionation and confocal microscopy showed that these vesicular structures are mainly early endosomes and endolysosomes. Our subsequent studies showed that accumulation of S100A8 and S100A9 in the endolysosomal compartment is associated with induction of their release from the cells. Furthermore, an inhibitor of lysosomal activity could modulate the release of S100A8 and S100A9 in the extracellular milieu. Our current results suggest that the S100A8 and S100A9 proteins are primarily associated with certain kinds of cytosolic vesicles and may be secreted via an endolysosomal pathway. PMID:26661255

Changes in plasma concentrations of S100A7 and S100A8 in dairy cows during pregnancy.

PubMed

Elgawish, R A; Ogata, Y; Hidaka, T; Nii, T; Yoshimura, Y; Isobe, N

2018-03-31

This study was carried out to examine the changes in plasma concentrations of the Ca-binding antimicrobial proteins S100A7 and S100A8 during pregnancy in dairy cows. Holstein Friesian cows (n = 19) were inseminated with Holstein Friesian semen. Blood was collected at days 30, 60, 90, 120, 150, 180, 210, 240 and 270 after insemination. Plasma was used for measuring the concentrations of S100A7 and S100A8. Both S100A7 and S100A8 concentrations showed similar patterns during gestation; they increased during the midgestation, between days 90 and 180, and then declined before calving. The findings indicated that plasma concentrations of S100A7 and S100A8 did not change significantly during pregnancy in cows. Further studies are required to determine the roles of S100A7 and S100A8 in physiological function during pregnancy in dairy cows. © 2018 Blackwell Verlag GmbH.

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy.

PubMed

Tammaro, Alessandra; Florquin, Sandrine; Brok, Mascha; Claessen, Nike; Butter, Loes M; Teske, Gwendoline J D; de Boer, Onno J; Vogl, Thomas; Leemans, Jaklien C; Dessing, Mark C

2018-05-10

Despite advances in our understanding of the mechanisms underlying progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9, is a damage-associated molecular pattern which can activate TLR4 or RAGE. Activation of these receptors is involved in the progression of renal fibrosis, however the role of S100A8/A9 herein remains unknown. Therefore, we analyzed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild-type and S100A9 KO mice lacking the heterodimer S100A8/A9 to Unilateral Ureteral Obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO-induced renal fibrosis, independently of leukocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO-induced apoptosis and critical epithelial-mesenchymal transition steps. In vitro studies revealed S100A8/A9 as a novel mediator of epithelial cell injury, through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease. This article is protected by copyright. All rights reserved. © 2018 British Society for Immunology.

S100A8 is a Novel Therapeutic Target for Anaplastic Thyroid Carcinoma

PubMed Central

Reeb, Ashley N.; Li, Wen; Sewell, Will; Marlow, Laura A.; Tun, Han W.; Smallridge, Robert C.; Copland, John A.; Spradling, Kyle; Chernock, Rebecca

2015-01-01

Context: Anaplastic thyroid carcinoma (ATC) is one of the most deadly human malignancies. It is 99% lethal, and patients have a median survival of only 6 months after diagnosis. Despite these grim statistics, the mechanism underlying the tumorigenic capability of ATC cells is unclear. Objective: S100A8 and S100A9 proteins have emerged as critical mediators in cancer. The aim was to investigate the expression and function of S100A8 and S100A9 in ATC and the mechanisms involved. Design: We determined the expression of S100A8 and S100A9 in human ATC by gene array analysis and immunohistochemistry. Using RNAi-mediated stable gene knockdown in human ATC cell lines and bioluminescent imaging of orthotopic and lung metastasis mouse models of human ATC, we investigated the effects of S100A8 and S100A9 on tumorigenesis and metastasis. Results: We demonstrated that S100A8 and S100A9 were overexpressed in ATC but not in other types of thyroid carcinomas. In vivo analysis in mice using ATC cells that had S100A8 knocked down revealed reduced tumor growth and lung metastasis, as well as significantly prolonged animal survival. Mechanistic investigations showed that S100A8 promotes ATC cell proliferation through an interaction with RAGE, which activates the p38, ERK1/2 and JNK signaling pathways in the tumor cells. Conclusions: These findings establish a novel role for S100A8 in the promoting and enhancing of ATC progression. They further suggest that the inhibition of S100A8 could represent a relevant therapeutic target, with the potential of enabling a more effective treatment path for this deadly disease. PMID:25423568

S100A8 is a novel therapeutic target for anaplastic thyroid carcinoma.

PubMed

Reeb, Ashley N; Li, Wen; Sewell, Will; Marlow, Laura A; Tun, Han W; Smallridge, Robert C; Copland, John A; Spradling, Kyle; Chernock, Rebecca; Lin, Reigh-Yi

2015-02-01

Anaplastic thyroid carcinoma (ATC) is one of the most deadly human malignancies. It is 99% lethal, and patients have a median survival of only 6 months after diagnosis. Despite these grim statistics, the mechanism underlying the tumorigenic capability of ATC cells is unclear. S100A8 and S100A9 proteins have emerged as critical mediators in cancer. The aim was to investigate the expression and function of S100A8 and S100A9 in ATC and the mechanisms involved. We determined the expression of S100A8 and S100A9 in human ATC by gene array analysis and immunohistochemistry. Using RNAi-mediated stable gene knockdown in human ATC cell lines and bioluminescent imaging of orthotopic and lung metastasis mouse models of human ATC, we investigated the effects of S100A8 and S100A9 on tumorigenesis and metastasis. We demonstrated that S100A8 and S100A9 were overexpressed in ATC but not in other types of thyroid carcinomas. In vivo analysis in mice using ATC cells that had S100A8 knocked down revealed reduced tumor growth and lung metastasis, as well as significantly prolonged animal survival. Mechanistic investigations showed that S100A8 promotes ATC cell proliferation through an interaction with RAGE, which activates the p38, ERK1/2 and JNK signaling pathways in the tumor cells. These findings establish a novel role for S100A8 in the promoting and enhancing of ATC progression. They further suggest that the inhibition of S100A8 could represent a relevant therapeutic target, with the potential of enabling a more effective treatment path for this deadly disease.

Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation.

PubMed

Vogl, Thomas; Stratis, Athanasios; Wixler, Viktor; Völler, Tom; Thurainayagam, Sumita; Jorch, Selina K; Zenker, Stefanie; Dreiling, Alena; Chakraborty, Deblina; Fröhling, Mareike; Paruzel, Peter; Wehmeyer, Corinna; Hermann, Sven; Papantonopoulou, Olympia; Geyer, Christiane; Loser, Karin; Schäfers, Michael; Ludwig, Stephan; Stoll, Monika; Leanderson, Tomas; Schultze, Joachim L; König, Simone; Pap, Thomas; Roth, Johannes

2018-05-01

Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-α-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-α-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects.

In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.

PubMed

Heinemann, Anna S; Pirr, Sabine; Fehlhaber, Beate; Mellinger, Lara; Burgmann, Johanna; Busse, Mandy; Ginzel, Marco; Friesenhagen, Judith; von Köckritz-Blickwede, Maren; Ulas, Thomas; von Kaisenberg, Constantin S; Roth, Johannes; Vogl, Thomas; Viemann, Dorothee

2017-03-01

The high susceptibility of newborn infants to sepsis is ascribed to an immaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid-derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo-MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo-MDSCs have been assigned to CD14 + /human leukocyte antigen (HLA)-DR - /low /CD33 + monocytes in humans and to CD11b + /Gr-1 int /Ly6G - /Ly6C hi cells in mice. We found monocytes with these phenotypes significantly expanded in their respective newborns. Functionally, however, they did not prove immunosuppressive but rather responded inflammatorily to microbial stimulation. Their expansion did not correlate with high S100A8/S100A9 levels in cord blood. Murine studies revealed an excessive expansion of CD11b + /Gr-1 int /Ly6G - /Ly6C hi monocytes in S100A9 -/- neonates compared to wild-type neonates. This strong baseline expansion was associated with hyperinflammatory responses during endotoxemia and fatal septic courses. Treating S100A9 -/- neonates directly after birth with S100A8/S100A9 alarmins prevented excessive expansion of this inflammatory monocyte population and death from septic shock. Our data suggest that a specific population of inflammatory monocytes promotes fatal courses of sepsis in neonates if its expansion is not regulated by S100A8/S100A9 alarmins.-Heinemann, A. S., Pirr, S., Fehlhaber, B., Mellinger, L., Burgmann, J., Busse, M., Ginzel, M., Friesenhagen, J., von Köckritz-Blickwede, M., Ulas, T., von Kaisenberg, C. S., Roth, J., Vogl, T., Viemann, D. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. © FASEB.

S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis.

PubMed

Hibino, Toshihiko; Sakaguchi, Masakiyo; Miyamoto, Shoko; Yamamoto, Mami; Motoyama, Akira; Hosoi, Junichi; Shimokata, Tadashi; Ito, Tomonobu; Tsuboi, Ryoji; Huh, Nam-Ho

2013-01-01

The calcium-binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiologic and pathophysiologic effects of this damage-associated "danger signal" are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN specifically bound to S100A9 but not S100A8. Induction of cytokines and matrix metalloproteases (MMP) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaling used the TNF receptor-associated factor TRAF2 distinct from the known S100-binding signaling pathway mediated by RAGE (AGER). S100A9 strongly promoted migration when EMMPRIN was highly expressed, independent of RAGE, whereas EMMPRIN blockade suppressed migration by S100A9. Immunohistologic analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions and the adjacent epidermis, where S100A9 was also strongly expressed. In epidermal-specific transgenic mice, tail vein-injected melanoma accumulated in skin expressing S100A9 but not S100A8. Together, our results establish EMMPRIN as a receptor for S100A9 and suggest the therapeutic use in targeting S100A9-EMMPRIN interactions.

The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2.

PubMed

Kerkhoff, Claus; Nacken, Wolfgang; Benedyk, Malgorzata; Dagher, Marie Claire; Sopalla, Claudia; Doussiere, Jacques

2005-03-01

The Ca2+- and arachidonic acid-binding S100A8/A9 protein complex was recently identified by in vitro studies as a novel partner of the phagocyte NADPH oxidase. The present study demonstrated its functional relevance by the impaired oxidase activity in neutrophil-like NB4 cells, after specific blockage of S100A9 expression, and bone marrow polymorphonuclear neutrophils from S100A9-/- mice. The impaired oxidase activation could also be mimicked in a cell-free system by pretreatment of neutrophil cytosol with an S100A9-specific antibody. Further analyses gave insights into the molecular mechanisms by which S100A8/A9 promoted NADPH oxidase activation. In vitro analysis of oxidase activation as well as protein-protein interaction studies revealed that S100A8 is the privileged interaction partner for the NADPH oxidase complex since it bound to p67phox and Rac, whereas S100A9 did interact with neither p67phox nor p47phox. Moreover, S100A8/A9 transferred the cofactor arachidonic acid to NADPH oxidase as shown by the impotence of a mutant S100A8/A9 complex unable to bind arachidonic acid to enhance NADPH oxidase activity. It is concluded that S100A8/A9 plays an important role in phagocyte NADPH oxidase activation.

TLR4 and RAGE conversely mediate pro-inflammatory S100A8/9-mediated inhibition of proliferation-linked signaling in myeloproliferative neoplasms.

PubMed

Kovačić, Marijana; Mitrović-Ajtić, Olivera; Beleslin-Čokić, Bojana; Djikić, Dragoslava; Subotički, Tijana; Diklić, Miloš; Leković, Danijela; Gotić, Mirjana; Mossuz, Pascal; Čokić, Vladan P

2018-06-26

Previously, the family of S100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins S100A4, S100A8, S100A9 and S100A12 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. We analyzed the S100A4, S100A8, S100A9 and S100A12 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34 + cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These S100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. From our data we conclude that the S100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that S100A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutation-dependent TLR4 blocking and increased by RAGE inhibition in MPN.

S100A8 and S100A9 Are Induced by Decreased Hydration in the Epidermis and Promote Fibroblast Activation and Fibrosis in the Dermis.

PubMed

Zhong, Aimei; Xu, Wei; Zhao, Jingling; Xie, Ping; Jia, Shengxian; Sun, Jiaming; Galiano, Robert D; Mustoe, Thomas A; Hong, Seok J

2016-01-01

The most critical function of the epidermis is to prevent water loss and maintain skin homeostasis. Disruption of the functional skin barrier causes delayed wound healing, hypertrophic scarring, and many skin diseases. Herein, we show that reduced hydration increases the expression of S100 protein family members, S100A8/S100A9, in stratified keratinocyte culture and human ex vivo skin culture. Immunohistological analyses show that S100A8/A9 are highly expressed in the epidermis of human hypertrophic scar and keloid tissues. Reduced hydration demonstrates activation of fibroblasts in the keratinocyte-fibroblast co-culture. In contrast, knockdown of S100A8 or S100A9 by RNA interference in keratinocytes failed to activate fibroblasts. Pretreatment with pharmacological blockers of S100A8/A9 receptors, Toll-like receptor 4 and receptor for advanced glycation end products, inhibits fibroblast activation induced by recombinant S100A8/A9 proteins. Moreover, we observe that local delivery of S100A8 protein results in a marked increase in hypertrophic scarring in the in vivo rabbit ear scar model. Our results indicate that hydration status promotes fibroblast activation and fibrosis by directly affecting the expression of inflammatory signaling in keratinocytes, thereby strongly suggesting S100A8/A9 to be novel targets in preventing scarring. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells

PubMed Central

Silva, Emmanuel J.; Argyris, Prokopios P.; Zou, Xianqiong; Ross, Karen F.; Herzberg, Mark C.

2014-01-01

Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility. PMID:25236491

Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells

PubMed Central

Ma, Li; Sun, Peng; Zhang, Jian-Cheng; Zhang, Qing; Yao, Shang-Long

2017-01-01

S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial-induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases. PMID:28498464

Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells.

PubMed

Ma, Li; Sun, Peng; Zhang, Jian-Cheng; Zhang, Qing; Yao, Shang-Long

2017-07-01

S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial‑induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines inclu-ding tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases.

S100A8/A9 as a biomarker for synovial inflammation and joint damage in patients with rheumatoid arthritis.

PubMed

Kang, Kwi Young; Woo, Jung-Won; Park, Sung-Hwan

2014-01-01

S100A8 and S100A9 are major leukocyte proteins, known as damage-associated molecular patterns, found at high concentrations in the synovial fluid of patients with rheumatoid arthritis (RA). A heterodimeric complex of S100A8/A9 is secreted by activated leukocytes and binds to Toll-like receptor 4, which mediates downstream signaling and promotes inflammation and autoimmunity. Serum and synovial fluid levels of S100A8/A9 are markedly higher in patients with RA than in patients with osteoarthritis or miscellaneous inflammatory arthritis. Serum levels of S100A8/A9 are significantly correlated with clinical and laboratory markers of inflammation, such as C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and the Disease Activity Score for 28 joints. Significant correlations have also been found between S100A8/A9 and radiographic and clinical assessments of joint damage, such as hand radiographs and the Rheumatoid Arthritis Articular Damage score. In addition, among known inflammatory markers, S100A8/A9 has the strongest correlation with total sum scores of ultrasonography assessment. Furthermore, baseline levels of S100A8/A9 are independently associated with progression of joint destruction in longitudinal studies and are responsive to change during conventional and biologic treatments. These findings suggest S100A8/A9 to be a valuable diagnostic and prognostic biomarker for RA.

Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity.

PubMed

Vogl, Thomas; Eisenblätter, Michel; Völler, Tom; Zenker, Stefanie; Hermann, Sven; van Lent, Peter; Faust, Andreas; Geyer, Christiane; Petersen, Beatrix; Roebrock, Kirsten; Schäfers, Michael; Bremer, Christoph; Roth, Johannes

2014-08-06

Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical molecular imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clinical disease activity in inflammatory and immunological processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in experimental leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive molecular target for novel imaging approaches to monitor clinically relevant inflammatory disorders on a molecular level.

Elucidating the structure and function of S100 proteins in membranes

NASA Astrophysics Data System (ADS)

Valenzuela, Stella M.; Berkahn, Mark; Martin, Donald K.; Huynh, Thuan; Yang, Zheng; Geczy, Carolyn L.

2006-01-01

S100 proteins are important Ca 2+-binding proteins involved in vital cellular functions including the modulation of cell growth, migration and differentiation, regulation of intracellular signal transduction/phosphorylation pathways, energy metabolism, cytoskeletal interactions and modulation of ion channels. Furthermore, they are implicated in oncogenesis and numerous other disease states. Three S100 proteins: S100A8, S100A9 and S100A12 are constitutively expressed in neutrophils and monocytes. At low levels of intracellular Ca 2+, S100A8 and S100A9 are located predominantly in the cytosol but when Ca 2+ concentrations are elevated as a consequence of activation, they translocate to membranes and complex with cytoskeletal components such as vimentin. The functions of S100A8 and S100A9 at the plasma membrane remain unclear. A possible role may be the regulation of ion channel proteins. The current study uses the techniques of Atomic Force Microscopy and production of artificial lipid membranes in the form of liposomes to investigate possible mechanisms for the insertion of these proteins into membranes in order to elucidate their structure and stoichiometry in the transmembrane state. We have successfully imaged the liposomes as a lipid bilayer, the S100A8/A9 protein complex in solution and the S100A8/A9 complex associating with lipid, using tapping-mode atomic force microscopy, in buffer.

The Role of IDO in Muc1 Targeted Immunotherapy

DTIC Science & Technology

2013-06-01

the immune system activation, such as S100A8 , S100A9, Fc receptors, MHC Class II molecules and even arginase were significantly up-regulated...protein analysis of CCN1 revealed that it was not significantly changed between 10 groups (Figure 26A). Also although S100A8 and S100A9 were...highly altered in our RNA microarray data, protein levels of S100A8 and S100A9 were highly variable within our tumors and thus an exact correlation to

S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells.

PubMed

Silva, Emmanuel J; Argyris, Prokopios P; Zou, Xianqiong; Ross, Karen F; Herzberg, Mark C

2014-10-01

Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility. Published by Elsevier Ltd.

Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation.

PubMed

Swindell, William R; Johnston, Andrew; Xing, Xianying; Little, Andrew; Robichaud, Patrick; Voorhees, John J; Fisher, Gary; Gudjonsson, Johann E

2013-01-01

The S100a8 and S100a9 genes encode a pro-inflammatory protein (calgranulin) that has been implicated in multiple diseases. However, involvement of S100a8/a9 in the basic mechanisms of intrinsic aging has not been established. In this study, we show that shifts in the abundance of S100a8 and S100a9 mRNA are a robust feature of aging in mammalian tissues, involving a range of cell types including the central nervous system. To identify transcription factors that control S100a9 expression, we performed a large-scale transcriptome analysis of 62 mouse and human cell types. We identified cell type-specific trends, as well as robust associations linking S100a9 coexpression to elevated frequency of ETS family motifs, and in particular, to motifs recognized by the transcription factor SPI/PU.1. Sparse occurrence of SATB1 motifs was also a strong predictor of S100a9 coexpression. These findings offer support for a novel mechanism by which a SPI1/PU.1-S100a9 axis sustains chronic inflammation during aging.

Recombinant bovine S100A8 and A9 enhance IL-1β secretion of interferon-gamma primed monocytes.

PubMed

Koy, Mirja; Hambruch, Nina; Hussen, Jamal; Pfarrer, Christiane; Seyfert, Hans-Martin; Schuberth, Hans-Joachim

2013-09-15

Calgranulin A (S100A8) and B (S100A9) are found at high levels in inflamed tissue and have been associated with acute and chronic inflammatory disorders. Calgranulins are discussed as damage-associated molecular patterns (DAMPs). To analyze the role of calgranulins for inflammatory responses, bovine S100A8 and S100A9 were cloned, successfully expressed and FPLC-purified. Both molecules did not induce NF-κB activation in boTLR4-transfected HEK293 cells and stimulation of bovine monocytes with both proteins did not result in interleukin 1β (IL-1β) secretion or an upregulated mRNA expression of selected genes (IL1B, TNF, CXCL8, IL10, IL12). However, Interferon γ (IFN-γ) primed bovine monocytes released significantly higher amounts of IL-1β after stimulation with S100A8, S100A9, and co-stimulation with adenosine triphosphate (ATP). In IL-4/IL-13-primed monocytes, the IL-1β release was completely abrogated. The results imply that TLR4/MyD88/NF-κB-independent S100A8/A9-mediated activation of the inflammasome in cattle is favored in a Th1 environment and that S100A8 and S100A9 act as a DAMP in cattle. Copyright © 2013 Elsevier B.V. All rights reserved.

Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels.

PubMed

Schelbergen, R F; van Dalen, S; ter Huurne, M; Roth, J; Vogl, T; Noël, D; Jorgensen, C; van den Berg, W B; van de Loo, F A; Blom, A B; van Lent, P L E M

2014-08-01

Synovitis is evident in a substantial subpopulation of patients with osteoarthritis (OA) and is associated with development of pathophysiology. Recently we have shown that adipose-derived stem cells (ASC) inhibit joint destruction in collagenase-induced experimental OA (CIOA). In the current study we explored the role of synovitis and alarmins S100A8/A9 in the immunomodulatory capacity of ASCs in experimental OA. CIOA, characterized by synovitis, and surgical DMM (destabilization of medial meniscus) OA were treated locally with ASCs. Synovial activation, cartilage damage and osteophyte size were measured on histological sections. Cytokines in synovial washouts and serum were determined using Luminex or enzyme-linked immunosorbent assay (S100A8/A9), mRNA levels with reverse-transcriptase (RT)-qPCR. Local administration of ASCs at various time-points (days 7 or 14) after DMM induction had no effect on OA pathology. At day 7 of CIOA, already 6 h after ASC injection mRNA expression of pro-inflammatory mediators S100A8/A9, interleukin-1beta (IL-1β) and KC was down-regulated in the synovium. IL-1β protein, although low, was down-regulated by ASC-treatment of CIOA. S100A8/A9 protein levels were very high at 6 and 48 h and were decreased by ASC-treatment. The protective action of ASC treatment in CIOA was only found when high synovial inflammation was present at the time of deposition which was reflected by high serum S100A8/A9 levels. Finally, successful treatment resulted in significantly lower levels of serum S100A8/A9. Our study indicates that synovial activation rapidly drives anti-inflammatory and protective effects of intra-articularly deposited ASCs in experimental OA which is reflected by decreased S100A8/A9 levels. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

[The Role of Calcium in the Conformational Changes of the Recombinant S100A8/S100A9].

PubMed

Gheibi, N; Asghari, H; Chegini, K G; Sahmani, M; Moghadasi, M

2016-01-01

Calprotectin is a member of the EF-hand proteins, composed of two subunits, S100A8 (MRP8) and S100A9 (MRP14). These proteins are involved in important processes including cell signaling, regulation of inflammatory responses, cell cycle control, differentiation, regulation of ion channel activity and defense against microbial agents in a calcium dependent manner. In the present study, recombinant S100A8 and S100A9 were expressed in E. coli BL21 and then purified using Ni-NTA affinity chromatography. The structure of the S100A8/A9 complex in the presence and absence of calcium was assessed by circular dichroism and fluorescence spectroscopy. The intrinsic fluorescence emission spectra of the S100A8/A9 complex in the presence of calcium showed a reduction in fluorescence intensity, reflecting conformational changes within the protein with the exposure of aromatic residues to the protein surface. The far ultraviolet-circular dichroism spectra of the complex in the presence of calcium revealed minor changes in the regular secondary structure of the complex. Also, increased thermal stability of the S100A8/A9 complex in the presence of calcium was indicated.

Contributions of the S100A9 C-Terminal Tail to High-Affinity Mn(II) Chelation by the Host-Defense Protein Human Calprotectin

PubMed Central

Brophy, Megan Brunjes; Nakashige, Toshiki G.; Gaillard, Aleth; Nolan, Elizabeth M.

2014-01-01

Human calprotectin (CP) is an antimicrobial protein that coordinates Mn(II) with high affinity in a Ca(II)-dependent manner at an unusual histidine-rich site (site 2) formed at the S100A8/S100A9 dimer interface. We present a 16-member CP mutant family where mutations in the S100A9 C-terminal tail (residues 96–114) are employed to evaluate the contributions of this region, which houses three histidines and four acidic residues, to Mn(II) coordination at site 2. The results from analytical size-exclusion chromatography, Mn(II) competition titrations, and electron paramagnetic resonance spectroscopy establish that the C-terminal tail is essential for high-affinity Mn(II) coordination by native CP in solution. The studies indicate that His103 and His105 (HXH motif) of the tail complete the Mn(II) coordination sphere in solution, affording an unprecedented biological His6 site. These solution studies are in agreement with a Mn(II)-CP crystal structure reported recently (PNAS 2013, 110, 3841). Remarkably high-affinity Mn(II) binding is retained when either H103 or H105 are mutated to Ala, when the HXH motif is shifted from positions 103–105 to 104–106, and when the human tail is substituted by the C-terminal tail of murine S100A9. Nevertheless, antibacterial activity assays employing human CP mutants reveal that the native disposition of His residues is important for conferring growth inhibition against Escherichia coli and Staphylococcus aureus. Within the S100 family, the S100A8/S100A9 heterooligomer is essential for providing high-affinity Mn(II) binding; the S100A7ox, S100A9(C3S), S100A12, and S100B homodimers do not exhibit such Mn(II)-binding capacity. PMID:24245608

S100A8/A9 activate key genes and pathways in colon tumor progression

PubMed Central

Ichikawa, Mie; Williams, Roy; Wang, Ling; Vogl, Thomas; Srikrishna, Geetha

2011-01-01

The tumor microenvironment plays an important role in modulating tumor progression. We earlier showed that S100A8/A9 proteins secreted by myeloid-derived suppressor cells (MDSC) present within tumors and metastatic sites promote an autocrine pathway for accumulation of MDSC. In a mouse model of colitis-associated colon cancer, we also showed that S100A8/A9 positive cells accumulate in all regions of dysplasia and adenoma. Here we present evidence that S100A8/A9 interact with RAGE and carboxylated glycans on colon tumor cells and promote activation of MAPK and NF-κB signaling pathways. Comparison of gene expression profiles of S100A8/A9-activated colon tumor cells versus unactivated cells led us to identify a small cohort of genes upregulated in activated cells, including Cxcl1, Ccl5 and Ccl7, Slc39a10, Lcn2, Zc3h12a, Enpp2 and other genes, whose products promote leukocyte recruitment, angiogenesis, tumor migration, wound healing, and formation of premetastatic niches in distal metastatic organs. Consistent with this observation, in murine colon tumor models we found that chemokines were up-regulated in tumors, and elevated in sera of tumor-bearing wild-type mice. Mice lacking S100A9 showed significantly reduced tumor incidence, growth and metastasis, reduced chemokine levels, and reduced infiltration of CD11b+Gr1+ cells within tumors and premetastatic organs. Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis. PMID:21228116

Establishment of S100A8 Transgenic Rats to Understand Innate Property of S100A8 and Its Immunological Role.

PubMed

Okada, Kohki; Itoh, Hiroshi; Kamikubo, Yasuhiko; Adachi, Souichi; Ikemoto, Masaki

2018-02-01

The innate properties of S100A8 as a regulator in acute inflammation have not yet been elucidated in detail. Our aims are to newly establish S100A8 transgenic rats (Tg-S100A8) and to elucidate the immunological functions of S100A8. Following the treatment with 5% dextran sulfate sodium for 1 week, the body weight in Tg-S100A8 weakly decreased after the start; however, that in Japanese Wistar rats (WT) significantly decreased in the end. The serum level of CRP in Tg-S100A8 was significantly lower than that in WT, although the concentration of CRP apparently increased in both Tg-S100A8 and WT. The dynamic mobility of S100A8 and S100A9 in macrophages was microscopically observed using fluorescent immunological staining, in which the S100A9 was dominantly expressed in many macrophages in the rectal tissue of WT. As determined by PCR and real-time PCR, the levels of S100A8 messenger RNA (mRNA) in several organ tissues of the Tg-S100A8, such as heart and small intestine, were apparently higher than those of WT, respectively. The expression of IL-6 and TNF-α mRNAs was negatively regulated in main organ tissues of the large colon of Tg-S100A8 followed by down-regulation of IL-6 protein. An important result was that the expression of S100A8 mRNA was strongly induced in many macrophages of Tg-S100A8, whereas that of some inflammatory cytokine mRNAs described above were significantly reduced. Tg-S100A8 has potential as a useful experimental model rat not only for investigating the innate properties of S100A8 as a regulator, but also for clarifying its functional role in immune cells from a myeloid origin, particularly macrophages.

Chronic Inflammatory Microenvironment in Epidermodysplasia Verruciformis Skin Lesions: Role of the Synergism Between HPV8 E2 and C/EBPβ to Induce Pro-Inflammatory S100A8/A9 Proteins.

PubMed

Podgórska, Marta; Ołdak, Monika; Marthaler, Anna; Fingerle, Alina; Walch-Rückheim, Barbara; Lohse, Stefan; Müller, Cornelia S L; Vogt, Thomas; Ustav, Mart; Wnorowski, Artur; Malejczyk, Magdalena; Majewski, Sławomir; Smola, Sigrun

2018-01-01

Persistent genus β-HPV (human papillomavirus) infection is a major co-factor for non-melanoma skin cancer in patients suffering from the inherited skin disease epidermodysplasia verruciformis (EV). Malignant EV lesions are particularly associated with HPV type 5 or 8. There is clinical and molecular evidence that HPV8 actively suppresses epithelial immunosurveillance by interfering with the recruitment of Langerhans cells, which may favor viral persistence. Mechanisms how persistent HPV8 infection promotes the carcinogenic process are, however, less well understood. In various tumor types chronic inflammation has a central role in tumor progression. The calprotectin complex consisting of S100A8 and S100A9 proteins has recently been identified as key driver of chronic and tumor promoting inflammation in skin carcinogenesis. It induces chemotaxis of neutrophil granulocytes and modulates inflammatory as well as immune responses. In this study, we demonstrate that skin lesions of EV-patients are massively infiltrated by inflammatory cells, including CD15 + granulocytes. At the same time we observed a very strong expression of S100A8 and S100A9 proteins in lesional keratinocytes, which was mostly confined to the suprabasal layers of the epidermis. Both proteins were hardly detected in non-lesional skin. Further experiments revealed that the HPV8 oncoproteins E6 and E7 were not involved in S100A8/A9 up-regulation. They rather suppressed differentiation-induced S100A8/A9 expression. In contrast, the viral transcription factor E2 strongly enhanced PMA-mediated S100A8/A9 up-regulation in primary human keratinocytes. Similarly, a tremendous up-regulation of both S100 proteins was observed, when minute amounts of the PMA-inducible CCAAT/enhancer binding protein β (C/EBPβ), which is expressed at low levels in the suprabasal layers of the epidermis, were co-expressed together with HPV8 E2. This confirmed our previous observation that C/EBPβ interacts and functionally synergizes with the HPV8 E2 protein in differentiation-dependent gene expression. Potent synergistic up-regulation of S100A8/A9 was seen at transcriptional and protein levels. S100A8/A9 containing supernatants from keratinocytes co-expressing HPV8 E2 and C/EBPβ significantly induced chemotaxis of granulocytes in migration assays supporting the relevance of our finding. In conclusion, our data suggest that the HPV8 E2 protein actively contributes to the recruitment of myeloid cells into EV skin lesions, which may support chronic inflammation and progression to skin cancer.

Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes

PubMed Central

Vogl, Thomas; Gharibyan, Anna L.; Morozova-Roche, Ludmilla A.

2012-01-01

S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation. PMID:22489132

Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis.

PubMed

Zhang, Xuemei; Ai, Feiyan; Li, Xiayu; She, Xiaoling; Li, Nan; Tang, Anliu; Qin, Zailong; Ye, Qiurong; Tian, Li; Li, Guiyuan; Shen, Shourong; Ma, Jian

2015-12-15

The aberrant expression of S100A8 and S100A9 is linked to nonresolving inflammation and ultimately to carcinogenesis, whereas the underlying mechanism that allows inflammation to progress to specific cancer types remains unknown. Here, we report that S100A8 was induced by inflammation and then promoted colorectal tumorigenesis downstream by activating Id3 (inhibitor of differentiation 3). Using gene expression profiling and immunohistochemistry, we found that both S100A8 and S100A9 were upregulated in the chemically-induced colitis-associated cancer mouse model and in human colorectal cancer specimens. Furthermore, we showed that S100A8 and S100A9 acted as chemoattractant proteins by recruiting macrophages, promoting the proliferation and invasion of colon cancer cell, as well as spurring the cycle that culminates in the acceleration of cancer metastasis in a nude mouse model. S100A8 regulated colon cancer cell cycle and proliferation by inducing Id3 expression while inhibiting p21. Id3 expression was regulated by Smad5, which was directly phosphorylated by Akt1. Our study revealed a novel mechanism in which inflammation-induced S100A8 promoted colorectal tumorigenesis by acting upstream to activate the Akt1-Smad5-Id3 axis. © 2015 UICC.

Stress-induced release of the S100A8/A9 alarmin is elevated in coronary artery disease patients with impaired cortisol response.

PubMed

Jonasson, L; Grauen Larsen, H; Lundberg, A K; Gullstrand, B; Bengtsson, A A; Schiopu, A

2017-12-13

Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secretion in two different cohorts subjected to a psychological stress test. In the first cohort of 60 CAD patients, psychological stress induced a rapid increase of circulating S100A8/A9. This rapid S100A8/A9 response strongly correlated with elevated evening saliva cortisol levels, suggesting an association with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. In the second cohort of 27 CAD patients and 28 controls, elevated S100A8/A9 levels were still detectable 24 h after stress in 40% of patients and 36% of controls, with a tendency for higher levels in patients. The sustained S100A8/A9 response was associated with a poor rapid cortisol release after stress in patients, but not in the control group. Our findings reveal for the first time that acute psychological stress induces elevated levels of S100A8/A9. We also provide hypothesis-generating evidence that dysregulated cortisol secretion in CAD patients might be associated with an exaggerated pro-inflammatory S100A8/A9 response.

Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner.

PubMed

Chakraborty, Deblina; Zenker, Stefanie; Rossaint, Jan; Hölscher, Anna; Pohlen, Michele; Zarbock, Alexander; Roth, Johannes; Vogl, Thomas

2017-01-01

Alveolar epithelial cells (AECs) are an essential part of the respiratory barrier in lungs for gas exchange and protection against pathogens. Damage to AECs occurs during lung injury and PAMPs/DAMPs have been shown to activate AECs. However, their interplay as well as the mechanism of AECs' activation especially by the alarmin S100A8/A9 is unknown. Thus, our aim was to study the mechanism of activation of AECs (type I and type II) by S100A8 and/or lipopolysaccharide (LPS) and to understand the role of endogenous S100A8/A9 in neutrophil recruitment in the lung. For our studies, we modified a previous protocol for isolation and culturing of murine AECs. Next, we stimulated the cells with S100A8 and/or LPS and analyzed cytokine/chemokine release. We also analyzed the contribution of the known S100-receptors TLR4 and RAGE in AEC activation. In a murine model of lung injury, we investigated the role of S100A8/A9 in neutrophil recruitment to lungs. S100A8 activates type I and type II cells in a dose- and time-dependent manner which could be quantified by the release of IL-6, KC, and MCP-1. We here clearly demonstrate that AEC s are activated by S100A8 via a TLR4-dependent pathway. Surprisingly, RAGE, albeit mainly expressed in lung tissue, plays no role. Additionally, we show that S100A8/A9 is an essential factor for neutrophil recruitment to lungs. We, therefore, conclude that S100A8 promotes acute lung injury via Toll-like receptor 4-dependent activation of AECs.

Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner

PubMed Central

Chakraborty, Deblina; Zenker, Stefanie; Rossaint, Jan; Hölscher, Anna; Pohlen, Michele; Zarbock, Alexander; Roth, Johannes; Vogl, Thomas

2017-01-01

Alveolar epithelial cells (AECs) are an essential part of the respiratory barrier in lungs for gas exchange and protection against pathogens. Damage to AECs occurs during lung injury and PAMPs/DAMPs have been shown to activate AECs. However, their interplay as well as the mechanism of AECs’ activation especially by the alarmin S100A8/A9 is unknown. Thus, our aim was to study the mechanism of activation of AECs (type I and type II) by S100A8 and/or lipopolysaccharide (LPS) and to understand the role of endogenous S100A8/A9 in neutrophil recruitment in the lung. For our studies, we modified a previous protocol for isolation and culturing of murine AECs. Next, we stimulated the cells with S100A8 and/or LPS and analyzed cytokine/chemokine release. We also analyzed the contribution of the known S100-receptors TLR4 and RAGE in AEC activation. In a murine model of lung injury, we investigated the role of S100A8/A9 in neutrophil recruitment to lungs. S100A8 activates type I and type II cells in a dose- and time-dependent manner which could be quantified by the release of IL-6, KC, and MCP-1. We here clearly demonstrate that AEC s are activated by S100A8 via a TLR4-dependent pathway. Surprisingly, RAGE, albeit mainly expressed in lung tissue, plays no role. Additionally, we show that S100A8/A9 is an essential factor for neutrophil recruitment to lungs. We, therefore, conclude that S100A8 promotes acute lung injury via Toll-like receptor 4-dependent activation of AECs. PMID:29180999

S100A8/A9 (Calprotectin) Negatively Regulates G2/M Cell Cycle Progression and Growth of Squamous Cell Carcinoma

PubMed Central

Khammanivong, Ali; Wang, Chengxing; Sorenson, Brent S.; Ross, Karen F.; Herzberg, Mark C.

2013-01-01

Malignant transformation results in abnormal cell cycle regulation and uncontrolled growth in head and neck squamous cell carcinoma (HNSCC) and other cancers. S100A8/A9 (calprotectin) is a calcium-binding heterodimeric protein complex implicated in cell cycle regulation, but the specific mechanism and role in cell cycle control and carcinoma growth are not well understood. In HNSCC, S100A8/A9 is downregulated at both mRNA and protein levels. We now report that downregulation of S100A8/A9 correlates strongly with a loss of cell cycle control and increased growth of carcinoma cells. To show its role in carcinogenesis in an in vitro model, S100A8/A9 was stably expressed in an S100A8/A9-negative human carcinoma cell line (KB cells, HeLa-like). S100A8/A9 expression increases PP2A phosphatase activity and p-Chk1 (Ser345) phosphorylation, which appears to signal inhibitory phosphorylation of mitotic p-Cdc25C (Ser216) and p-Cdc2 (Thr14/Tyr15) to inactivate the G2/M Cdc2/cyclin B1 complex. Cyclin B1 expression then downregulates and the cell cycle arrests at the G2/M checkpoint, reducing cell division. As expected, S100A8/A9-expressing cells show both decreased anchorage-dependent and -independent growth and mitotic progression. Using shRNA, silencing of S100A8/A9 expression in the TR146 human HNSCC cell line increases growth and survival and reduces Cdc2 inhibitory phosphorylation at Thr14/Tyr15. The level of S100A8/A9 endogenous expression correlates strongly with the reduced p-Cdc2 (Thr14/Tyr14) level in HNSCC cell lines, SCC-58, OSCC-3 and UMSCC-17B. S100A8/A9-mediated control of the G2/M cell cycle checkpoint is, therefore, a likely suppressive mechanism in human squamous cell carcinomas and may suggest new therapeutic approaches. PMID:23874958

Inhibition of Expression of the S100A8 Gene Encoding the S100 Calcium-Binding Protein A8 Promotes Apoptosis by Suppressing the Phosphorylation of Protein Kinase B (Akt) in Endometrial Carcinoma and HEC-1A Cells.

PubMed

Liu, Chang; Xing, Guangyang; Wu, Cailiang; Zhu, Jun; Wei, Min; Liu, Dajiang; Ge, Yan; Chen, Yao; Lei, Ting; Yang, Yongxiu

2018-03-29

BACKGROUND The aim of this study was to investigate the expression and silencing of the S100A8 gene, which encodes the S100 calcium-binding protein A8 (S100A8), and apoptosis and phosphorylation of protein kinase B (Akt) in tissue samples of endometrial carcinoma and HEC-1A endometrial adenocarcinoma cells in vitro. MATERIAL AND METHODS Immunohistochemistry (IHC) was used to detect expression of the S100A8 protein in 74 tissue samples of endometrial cancer and 22 normal endometrial tissue samples. A stable S100A8 gene knockdown cell line was constructed using lentiviral packing short hairpin RNA (shRNA) transfected into HEC-1A cells. S100A8 mRNA and S100A8 protein levels were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. The effects of expression of the S100A8 gene by endometrial cancer cells was investigated by the MTT assay, cell cycle and apoptotic assays, qRT-PCR, and Western blotting. RESULTS IHC showed high levels of expression of S100A8 protein in endometrial carcinoma tissues, and HEC-1A adenocarcinoma cells (in G1 and G2). Increased expression of S100A8 protein was found endometrial cancer tissues compared with normal endometrial tissues (79.7% vs. 4.5%). S100A8 gene knockdown reduced cell proliferation in the HEC-1A cells compared with control cells, induced cell apoptosis, inhibited the phosphorylation of protein kinase B (Akt), and induced the expression of pro-apoptotic genes, including the cytochrome C gene, CYCS, BAD, BAX, FOXO1, FOXO3, CASP9, and CASP3. CONCLUSIONS In endometrial carcinoma cells, down-regulation of the S100A8 gene induced cell apoptosis via inhibition of the phosphorylated or active form of protein kinase B (Akt).

Inhibition of Expression of the S100A8 Gene Encoding the S100 Calcium-Binding Protein A8 Promotes Apoptosis by Suppressing the Phosphorylation of Protein Kinase B (Akt) in Endometrial Carcinoma and HEC-1A Cells

PubMed Central

Liu, Chang; Xing, Guangyang; Wu, Cailiang; Zhu, Jun; Wei, Min; Liu, Dajiang; Ge, Yan; Chen, Yao; Lei, Ting

2018-01-01

Background The aim of this study was to investigate the expression and silencing of the S100A8 gene, which encodes the S100 calcium-binding protein A8 (S100A8), and apoptosis and phosphorylation of protein kinase B (Akt) in tissue samples of endometrial carcinoma and HEC-1A endometrial adenocarcinoma cells in vitro. Material/Methods Immunohistochemistry (IHC) was used to detect expression of the S100A8 protein in 74 tissue samples of endometrial cancer and 22 normal endometrial tissue samples. A stable S100A8 gene knockdown cell line was constructed using lentiviral packing short hairpin RNA (shRNA) transfected into HEC-1A cells. S100A8 mRNA and S100A8 protein levels were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. The effects of expression of the S100A8 gene by endometrial cancer cells was investigated by the MTT assay, cell cycle and apoptotic assays, qRT-PCR, and Western blotting. Results IHC showed high levels of expression of S100A8 protein in endometrial carcinoma tissues, and HEC-1A adenocarcinoma cells (in G1 and G2). Increased expression of S100A8 protein was found endometrial cancer tissues compared with normal endometrial tissues (79.7% vs. 4.5%). S100A8 gene knockdown reduced cell proliferation in the HEC-1A cells compared with control cells, induced cell apoptosis, inhibited the phosphorylation of protein kinase B (Akt), and induced the expression of pro-apoptotic genes, including the cytochrome C gene, CYCS, BAD, BAX, FOXO1, FOXO3, CASP9, and CASP3. Conclusions In endometrial carcinoma cells, down-regulation of the S100A8 gene induced cell apoptosis via inhibition of the phosphorylated or active form of protein kinase B (Akt). PMID:29595187

S100A8/A9 Stimulates Keratinocyte Proliferation in the Development of Squamous Cell Carcinoma of the Skin via the Receptor for Advanced Glycation-End Products

PubMed Central

Iotzova-Weiss, Guergana; Dziunycz, Piotr J.; Freiberger, Sandra N.; Läuchli, Severin; Hafner, Jürg; Vogl, Thomas; French, Lars E.; Hofbauer, Günther F. L.

2015-01-01

Squamous cell carcinoma (SCC) is the most common neoplasm in organ transplant recipients (OTR) on long-term immunosuppression and occurs 60- to 100-fold more frequently than in the general population. Here, we present the receptor for advanced glycation end products (RAGE) and S100A8/A9 as important factors driving normal and tumor keratinocyte proliferation. RAGE and S100A8/A9 were transcriptionally upregulated in SCC compared to normal epidermis, as well as in OTR compared to immunocompetent patients (IC) with SCC. The proliferation of normal and SCC keratinocytes was induced by exposure to exogenous S100A8/A9 which in turn was abolished by blocking of RAGE. The migratory activities of normal and SCC keratinocytes were also increased upon exposure to S100A8/A9. We demonstrated that exogenous S100A8/A9 induces phosphorylation of p38 and SAPK/JNK followed by activation of ERK1/2. We hypothesize that RAGE and S100A8/A9 contribute to the development of human SCC by modulating keratinocyte growth and migration. These processes do not seem to be impaired by profound drug-mediated immunosuppression in OTR. PMID:25811984

The S100A8/A9 protein as a partner for the cytosolic factors of NADPH oxidase activation in neutrophils.

PubMed

Doussiere, Jacques; Bouzidi, Farid; Vignais, Pierre V

2002-07-01

In a previous study, the S100A8/A9 protein, a Ca2+- and arachidonic acid-binding protein, abundant in neutrophil cytosol, was found to potentiate the activation of the redox component of the O2- generating oxidase in neutrophils, namely the membrane-bound flavocytochrome b, by the cytosolic phox proteins p67phox, p47phox and Rac (Doussière J., Bouzidi F. and Vignais P.V. (2001) Biochem. Biophys. Res. Commun.285, 1317-1320). This led us to check by immunoprecipitation and protein fractionation whether the cytosolic phox proteins could bind to S100A8/A9. Following incubation of a cytosolic extract from nonactivated bovine neutrophil with protein A-Sepharose bound to anti-p67phox antibodies, the recovered immunoprecipitate contained the S100 protein, p47phox and p67phox. Cytosolic protein fractionation comprised two successive chromatographic steps on hydroxyapatite and DEAE cellulose, followed by isoelectric focusing. The S100A8/A9 heterodimeric protein comigrated with the cytosolic phox proteins, and more particularly with p67phox and Rac2, whereas the isolated S100A8 protein displayed a tendancy to bind to p47phox. Using a semirecombinant cell-free system of oxidase activation consisting of recombinant p67phox, p47phox and Rac2, neutrophil membranes and arachidonic acid, we found that the S100A8/A9-dependent increase in the elicited oxidase activity corresponded to an increase in the turnover of the membrane-bound flavocytochrome b, but not to a change of affinity for NADPH or O2. In the absence of S100A8/A9, oxidase activation departed from michaelian kinetics above a critical threshold concentration of cytosolic phox proteins. Addition of S100A8/A9 to the cell-free system rendered the kinetics fully michaelian. The propensity of S100A8/A9 to bind the cytosolic phox proteins, and the effects of S100A8/A9 on the kinetics of oxidase activation, suggest that S100A8/A9 might be a scaffold protein for the cytosolic phox proteins or might help to deliver arachidonic acid to the oxidase, thus favoring the productive interaction of the cytosolic phox proteins with the membrane-bound flavocytochrome b.

S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-κB pathways

PubMed Central

Kang, Jin Hyun; Hwang, Sae Mi; Chung, Il Yup

2015-01-01

Airway mucus hyperproduction is a common feature of chronic airway diseases such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis, which are closely associated with neutrophilic airway inflammation. S100A8, S100A9 and S100A12 are highly abundant proteins released by neutrophils and have been identified as important biomarkers in many inflammatory diseases. Herein, we report a new role for S100A8, S100A9 and S100A12 for producing MUC5AC, a major mucin protein in the respiratory tract. All three S100 proteins induced MUC5AC mRNA and the protein in normal human bronchial epithelial cells as well as NCI-H292 lung carcinoma cells in a dose-dependent manner. A Toll-like receptor 4 (TLR4) inhibitor almost completely abolished MUC5AC expression by all three S100 proteins, while neutralization of the receptor for advanced glycation end-products (RAGE) inhibited only S100A12-mediated production of MUC5AC. The S100 protein-mediated production of MUC5AC was inhibited by the pharmacological agents that block prominent signalling molecules for MUC5AC expression, such as mitogen-activated protein kinases, nuclear factor-κB (NF-κB) and epidermal growth factor receptor. S100A8, S100A9 and S100A12 equally elicited both phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-κB/degradation of cytosolic IκB with similar kinetics through TLR4. In contrast, S100A12 preferentially activated the ERK pathway rather than the NF-κB pathway through RAGE. Collectively, these data reveal the capacity of these three S100 proteins to induce MUC5AC production in airway epithelial cells, suggesting that they all serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction. PMID:24975020

Identification of an S100A8 Receptor Neuroplastin-β and its Heterodimer Formation with EMMPRIN.

PubMed

Sakaguchi, Masakiyo; Yamamoto, Mami; Miyai, Masashi; Maeda, Tatsuo; Hiruma, Junichiro; Murata, Hitoshi; Kinoshita, Rie; Winarsa Ruma, I Made; Putranto, Endy Widya; Inoue, Yusuke; Morizane, Shin; Huh, Nam-Ho; Tsuboi, Ryoji; Hibino, Toshihiko

2016-11-01

We previously reported a positive feedback loop between S100A8/A9 and proinflammatory cytokines mediated by extracellular matrix metalloproteinase inducer, an S100A9 receptor. Here, we identify neuroplastin-β as an unreported S100A8 receptor. Neuroplastin-β and extracellular matrix metalloproteinase inducer form homodimers and a heterodimer, and they are co-localized on the surface of cultured normal human keratinocytes. Knockdown of both receptors suppressed cell proliferation and proinflammatory cytokine induction. Upon stimulation with S100A8, neuroplastin-β recruited GRB2 and activated extracellular signal-regulated kinase, resulting in keratinocyte proliferation. Keratinocyte proliferation in response to inflammatory stimuli was accelerated in involucrin promoter-driven S100A8 transgenic mice. Further, S100A8 and S100A9 were strongly up-regulated and co-localized in lesional skin of atopic dermatitis patients. Our results indicate that neuroplastin-β and extracellular matrix metalloproteinase inducer form a functional heterodimeric receptor for S100A8/A9 heterodimer, followed by recruitment of specific adaptor molecules GRB2 and TRAF2, and this signaling pathway is involved in activation of both keratinocyte proliferation and skin inflammation in atopic skin. Suppression of this pathway might have potential for treatment of skin diseases associated with chronic inflammation such as atopic dermatitis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Low Concentration of S100A8/9 Promotes Angiogenesis-Related Activity of Vascular Endothelial Cells: Bridges among Inflammation, Angiogenesis, and Tumorigenesis?

PubMed Central

Li, Changyou; Li, Siyuan; Jia, Changkai; Yang, Lingling; Song, Zicheng; Wang, Yiqiang

2012-01-01

Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC) line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation. In the low concentration range up to 10 μg/mL, either each alone or in combination, S100A8 and S100A9 proteins promoted proliferation of HUVEC cells in a dose-dependent manner. The presence of both proteins in culture showed additive effects over each single protein. Both proteins enhanced HUVEC cells to migrate across the transwell membrane and to form tube-like structures on the Matrigel surface. When mixed in Matrigel and injected subcutaneously in Balb/c mice, both proteins increased vessel development in the gel plugs. Microarray assay of HUVEC cells treated with 10 μg/mL S100A8 revealed that ribosome pathway, pathogenic Escherichia coli infection pathway, apoptosis, and stress response genes were modulated by S100A8 treatment. We propose that S100A8 and S100A9 proteins from either infiltrating inflammatory cells or tumor cells play an important role in the interplay among inflammation, angiogenesis, and tumorigenesis. PMID:22685372

S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis.

PubMed

Denstaedt, Scott J; Spencer-Segal, Joanna L; Newstead, Michael W; Laborc, Klaudia; Zhao, Anne P; Hjelmaas, Alexander; Zeng, Xianying; Akil, Huda; Standiford, Theodore J; Singer, Benjamin H

2018-05-01

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors. Copyright © 2018 by The American Association of Immunologists, Inc.

Phagocyte-specific S100 proteins in the local response to the Echinococcus granulosus larva.

PubMed

Basika, Tatiana; Muñoz, Natalia; Casaravilla, Cecilia; Irigoín, Florencia; Batthyány, Carlos; Bonilla, Mariana; Salinas, Gustavo; Pacheco, José Pedro; Roth, Johaness; Durán, Rosario; Díaz, Alvaro

2012-02-01

Infection by larval Echinococcus granulosus is usually characterized by tight inflammatory control. However, various degrees of chronic granulomatous inflammation are also observed, reaching a high point in infection of cattle by the most prevalent parasite strain worldwide, which is not well adapted to this host species. In this context, epithelioid and multinucleated giant macrophages surround the parasite, and the secreted products of these cells often associate with the larval wall. The phagocyte-specific S100 proteins, S100A8, S100A9 and S100A12, are important non-conventionally secreted amplifiers of inflammatory responses. We have analysed by proteomics and immunohistochemistry the presence of these proteins at the E. granulosus larva-host interface. We found that, in the context of inflammatory control as observed in human infections, the S100 proteins are not abundant, but S100A9 and S100A8 can be expressed by eosinophils distal to the parasite. In the granulomatous inflammation context as observed in cattle infections, we found that S100A12 is one of the most abundant host-derived, parasite-associated proteins, while S100A9 and S100A8 are not present at similarly high levels. As expected, S100A12 derives mostly from the epithelioid and multinucleated giant cells. S100A12, as well as cathepsin K and matrix metalloproteinase-9, also expressed by E. granulosus-elicited epithelioid cells, are connected to the Th17 arm of immunity, which may therefore be involved in this granulomatous response.

TLR9 Ligands Induce S100A8 in Macrophages via a STAT3-Dependent Pathway which Requires IL-10 and PGE2

PubMed Central

Hsu, Kenneth; Chung, Yuen Ming; Endoh, Yasumi; Geczy, Carolyn L.

2014-01-01

S100A8 and S100A9 are highly-expressed calcium-binding proteins in neutrophils and monocytes, and in subsets of macrophages in inflammatory lesions. Unmethylated CpG motifs found in bacterial and viral DNA are potent activators of innate immunity via Toll-like receptor 9 (TLR9). S100A8, but not S100A9, mRNA and protein was directly induced by CpG-DNA in murine and human macrophages. Induction in murine macrophages peaked at 16 h. CpG-DNA-induced S100A8 required de novo protein synthesis; IL-10 and Prostaglandin E2 (PGE2) synergistically enhanced expression and promoted earlier gene induction. Inhibitors of endogenous IL-10, PGE2, and the E prostanoid (EP) 4 receptor strongly suppressed S100A8 expression, particularly when combined. Thus, S100A8 induction by E. coli DNA required both IL-10 and PGE2/EP4 signaling. The MAPKs, PI3K and JAK pathways were essential, whereas ERK1/2 appeared to play a direct role. S100A8 induction by CpG-DNA was controlled at the transcriptional level. The promoter region responsible for activation, either directly, or indirectly via IL-10 and PGE2, was located within a −178 to −34-bp region and required STAT3 binding. Because of the robust links connecting IL-10 and PGE2 with an anti-inflammatory macrophage phenotype, the induction profile of S100A8 strongly indicates a role for this protein in resolution of inflammation. PMID:25098409

TLR9 ligands induce S100A8 in macrophages via a STAT3-dependent pathway which requires IL-10 and PGE2.

PubMed

Hsu, Kenneth; Chung, Yuen Ming; Endoh, Yasumi; Geczy, Carolyn L

2014-01-01

S100A8 and S100A9 are highly-expressed calcium-binding proteins in neutrophils and monocytes, and in subsets of macrophages in inflammatory lesions. Unmethylated CpG motifs found in bacterial and viral DNA are potent activators of innate immunity via Toll-like receptor 9 (TLR9). S100A8, but not S100A9, mRNA and protein was directly induced by CpG-DNA in murine and human macrophages. Induction in murine macrophages peaked at 16 h. CpG-DNA-induced S100A8 required de novo protein synthesis; IL-10 and Prostaglandin E2 (PGE2) synergistically enhanced expression and promoted earlier gene induction. Inhibitors of endogenous IL-10, PGE2, and the E prostanoid (EP) 4 receptor strongly suppressed S100A8 expression, particularly when combined. Thus, S100A8 induction by E. coli DNA required both IL-10 and PGE2/EP4 signaling. The MAPKs, PI3K and JAK pathways were essential, whereas ERK1/2 appeared to play a direct role. S100A8 induction by CpG-DNA was controlled at the transcriptional level. The promoter region responsible for activation, either directly, or indirectly via IL-10 and PGE2, was located within a -178 to -34-bp region and required STAT3 binding. Because of the robust links connecting IL-10 and PGE2 with an anti-inflammatory macrophage phenotype, the induction profile of S100A8 strongly indicates a role for this protein in resolution of inflammation.

S100-alarmins: potential therapeutic targets for arthritis.

PubMed

Austermann, Judith; Zenker, Stefanie; Roth, Johannes

2017-07-01

In arthritis, inflammatory processes are triggered by numerous factors that are released from joint tissues, promoting joint destruction and pathological progression. During inflammation, a novel family of pro-inflammatory molecules called alarmins is released, amplifying inflammation and joint damage. Areas covered: With regard to the role of the alarmins S100A8 and S100A9 in the pathogenesis of arthritis, recent advances and the future prospects in terms of therapeutic implications are considered. Expert opinion: There is still an urgent need for novel treatment strategies addressing the local mechanisms of joint inflammation and tissue destruction, offering promising therapeutic alternatives. S100A8 and S100A9, which are the most up-regulated alarmins during arthritis, are endogenous triggers of inflammation, defining these proteins as promising targets for local suppression of arthritis. In murine models, the blockade of S100A8/S100A9 ameliorates inflammatory processes, including arthritis, and there are several lines of evidence that S100-alarmins may already be targeted in therapeutic approaches in man.

The Calcium-binding Proteins S100A8 and S100A9 Initiate the Early Inflammatory Program in Injured Peripheral Nerves*

PubMed Central

Chernov, Andrei V.; Dolkas, Jennifer; Hoang, Khang; Angert, Mila; Srikrishna, Geetha; Vogl, Thomas; Baranovskaya, Svetlana; Strongin, Alex Y.; Shubayev, Veronica I.

2015-01-01

To shed light on the early immune response processes in severed peripheral nerves, we performed genome-wide transcriptional profiling and bioinformatics analyses of the proximal (P, regenerating) and distal (D, degenerating) nerve stumps on day 1 in the sciatic nerve axotomy model in rats. Multiple cell death-related pathways were activated in the degenerating D stump, whereas activation of the cytoskeletal motility and gluconeogenesis/glycolysis pathways was most prominent in the P stump of the axotomized nerve. Our bioinformatics analyses also identified the specific immunomodulatory genes of the chemokine, IL, TNF, MHC, immunoglobulin-binding Fc receptor, calcium-binding S100, matrix metalloproteinase, tissue inhibitor of metalloproteinase, and ion channel families affected in both the P and D segments. S100a8 and S100a9 were the top up-regulated genes in both the P and D segments. Stimulation of cultured Schwann cells using the purified S100A8/A9 heterodimer recapitulated activation of the myeloid cell and phagocyte chemotactic genes and pathways, which we initially observed in injured nerves. S100A8/A9 heterodimer injection into the intact nerve stimulated macrophage infiltration. We conclude that, following peripheral nerve injury, an immediate acute immune response occurs both distal and proximal to the lesion site and that the rapid transcriptional activation of the S100a8 and S100a9 genes results in S100A8/A9 hetero- and homodimers, which stimulate the release of chemokines and cytokines by activated Schwann cells and generate the initial chemotactic gradient that guides the transmigration of hematogenous immune cells into the injured nerve. PMID:25792748

Chronic liver inflammation and hepatocellular carcinogenesis are independent of S100A9.

PubMed

De Ponti, Aurora; Wiechert, Lars; Stojanovic, Ana; Longerich, Thomas; Marhenke, Silke; Hogg, Nancy; Vogel, Arndt; Cerwenka, Adelheid; Schirmacher, Peter; Hess, Jochen; Angel, Peter

2015-05-15

The S100A8/A9 heterodimer (calprotectin) acts as a danger signal when secreted into the extracellular space during inflammation and tissue damage. It promotes proinflammatory responses and drives tumor development in different models of inflammation-driven carcinogenesis. S100A8/A9 is strongly expressed in several human tumors, including hepatocellular carcinoma (HCC). Apart from this evidence, the role of calprotectin in hepatocyte transformation and tumor microenvironment is still unknown. The aim of this study was to define the function of S100A8/A9 in inflammation-driven HCC. Mice lacking S100a9 were crossed with the Mdr2(-/-) model, a prototype of inflammation-induced HCC formation. S100a9(-/-) Mdr2(-/-) (dKO) mice displayed no significant differences in tumor incidence or multiplicity compared to Mdr2(-/-) animals. Chronic liver inflammation, fibrosis and oval cell activation were not affected upon S100a9 deletion. Our data demonstrate that, although highly upregulated, calprotectin is dispensable in the onset and development of HCC, and in the maintenance of liver inflammation. © 2014 UICC.

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8/S100A9

PubMed Central

Schneider, Rebekka K.; Schenone, Monica; Ferreira, Monica Ventura; Kramann, Rafael; Joyce, Cailin E.; Hartigan, Christina; Beier, Fabian; Brümmendorf, Tim H.; Gehrming, Ulrich; Platzbecker, Uwe; Büsche, Guntram; Knüchel, Ruth; Chen, Michelle C.; Waters, Christopher S.; Chen, Edwin; Chu, Lisa P.; Novina, Carl D.; Lindsley, R. Coleman; Carr, Steven A.; Ebert, Benjamin L.

2016-01-01

Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100a8/S100a9 proteins in purified erythroblasts. S100a8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100a8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS. PMID:26878232

Immune Modulating Topical S100A8/A9 Inhibits Growth of Pseudomonas aeruginosa and Mitigates Biofilm Infection in Chronic Wounds.

PubMed

Trøstrup, Hannah; Lerche, Christian Johann; Christophersen, Lars; Jensen, Peter Østrup; Høiby, Niels; Moser, Claus

2017-06-26

Pseudomonas aeruginosa biofilm maintains and perturbs local host defense, hindering timely wound healing. Previously, we showed that P. aeruginosa suppressed S100A8/A9 of the murine innate host defense. We assessed the potential antimicrobial effect of S100A8/A9 on biofilm-infected wounds in a murine model and P. aeruginosa growth in vitro. Seventy-six mice, inflicted with a full-thickness burn wound were challenged subcutaneously (s.c.) by 10⁶ colony-forming units (CFUs) of P. aeruginosa biofilm. Mice were subsequently randomized into two treatment groups, one group receiving recombinant murine S100A8/A9 and a group of vehicle controls (phosphate-buffered saline, PBS) all treated with s.c. injections daily for up to five days. Wounds were analyzed for quantitative bacteriology and contents of key inflammatory markers. Count of blood polymorphonuclear leukocytes was included. S100A8/A9-treatment ameliorated wound infection, as evaluated by quantitative bacteriology ( p ≤ 0.05). In vitro, growth of P. aeruginosa was inhibited dose-dependently by S100A8/A9 in concentrations from 5 to 40 μg/mL, as determined by optical density-measurement (OD-measurement) and quantitative bacteriology. Treatment slightly augmented key inflammatory cytokine Tumor Necrosis Factor-α (TNF-α), but dampened interferon-γ (IFN-γ) levels and blood polymorphonuclear count. In conclusion, topical S100A8/A9 displays remarkable novel immune stimulatory and anti-infective properties in vivo and in vitro. Importantly, treatment by S100A8/A9 provides local infection control. Implications for a role as adjunctive treatment in healing of chronic biofilm-infected wounds are discussed.

S100A8/A9 (Calprotectin), Interleukin-6, and C-Reactive Protein in Obesity and Diabetes before and after Roux-en-Y Gastric Bypass Surgery.

PubMed

Lylloff, Louise; Bathum, Lise; Madsbad, Sten; Grundtvig, Josefine Liv Gilling; Nordgaard-Lassen, Inge; Fenger, Mogens

2017-01-01

In obesity, which is a major contributor to insulin resistance and diabetes, the circulating level of S100A8/A9 (calprotectin) is elevated and declines after Roux-en-Y gastric bypass surgery (RYGB). However, studies on S100A8/A9 and the pathophysiological mechanisms in insulin resistance and diabetes are few and contradictory. We studied 48 subjects who underwent RYGB, comprising a non-diabetic control group and two diabetic groups in whom diabetes either regressed or persisted, 6-12 months post-surgically. S100A8/A9, interleukin 6 (IL-6) as well as other inflammatory and diabetes-related markers were measured pre- and post-surgically. Significant and similar decreases of BMI were found in all groups. S100A8/A9 and IL-6 decreased significantly in the group with diabetes remission and in the control group, but not in the group with persistent diabetes. The relative changes in S100A8/A9 and IL-6 correlated significantly (r = 0.905, p = 0.005) only in the group with persistent diabetes. In contrast, leukocyte count and C-reactive protein correlated significantly to S100A8/A9 only in the control group. Our study is suggestive of S100A8/A9 and IL-6 being related to a persistent diabetes status post-surgically and of different pathophysiological mechanisms being involved in the post-surgical changes in the three groups, despite similar decreases in BMI. © 2017 The Author(s) Published by S. Karger GmbH, Freiburg.

Characterization of the Protein Components of Matrix Stones Sheds Light on S100-A8 and S100-A9 Relevance in the Inflammatory Pathogenesis of These Rare Renal Calculi.

PubMed

Martelli, Claudia; Marzano, Valeria; Iavarone, Federica; Huang, Liling; Vincenzoni, Federica; Desiderio, Claudia; Messana, Irene; Beltrami, Paolo; Zattoni, Filiberto; Ferraro, Pietro Manuel; Buchholz, Noor; Locci, Giorgia; Faa, Gavino; Castagnola, Massimo; Gambaro, Giovanni

2016-09-01

Among the different types of kidney stones, matrix stones are uncommon urinary calculi composed of a soft, pliable, amorphous substance with little crystalline content. To gain insight into the pathogenesis we investigated the protein component by analyzing the proteomic profiles of surgically removed matrix stones. A total of 5 stones were harvested from 4 patients who underwent surgery for medical reasons at 3 clinical centers during a 7-year period. Matrix stone proteome characterization was performed by mass spectrometry based techniques using an integrated top-down/bottom-up proteomic platform. We identified 142 nonredundant proteins and peptides across all samples. Neutrophil defensin 1, and proteins S100-A8 and S100-A9 were the main components of these renal calculi. The abundance of identified inflammatory molecules points to an inflammatory process as the event that initializes soft calculi formation rather than as a consequence of such formation. The post-translational oxidative changes in S100-A8 and A9, and the presence of thymosin β-4, granulins and ubiquitin also suggest the intervention of host defenses through a superimposed, vigorous counter inflammatory process. The post-translational changes seen in the proteins and peptides, and the known self-assembling capability of S100-A8 and S100-A9 probably explain the gelatinous consistency of these stones. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis

PubMed Central

Yano, Junko; Palmer, Glen E.; Eberle, Karen E.; Peters, Brian M.; Vogl, Thomas; McKenzie, Andrew N.

2014-01-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response to C. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previous in vitro data and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluated in vitro or in vivo in the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression and C. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reported in vitro data, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxis in vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9−/− mice, had no effect on the PMN response in vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction in C. albicans-induced S100A8/S100A9 mRNAs in vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response to C. albicans involves PRRs in addition to SIGNR1 and TLR4, or other induction pathways. PMID:24478092

Vaginal epithelial cell-derived S100 alarmins induced by Candida albicans via pattern recognition receptor interactions are sufficient but not necessary for the acute neutrophil response during experimental vaginal candidiasis.

PubMed

Yano, Junko; Palmer, Glen E; Eberle, Karen E; Peters, Brian M; Vogl, Thomas; McKenzie, Andrew N; Fidel, Paul L

2014-02-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response to C. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previous in vitro data and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluated in vitro or in vivo in the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression and C. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reported in vitro data, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxis in vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9(-/-) mice, had no effect on the PMN response in vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction in C. albicans-induced S100A8/S100A9 mRNAs in vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response to C. albicans involves PRRs in addition to SIGNR1 and TLR4, or other induction pathways.

Crystal structure of human S100A8 in complex with zinc and calcium.

PubMed

Lin, Haili; Andersen, Gregers Rom; Yatime, Laure

2016-06-01

S100 proteins are a large family of calcium binding proteins present only in vertebrates. They function intra- and extracellularly both as regulators of homeostatic processes and as potent effectors during inflammation. Among these, S100A8 and S100A9 are two major constituents of neutrophils that can assemble into homodimers, heterodimers and higher oligomeric species, including fibrillary structures found in the ageing prostate. Each of these forms assumes specific functions and their formation is dependent on divalent cations, notably calcium and zinc. In particular, zinc appears as a major regulator of S100 protein function in a disease context. Despite this central role, no structural information on how zinc bind to S100A8/S100A9 and regulates their quaternary structure is yet available. Here we report two crystallographic structures of calcium and zinc-loaded human S100A8. S100A8 binds two zinc ions per homodimer, through two symmetrical, all-His tetracoordination sites, revealing a classical His-Zn binding mode for the protein. Furthermore, the presence of a (Zn)2-cacodylate complex in our second crystal form induces ligand swapping within the canonical His4 zinc binding motif, thereby creating two new Zn-sites, one of which involves residues from symmetry-related molecules. Finally, we describe the calcium-induced S100A8 tetramer and reveal how zinc stabilizes this tetramer by tightening the dimer-dimer interface. Our structures of Zn(2+)/Ca(2+)-bound hS100A8 demonstrate that S100A8 is a genuine His-Zn S100 protein. Furthermore, they show how zinc stabilizes S100A8 tetramerization and potentially mediates the formation of novel interdimer interactions. We propose that these zinc-mediated interactions may serve as a basis for the generation of larger oligomers in vivo.

Effect of poly and mono-unsaturated fatty acids on stability and structure of recombinant S100A8/A9.

PubMed

Asghari, Hamideh; Chegini, Koorosh Goodarzvand; Amini, Abbas; Gheibi, Nematollah

2016-03-01

Recombinant pET 15b vectors containing the coding sequences S100A8 and S100A9 are expressed in Escherichia coli BL21 (DE3) and purified using Ni-NTA affinity chromatography. The structural changes of S100A8/A9 complex are analyzed upon interaction with poly/mono-unsaturated fatty acids (UFAs). The thermodynamic values, Gibbs free energy and the protein melting point, are obtained through thermal denaturation of protein both with and without UFAs by thermal scanning of protein emission using the fluorescence spectroscopy technique. The far-ultraviolet circular dichroism spectra show that all studied unsaturated fatty acids, including arachidonic, linoleic, alpha-linolenic and oleic acids, induce changes in the secondary structure of S100A8/A9 by reducing the α-helix and β-sheet structures. The tertiary structure of S100A8/A9 has fluctuations in the fluorescence emission spectra after the incubation of protein with UFAs. The blue-shift of emission maximum wavelength and the increase in fluorescence intensity of anilino naphthalene-8-sulfonic acid confirm that the partial unfolding is caused by the conformational changes in the tertiary structure in the presence of UFAs. The structural changes in S100A8/A9 and its lower stability in the presence of UFAs may be necessary for S100A8/A9 to play a biological role in the inflammatory milieu. Copyright © 2015 Elsevier B.V. All rights reserved.

S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus.

PubMed

Trøstrup, Hannah; Holstein, Per; Christophersen, Lars; Jørgensen, Bo; Karlsmark, Tonny; Høiby, Niels; Moser, Claus; Ågren, Magnus S

2016-07-01

Chronic wounds and in particular diabetic foot ulcers (DFUs) are a growing clinical challenge, but the underlying molecular pathophysiological mechanisms are unclear. Recently, we reported reduced levels of the immunomodulating and antimicrobial S100A8/A9 in non-healing venous leg ulcers (VLUs), while another study found increased S100A8/A9 in DFUs. To clarify these apparently contradictory findings, we compared S100A8/A9 as well as an inducer, lipopolysaccharide (LPS) and selected innate immune response mediators in wound fluids from non-healing DFUs and VLUs with healing wounds. Wound fluids were collected from neuropathic DFUs (n = 6) and VLUs (n = 9) of median 2-year duration, and split-thickness skin graft donor site wounds (n = 10) by standardized method. None of the patients had ischaemic extremities or clinically infected wounds. LPS was determined by limulus amoebocyte lysate test, and S100A8/A9, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-10 and vascular endothelial growth factor (VEGF) by immunospecific quantitative assays. LPS levels were median 8.7 (interquartile range 5.4-21.2) ng/ml in DFUs compared with 121 (22-2000) ng/ml in VLUs. S100A8/A9 was higher (p = 0.020) in DFUs [718 (634-811) µg/ml] than in VLUs [303 (252-533) µg/ml]. Neither G-CSF nor IL-10 wound fluid levels differed significantly between the chronic wound groups. VEGF levels correlated with LPS (r = 0.758, p = 0.011, n = 10) and were higher (p = 0.024) in VLU wound fluids. LPS (p < 0.0001), S100A8/A9 (p = 0.005), G-CSF (p = 0.003), IL-10 (p = 0.003) and VEGF (p = 0.005) were increased in chronic wound fluids combined compared with the sterile donor site wound fluids. The protein alterations in the wounds were not reflected in the patients' sera. Low S100A8/A9 levels may contribute to poor wound healing in colonized chronic wounds with striking difference between DFUs and VLUs.

S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte–Renal Cell Interactions

PubMed Central

Pepper, Ruth J.; Wang, Hsu-Han; Rajakaruna, Gayathri K.; Papakrivopoulou, Eugenia; Vogl, Thomas; Pusey, Charles D.; Cook, H. Terence; Salama, Alan D.

2015-01-01

Glomerulonephritis is a common cause of end-stage renal disease. Infiltrating leukocytes interacting with renal cells play a critical role during the initiation and progression of glomerulonephritis, but the exact mechanisms are not clearly defined. By using the murine model of nephrotoxic nephritis, we investigated the role of S100A8/A9 [myeloid-related protein (MRP) 8/14, calprotectin] in promoting glomerulonephritis. In nephrotoxic nephritis, wild-type (WT) mice with glomerulonephritis have elevated serum levels of S100A8/A9, whereas mice deficient in MRP14 (S100a9−/−), and hence S100A8/A9, are significantly protected from disease. By using bone marrow transplants, we showed that MRP14 deficiency is required in both the hemopoietic and intrinsic cells for the protective effect. In vitro, both the WT bone marrow–derived macrophages and renal mesangial cells stimulated with S100A8/A9 secrete IL-6, CXCL1, and tumor necrosis factor α; however, Mrp14−/− cells exhibit significantly blunted proinflammatory responses. The interaction of WT bone marrow–derived macrophages with renal microvascular endothelial cells results in increased levels of monocyte chemotactic protein 1, IL-8, and IL-6 cytokines, which is attenuated in Mrp14−/− bone marrow–derived macrophages. Data shows that S100A8/A9 plays a critical role during glomerulonephritis, exerting and amplifying autocrine and paracrine proinflammatory effects on bone marrow–derived macrophages, renal endothelial cells, and mesangial cells. Therefore, complete S100A8/A9 blockade may be a new therapeutic target in glomerulonephritis. PMID:25759267

Expression of S100 beta in sensory and secretory cells of the vertebrate inner ear

NASA Technical Reports Server (NTRS)

Fermin, C. D.; Martin, D. S.

1995-01-01

We evaluated anti-S100 beta expression in the chick (Gallus domesticus) inner ear and determined that: 1) the monomer anti-S100 beta is expressed differentially in the vestibular and auditory perikarya; 2) expression of S100 beta in the afferent nerve terminals is time-related to synapse and myelin formation; 3) the expression of the dimer anti-S100 alpha alpha beta beta and monomer anti-S100 beta overlaps in most inner ear cell types. Most S100 alpha alpha beta beta positive cells express S100 beta, but S100 beta positive cells do not always express S100 alpha alpha beta beta. 4) the expression of S100 beta is diffused over the perikaryal cytoplasm and nuclei of the acoustic ganglia but is concentrated over the nuclei of the vestibular perikarya. 6) S100 beta is expressed in secretory cells, and it is co-localized with GABA in sensory cells. 7) Color thresholding objective quantitation indicates that the amount of S100 beta was higher (mean 22, SD +/- 4) at E19 than at E9 (mean 34, SD +/- 3) in afferent axons. 8) Moreover, S100 beta was unchanged between E11-E19 in the perikaryal cytoplasm, but did change over the nuclei. At E9, 74%, and at E21, 5% of vestibular perikarya were positive. The data suggest that S100 beta may be physically associated with neuronal and ionic controlling cells of the vertebrate inner ear, where it could provide a dual ionic and neurotrophic modulatory function.

S100A8 and S100A9: New Insights into Their Roles in Malignancy

PubMed Central

Srikrishna, Geetha

2011-01-01

Recent studies have highlighted key roles played by non-neoplastic host cells of the tumor microenvironment, and by secreted factors from tumor and host cells, in promoting malignancy. In this regard, damage-associated molecular pattern (DAMP) molecules such as S100A8 and S100A9, with well-known functions in inflammation, have been increasingly recognized not only as markers, but also as new candidates with important roles in modulating tumor growth and metastasis. This review focuses on our current understanding of the pro- and anti-tumorigenic functions of S100A8 and S100A9. Elucidating molecular pathways mediated by these proteins promises to provide potential novel targets for the development of cancer therapeutics and to establish valid biomarkers to identify early stages of tumor progression. PMID:21912088

S100A12 and the S100/Calgranulins - Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

PubMed Central

Oesterle, Adam; Hofmann Bowman, Marion A

2016-01-01

Atherosclerosis is mediated by local and systematic inflammation. The multi-ligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans, and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell targeted expression of S100A12 demonstrate increased coronary and aortic calcification as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis susceptible Apolipoprotein E (ApoE) null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the Quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 ApoE null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. PMID:26515415

Enzyme-linked immunosorbent assay for S100A9 in the stool of rats with dextran sulfate sodium-induced colitis.

PubMed

Sekiya, Shunsuke; Murata, Makoto; Arai, Satoshi; Murayama, Hiroshi; Kawasaki, Atushi; Ashida, Noriyuki; Okada, Kohki; Ikemoto, Masaki

2016-12-01

Calprotectin, a heterodimer of S100A8 and S100A9, has been reported to be a useful biomarker in inflammatory bowel disease (IBD); however, the relationship between the fecal level of S100A9 and the extent of inflammation in IBD remains unclear. Our aim was to develop a new enzyme-linked immunosorbent assay (ELISA) for rat S100A9, and to investigate whether changes in fecal S100A9 levels reflect the inflammatory conditions in the intestinal tracts of rats with dextran sulfate sodium (DSS)-induced colitis. Anti-rat S100A9 monoclonal antibodies were raised in mice and used for the development of a novel ELISA for rat S100A9. The performance of our ELISA was assessed by dilution and recovery tests, and the detection range was 3.75-240ng/mL. The dilution test showed good linearity. The recovery of fecal S100A9 was 95.1% (mean), with a range of 86.1%-108.8%. Colitis was induced in rats by oral administration of 3% DSS/drinking water (DW) for 11days (D group), while DW alone was provided to rats of the control group (C group) during the same period. The extent of inflammation was evaluated with the disease activity index (DAI), and the concentration of fecal S100A9 was determined by ELISA. Both the DAI scores and the fecal S100A9 levels were significantly higher in the D group than in the C group. Microscopic observation revealed that S100A9 was dominantly produced in many immune cells of myeloid origin in rat rectal tissues. These results indicate that the novel ELISA may be applied to clinically evaluate IBD in rats with high sensitivity. In conclusion, our ELISA is useful in toxicological and pharmacological evaluations. Copyright © 2016 Elsevier B.V. All rights reserved.

Presence of S100A8/Gr1-Positive Myeloid-Derived Suppressor Cells in Primary Tumors and Visceral Organs Invaded by Breast Carcinoma Cells.

PubMed

Tanriover, Gamze; Eyinc, Mehmet Berk; Aliyev, Elnur; Dilmac, Sayra; Erin, Nuray

2018-04-26

Increased S100A8/A9 expression in Gr1-positive cells has been shown in myeloid-derived suppressor cells and may play a role in the formation of a metastatic milieu. We aimed to determine S100A8/A9 expression alone and with coexpression of Gr1 (a myeloid marker) in primary tumor and visceral tissues invaded by metastatic breast carcinoma. Female BALB/c mice were injected with 4TLM, 4THM, and 67NR orthotopically. Confluent cells (75%-80%) were used. Primary tumor, lung, liver, and spleen tissue samples were removed 26 days after injection. Peripheral blood smears and metastasis assay were performed, as was immunohistochemistry and staining. S100A8/A9 immunoreactivity alone or coexpressed with Gr1 was found in primary tumors formed by 4TLM and 4THM cells, which was markedly higher than in primary tumors formed by nonmetastatic 67NR cells. Similarly, liver and lung tissues obtained from mice injected with 4TLM or 4THM cells were invaded by S100A8/A9-positive and Gr1-positive cells. Double-positive cells were markedly fewer in liver and lung tissues of animals injected with 67NR cells. S100A8/A9-positive cells were mostly localized in red pulp of spleens. We observed an increased number of neutrophils in the peripheral blood of mice injected with metastatic breast carcinoma cells. Tumor-derived factors may increase S100A8/A9-positive cells locally and systemically, and S100A8/A9-positive cells may provide an appropriate milieu for the formation of metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Modifying effects of carboxyl group on the interaction of recombinant S100A8/A9 complex with tyrosinase.

PubMed

NematiNiko, Fatemeh; Chegini, Koorosh Goodarzvand; Asghari, Hamideh; Amini, Abbas; Gheibi, Nematollah

2017-03-01

Tyrosinase is a determinant enzyme for modulating melanin production as its abnormal activity can result in an increased amount of melanin. Reduction of tyrosinase activity has been targeted for preventing and healing hyperpigmentation of skin, such as melanoma and age related spots. The aim of this systematic study is to investigate whether recombinant S100A8/A9 and its modified form reduce the activity of mushroom tyrosinase (MT) through changing its structure. Recombinant His-Tagged S100A8 and S100A9 are expressed in Escherichia coli BL21 (DE3) and modified using Woodward's reagent K which is a carboxyl group modifier. The structures of S100A8/A9 and its modified form are studied using fluorescence and circular dichroism spectroscopy, and the activity of MT is measured using UV-visible spectrophotometry in the presence of its substrate, L-3,4-dihydroxyphenylalanine (L-DOPA). The results show a lower stability of the modified protein when compared with its unmodified form. The interaction of S100A8/A9 with MT changes the structure and successfully reduces the activity of mushroom tyrosinase. Recombinant S100A8/A9 complex decreases MT activity which can control malignant melanoma, the most dangerous type of skin cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Up-regulation of Proinflammatory Genes and Cytokines Induced by S100A8 in CD8+ T Cells in Lichen Planus.

PubMed

de Carvalho, Gabriel Costa; Domingues, Rosana; de Sousa Nogueira, Marcelle Almeida; Calvielli Castelo Branco, Anna C; Gomes Manfrere, Kelly C; Pereira, Naiura Vieira; Aoki, Valéria; Sotto, Mirian Nacagami; Da Silva Duarte, Alberto J; Sato, Maria Notomi

2016-05-01

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. The inflammatory status of LP may be related to S100A8 (myeloid-related protein 8; MRP8) activation of cytotoxic cells. The aims of this study were to evaluate S100A8 expression in skin lesions and the in vitro effects of S100A8 on CD8+ T cells and natural killer (NK) cells in LP. Increased levels of S100A8/S100A9 were detected in the skin lesions as well as in the sera of subjects with LP. S100A8 expression induced an increased cytotoxic response by peripheral blood CD8+CD107a+ T cells as well as by NK CD56bright cells in patients with LP. Increased expression of interleukin (IL)-1?, tumour necrosis factor (TNF) and IL-6 in the CD8+ T cells of patients with LP was induced by S100A8, in contrast to the control group that produced IL- 10 and interferon type I genes. These data suggest that, in individuals with LP, S100A8 may exert distinct immunomodulatory and cytotoxicity functions.

Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment.

PubMed

Eisenblaetter, Michel; Flores-Borja, Fabian; Lee, Jae Jin; Wefers, Christina; Smith, Hannah; Hueting, Rebekka; Cooper, Margaret S; Blower, Philip J; Patel, Dominic; Rodriguez-Justo, Manuel; Milewicz, Hanna; Vogl, Thomas; Roth, Johannes; Tutt, Andrew; Schaeffter, Tobias; Ng, Tony

2017-01-01

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r 2 =0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment

PubMed Central

Eisenblaetter, Michel; Flores-Borja, Fabian; Lee, Jae Jin; Wefers, Christina; Smith, Hannah; Hueting, Rebekka; Cooper, Margaret S; Blower, Philip J; Patel, Dominic; Rodriguez-Justo, Manuel; Milewicz, Hanna; Vogl, Thomas; Roth, Johannes; Tutt, Andrew; Schaeffter, Tobias; Ng, Tony

2017-01-01

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology. PMID:28744322

Association of Serum Calprotectin (S100A8/A9) Level With Disease Relapse in Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

PubMed

Pepper, Ruth J; Draibe, Juliana B; Caplin, Ben; Fervenza, Fernando C; Hoffman, Gary S; Kallenberg, Cees G M; Langford, Carol A; Monach, Paul A; Seo, Philip; Spiera, Robert; William St Clair, E; Tchao, Nadia K; Stone, John H; Specks, Ulrich; Merkel, Peter A; Salama, Alan D

2017-01-01

S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group (P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 (P = 0.0043) and baseline and month 6 (P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse (P = 0.028). An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. © 2016, American College of Rheumatology.

Association between serum levels of the proinflammatory protein S100A8/A9 and clinical and structural characteristics of patients with established knee, hip, and hand osteoarthritis.

PubMed

Mahler, E A M; Zweers, M C; van Lent, P L; Blom, A B; van den Hoogen, F H; van den Berg, W B; Roth, J; Vogl, T; Bijlsma, J W J; van den Ende, C H M; den Broeder, A A

2015-01-01

To explore the association between S100A8/A9 serum levels with clinical and structural characteristics of patients with established knee, hip, or hand osteoarthritis (OA). A cross-sectional exploratory study was conducted with 162 OA patients. Measures for pain, stiffness, and function included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire or the Australian Canadian Osteoarthritis Hand (AUSCAN) Index and for structural abnormalities, osteophytes and joint space narrowing grades. The association between S100A8/A9 and clinical or structural characteristics was analysed using linear regression or logistic regression where appropriate. The mean age of the OA patients was 56 years, 71% were female, and 61% had a Kellgren and Lawrence (K&L) score ≥ 2. The serum S100A8/A9 level did not differ between knee, hip, and hand OA patients and no association was found between serum S100A8/A9 and clinical characteristics. The serum S100A8/A9 level was negatively associated with the sum score of osteophytes after adjusting for sex and body mass index (BMI) [adjusted β -0.015, 95% confidence interval (CI) -0.030 to 0.001, p = 0.062] and positively associated with erythrocyte sedimentation rate (ESR) > 12 mm/h (adjusted OR 1.002, 95% CI 1.000-1.004 p = 0.049) for each increase in S100A8/A9 of 1 ng/mL. For hand OA patients, a negative association of S100A8/A9 with sum score of joint space narrowing was found (adjusted β -0.007, 95% CI -0.016 to 0.001, p = 0.099). The results from this cross-sectional exploratory study do not support an important role for serum S100A8/A9 levels as a biomarker for clinical and structural characteristics in established knee, hip, and hand OA patients. The inverse association with structural abnormalities and the positive association with ESR may reflect inflammatory synovial processes in patients with OA before structural abnormalities occur.

CXCL4-induced plaque macrophages can be specifically identified by co-expression of MMP7+S100A8+ in vitro and in vivo.

PubMed

Erbel, Christian; Tyka, Mirjam; Helmes, Christian M; Akhavanpoor, Mohmmadreza; Rupp, Gregor; Domschke, Gabriele; Linden, Fabian; Wolf, Antonia; Doesch, Andreas; Lasitschka, Felix; Katus, Hugo A; Gleissner, Christian A

2015-04-01

Macrophage heterogeneity in human atherosclerotic plaques has been recognized; however, markers for unequivocal identification of some subtypes are lacking. We found that the platelet chemokine CXCL4 induces a unique macrophage phenotype, which we proposed to call 'M4'. Here, we sought to identify suitable markers that identify M4 macrophages in vitro and in vivo. Using a stringent algorithm, we identified a set of potential markers from transcriptomic data derived from polarized macrophages. We specifically focused on matrix metalloproteinase (MMP)7 and S100A8, the co-expression of which has not been described in any macrophage type thus far. We found dose- and time-dependent MMP7 and S100A8 expression in M4 macrophages at the gene and protein levels. CXCL4-induced up-regulation of both MMP7 and S100A8 was curbed in the presence of heparin, which binds to CXCL4 and glycosaminoglycans, most likely representing the macrophage receptor for CXCL4. Immunofluorescence of post-mortem atherosclerotic coronary arteries identified CD68(+)MMP7(+), CD68(+)MMP7(-), CD68(+)S100A8(+) and CD68(+)S100A8(-) macrophages. A small proportion of MMP7(+)S100A8(+) macrophages most likely represent M4 macrophages. In summary, we have identified co-expression of MMP7 and S100A8 to be a marker combination exclusively found in M4 macrophages. This finding may allow further dissection of the role of M4 macrophages in atherosclerosis and other pathologic conditions. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Daggett Municipal, California. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F.

DTIC Science & Technology

1982-07-02

99.9 99.998.8 󈨧.3 99.6 99.61 99.6 99.6 99.6 ! ., 9.9. 90.o0o.o0.o .o 8 o.o9. )o tD i . . 8i 99. 3: 99.6 99.6 99.6 99.61 99.6 99.9! 99.9 00.0 0...00.100p 100. 100.0 100. 00. 00.0000. 00.00 000 6 99 1 01~ TD 0. 10 . 0~ Ica 10.01 000 00.100. 100.01100. 00.e 00.0100.0000 S98.; 99. ~ 0.1.0100 00 0 0...242 2 27 -21 29 .301 .31 O.S./W B.bA~ W.,S bbD -P--n 8/ 87 I I 1 61 6 4/ 3 .1 71 .2 .81 1.31 1.1 1.2 551 5S 6/ A51, . 1 ,8 1,9 1 1,1 ’te , I I 81 88 l n

Zinc Replenishment Reverses Overexpression of the Proinflammatory Mediator S100A8 and Esophageal Preneoplasia in the Rat

PubMed Central

Taccioli, Cristian; Wan, Shao-Gui; Liu, Chang-Gong; Alder, Hansjuerg; Volinia, Stefano; Farber, John L.; Croce, Carlo M.

2009-01-01

Background & Aims Zinc-deficiency is implicated in the pathogenesis of human esophageal cancer. In the rat esophagus, it induces cell proliferation, modulates genetic expression, and enhances carcinogenesis. Zinc-replenishment reverses proliferation and inhibits carcinogenesis. The zinc-deficient rat model allows the identification of biological differences affected by zinc during early esophageal carcinogenesis. Methods We evaluated gene expression profiles of esophageal epithelia from zinc-deficient and replenished rats versus sufficient rats using Affymetrix Rat Genome GeneChip. We characterized the role of the top-upregulated gene S100A8 in esophageal hyperplasia/reversal and in chemically-induced esophageal carcinogenesis in zinc-modulated animals by immunohistochemistry and real-time quantitative polymerase chain reaction. Results The hyperplastic deficient esophagus has a distinct expression signature with the proinflammation-gene S100A8 and S100A9 upregulated 57- and 5-fold. “Response to external stimulus” comprising S100A8 was the only significantly overrepresented biological pathway among the upregulated genes. Zinc-replenishment rapidly restored to control levels the expression of S100A8/A9 and 27 other genes and reversed the hyperplastic phenotype. With its receptor RAGE, co-localization and overexpression of S100A8 protein occurred in the deficient esophagus that overexpressed NF-κB p65 and COX-2 protein. Zinc-replenishment but not by a COX-2 inhibitor reduced the overexpression of these 4 proteins. Additionally, esophageal S100A8/A9 mRNA levels were directly associated with the diverse tumorigenic outcome in zinc-deficient and zinc-replenished rats. Conclusions In vivo zinc regulates S100A8 expression and modulates the link between S100A8-RAGE interaction and downstream NF-κB/COX-2 signaling. The finding that zinc regulates an inflammatory pathway in esophageal carcinogenesis may lead to prevention and therapy for this cancer. PMID:19111725

Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment.

PubMed

Deguchi, A; Tomita, T; Ohto, U; Takemura, K; Kitao, A; Akashi-Takamura, S; Miyake, K; Maru, Y

2016-03-17

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

Blocking the interaction between S100A9 protein and RAGE V domain using S100A12 protein.

PubMed

Katte, Revansiddha; Yu, Chin

2018-01-01

The proteins S100A9 and S100A12 are associated with the human S100 calcium-binding protein family. These proteins promote interaction with target proteins and alter their conformation when they bind to calcium ions in EF-hand motifs. The V domain of RAGE (Receptor for Advanced Glycation End products) is crucial for S100A9 binding. The binding of RAGE with S100 family proteins aids in cell proliferation. In this report, we demonstrate that S100A12 protein hinders the binding of S100A9 with the RAGE V-domain. We used fluorescence and NMR spectroscopy to analyze the interaction of S100A9 with S100A12. The binary complex models of S100A9-S100A12 were developed using data obtained from 1H-15N HSQC NMR titrations and the HADDOCK program. We overlaid the complex models of S100A9-S100A12 with the same orientation of S100A9 and the RAGE V-domain. This complex showed that S100A12 protein blocks the interaction between S100A9 and the RAGE V-domain. It means S100A12 may be used as an antagonist for S100A9. The results could be favorable for developing anti-cancer drugs based on S100 family proteins.

[S100A7 promotes the metastasis and epithelial-mesenchymal transition on HeLa and CaSki cells].

PubMed

Tian, T; Hua, Z; Wang, L Z; Wang, X Y; Chen, H Y; Liu, Z H; Cui, Z M

2018-02-25

Objective: To elucidate the impact of over-expression of S100A7 on migration, invasion, proliferation, cell cycle, and epithelial-mesenchymal transition (EMT) in human cervical cancer HeLa and CaSki cells. Methods: (1) Immunohistochemistry of SP was used to examine the expression of S100A7 in 40 cases of squamous cervical cancer tissues and 20 cases of normal cervical tissues. (2) The vectors of pLVX-IRES-Neo-S100A7 and pLVX-IRES-Neo were used to transfect human cervical cancer HeLa and CaSki cells, and the positive clones were screened and identified. Next, transwell migration assay, cell counting kit-8 (CCK-8) assay and fluorescence activating cell sorter (FACS) were used to detect the effect of S100A7-overexpression on the migration, invasion, proliferation and cell cycle of cervical cancer cells. Furthermore, western blot was performed to observe the expression of epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin, vimentin, and fibronectin) of EMT. Results: (1) S100A7 expression was significantly higher in cervical squamous cancer tissues (median 91.6) than that in normal cervical tissues (median 52.1; Z=- 2.948, P= 0.003) . (2) Stable S100A7-overexpressed cells were established using lentiviral-mediated gene delivery in HeLa and CaSki cells. S100A7 was detected by real-time quantitative reverse transcription PCR, S100A7 mRNA of S100A7-overexpressed cells were 119±3 and 177±16, increased significantly compared with control groups of median ( P< 0.01) . Compared with the control cells, the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane assay were increased significanatly (572±51 vs 337±25, P< 0.01; 100±8 vs 41±4, P< 0.01) .Matrigel invasion assay showed that the number of S100A7-overexpressed HeLa and CaSki cells that passed the transwell membrane were respectively 441±15 and 110±14, elevated significantly compared with control cells (156±21 and 59±7; P< 0.05) . However, S100A7 overexpression didn't influence the proliferation and cell cycle progression of HeLa and CaSki cells ( P> 0.05) . Expression of E-cadherin was dramatically decreased, while N-cadherin, vimentin, and fibronectin increased in S100A7-overexpressed cells. Conclusion: S100A7 enhances the migration, invasion and EMT of HeLa cells and CaSki cells, and may be plays an important role in the development of cervical cancer.

Validation of an enzyme-linked immunosorbent assay (ELISA) for the measurement of canine S100A12.

PubMed

Heilmann, Romy M; Cranford, Shannon M; Ambrus, Andy; Grützner, Niels; Schellenberg, Stefan; Ruaux, Craig G; Suchodolski, Jan S; Steiner, Jörg M

2016-03-01

Canine S100 calcium-binding protein A12 (cS100A12) shows promise as biomarker of inflammation in dogs. A previously developed cS100A12-radioimmunoassay (RIA) requires radioactive tracers and is not sensitive enough for fecal cS100A12 concentrations in 79% of tested healthy dogs. An ELISA assay may be more sensitive than RIA and does not require radioactive tracers. The purpose of the study was to establish a sandwich ELISA for serum and fecal cS100A12, and to establish reference intervals (RI) for normal healthy canine serum and feces. Polyclonal rabbit anti-cS100A12 antibodies were generated and tested by Western blotting and immunohistochemistry. A sandwich ELISA was developed and validated, including accuracy and precision, and agreement with cS100A12-RIA. The RI, stability, and biologic variation in fecal cS100A12, and the effect of corticosteroids on serum cS100A12 were evaluated. Lower detection limits were 5 μg/L (serum) and 1 ng/g (fecal), respectively. Intra- and inter-assay coefficients of variation were ≤ 4.4% and ≤ 10.9%, respectively. Observed-to-expected ratios for linearity and spiking recovery were 98.2 ± 9.8% (mean ± SD) and 93.0 ± 6.1%, respectively. There was a significant bias between the ELISA and the RIA. The RI was 49-320 μg/L for serum and 2-484 ng/g for fecal cS100A12. Fecal cS100A12 was stable for 7 days at 23, 4, -20, and -80°C; biologic variation was negligible but variation within one fecal sample was significant. Corticosteroid treatment had no clinically significant effect on serum cS100A12 concentrations. The cS100A12-ELISA is a precise and accurate assay for serum and fecal cS100A12 in dogs. © 2016 American Society for Veterinary Clinical Pathology.

Influence of energy balance on the antimicrobial peptides S100A8 and S100A9 in the endometrium of the post-partum dairy cow.

PubMed

Swangchan-Uthai, Theerawat; Chen, Qiusheng; Kirton, Sally E; Fenwick, Mark A; Cheng, Zhangrui; Patton, Joe; Fouladi-Nashta, Ali A; Wathes, D Claire

2013-05-01

Uterine inflammation occurs after calving in association with extensive endometrial remodelling and bacterial contamination. If the inflammation persists, it leads to reduced fertility. Chronic endometritis is highly prevalent in high-yielding cows that experience negative energy balance (NEB) in early lactation. This study investigated the effect of NEB on the antimicrobial peptides S100A8 and S100A9 in involuting uteri collected 2 weeks post partum. Holstein-Friesian cows (six per treatment) were randomly allocated to two interventions designed to produce mild or severe NEB (MNEB and SNEB) status. Endometrial samples were examined histologically, and the presence of neutrophils, macrophages, lymphocytes and natural killer cells was confirmed using haematoxylin and eosin and immunostaining. SNEB cows had greater signs of uterine inflammation. Samples of previously gravid uterine horn were used to localise S100A8 and S100A9 by immunohistochemistry. Both S100 proteins were present in bovine endometrium with strong staining in epithelial and stromal cells and in infiltrated leucocytes. Immunostaining was significantly higher in SNEB cows along with increased numbers of segmented neutrophils. These results suggest that the metabolic changes of a post-partum cow suffering from NEB delay uterine involution and promote a chronic state of inflammation. We show that upregulation of S100A8 and S100A9 is clearly a key component of the early endometrial response to uterine infection. Further studies are warranted to link the extent of this response after calving to the likelihood of cows developing endometritis and to their subsequent fertility.

Influence of energy balance on the antimicrobial peptides S100A8 and S100A9 in the endometrium of the post-partum dairy cow

PubMed Central

Swangchan-Uthai, Theerawat; Chen, Qiusheng; Kirton, Sally E; Fenwick, Mark A; Cheng, Zhangrui; Patton, Joe; Fouladi-Nashta, Ali A; Wathes, D Claire

2013-01-01

Uterine inflammation occurs after calving in association with extensive endometrial remodelling and bacterial contamination. If the inflammation persists, it leads to reduced fertility. Chronic endometritis is highly prevalent in high-yielding cows that experience negative energy balance (NEB) in early lactation. This study investigated the effect of NEB on the antimicrobial peptides S100A8 and S100A9 in involuting uteri collected 2 weeks post partum. Holstein-Friesian cows (six per treatment) were randomly allocated to two interventions designed to produce mild or severe NEB (MNEB and SNEB) status. Endometrial samples were examined histologically, and the presence of neutrophils, macrophages, lymphocytes and natural killer cells was confirmed using haematoxylin and eosin and immunostaining. SNEB cows had greater signs of uterine inflammation. Samples of previously gravid uterine horn were used to localise S100A8 and S100A9 by immunohistochemistry. Both S100 proteins were present in bovine endometrium with strong staining in epithelial and stromal cells and in infiltrated leucocytes. Immunostaining was significantly higher in SNEB cows along with increased numbers of segmented neutrophils. These results suggest that the metabolic changes of a post-partum cow suffering from NEB delay uterine involution and promote a chronic state of inflammation. We show that upregulation of S100A8 and S100A9 is clearly a key component of the early endometrial response to uterine infection. Further studies are warranted to link the extent of this response after calving to the likelihood of cows developing endometritis and to their subsequent fertility. PMID:23533291

Transgenic expression of S100A2 in hairless mouse skin enhances Cxcl13 mRNA in response to solar-simulated radiation.

PubMed

Li, Yong; Gudjonsson, Johann E; Woods, Timothy L; Zhang, Tong; Johnston, Andrew; Stoll, Stefan W; Elder, James T

2009-03-01

S100A2 is a homodimeric protein that undergoes oxidative cross-linking and translocation from the nucleus to the cytosol in the context of oxidative stress. Suggestive of a role for S100A2 in the cutaneous response to ultraviolet light, we found altered S100A2 immunostaining in photodamaged human skin, and crosslinking of S100A2 after ultraviolet A (UVA) irradiation of normal human keratinocytes (NHK). Skin from mice, rats, and rabbits did not contain S100A2 protein, whereas skin samples from pigs, frogs and humans were strongly positive. Survival after UVA irradiation was significantly greater in NHK compared to mouse keratinocytes, suggesting a protective role for S100A2. To test this hypothesis in vivo, we expressed S100A2 in SKH2/J hairless mice under the control of a bovine keratin 5 promoter, and compared responses of TG and WT mice from 1 to 7 days after a single dose (0.5-1 MED) of solar-simulated radiation (SSR) from UVA-340 bulbs. WT and TG mice manifested a similarly robust response to SSR, characterized by epidermal hyperplasia, marked induction of p21(WAF), and a twofold increase in p53. Thymine dimers (TD) were markedly increased in the epidermis and the dermis, but while over 95% of the epidermal TD were removed by 5-6 days, elevated dermal TD persisted nearly unchanged for 7 days. Global transcriptional profiling of WT and TG mice revealed strong induction of multiple transcripts, including keratins K6 and K16, defensin beta 3, S100A8, S100A9, Sprr2i and Sprr2f. However, the only S100A2-dependent difference we observed was an induction of Cxcl13 transcripts in TG, but not WT mice (4.4-fold vs. 0.7-fold, n = 3, P = 0.022). This finding was confirmed in an independent set of mice analyzed by quantitative RT-PCR (8.8-fold vs. 1.2-fold, n = 4, P = 0.001). The finding of persistent dermal DNA damage after suberythemal doses of SSR merits further study.

Increased Levels of S100A8/A9 in Patients with Peritonsillar Abscess: A New Promising Diagnostic Marker to Differentiate between Peritonsillar Abscess and Peritonsillitis.

PubMed

Spiekermann, Christoph; Russo, Antonella; Stenner, Markus; Rudack, Claudia; Roth, Johannes; Vogl, Thomas

2017-01-01

Peritonsillar abscess (PTA) is a very frequent reason for urgent outpatient consultation and otolaryngological hospital admission. Early, correct diagnosis and therapy of peritonsillar abscess are important to prevent possible life-threatening complications. Based on physical examinations, a reliable differentiation between peritonsillar cellulitis and peritonsillar abscess is restricted. A heterodimeric complex called calprotectin consists of the S100 proteins A8 and A9 (S100A8/A9) and is predominantly expressed not only in monocytes and neutrophils but also in epithelial cells. Due to its release by activated phagocytes at local sites of inflammation, we assumed S100A8/A9 to be a potential biomarker for peritonsillar abscess. We examined serum and saliva of patients with peritonsillitis, acute tonsillitis, peritonsillar abscess, and healthy controls and found significantly increased levels of S100A8/A9 in patients with PTA. Furthermore, we could identify halitosis, trismus, uvula edema, and unilateral swelling of the arched palate to be characteristic symptoms for PTA. Using a combination of these characteristic symptoms and S100A8/A9 levels, we developed a PTA score as an objective and appropriate tool to differentiate between peritonsillitis and peritonsillar abscess with a sensitivity of 92% and specificity of 93%.

Two proteins modulating transendothelial migration of leukocytes recognize novel carboxylated glycans on endothelial cells.

PubMed

Srikrishna, G; Panneerselvam, K; Westphal, V; Abraham, V; Varki, A; Freeze, H H

2001-04-01

We recently showed that a class of novel carboxylated N:-glycans was constitutively expressed on endothelial cells. Activated, but not resting, neutrophils expressed binding sites for the novel glycans. We also showed that a mAb against these novel glycans (mAbGB3.1) inhibited leukocyte extravasation in a murine model of peritoneal inflammation. To identify molecules that mediated these interactions, we isolated binding proteins from bovine lung by their differential affinity for carboxylated or neutralized glycans. Two leukocyte calcium-binding proteins that bound in a carboxylate-dependent manner were identified as S100A8 and annexin I. An intact N terminus of annexin I and heteromeric assembly of S100A8 with S100A9 (another member of the S100 family) appeared necessary for this interaction. A mAb to S100A9 blocked neutrophil binding to immobilized carboxylated glycans. Purified human S100A8/A9 complex and recombinant human annexin I showed carboxylate-dependent binding to immobilized bovine lung carboxylated glycans and recognized a subset of mannose-labeled endothelial glycoproteins immunoprecipitated by mAbGB3.1. Saturable binding of S100A8/A9 complex to endothelial cells was also blocked by mAbGB3.1. These results suggest that the carboxylated glycans play important roles in leukocyte trafficking by interacting with proteins known to modulate extravasation.

Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial

PubMed Central

Pratley, Richard E.; Eldor, Roy; Raji, Annaswamy; Golm, Gregory; Huyck, Susan B.; Qiu, Yanping; Sunga, Sheila; Johnson, Jeremy; Terra, Steven G.; Mancuso, James P.; Engel, Samuel S.

2018-01-01

Aim To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. Methods In this study (http://Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co‐administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. Results At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (−1.5%) and E15/S100 (−1.5%) than with individual agents (−1.0%, −1.1% and −1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin‐treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups. Conclusions In patients with uncontrolled type 2 diabetes while using metformin, co‐administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents. PMID:29266675

Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes.

PubMed

Ortega, Francisco J; Mercader, Josep M; Moreno-Navarrete, José M; Sabater, Mónica; Pueyo, Neus; Valdés, Sergio; Ruiz, Bartomeu; Luche, Elodie; Serino, Matteo; Naon, Deborah; Ricart, Wifredo; Botas, Patricia; Delgado, Elias; Burcelin, Remy; Frühbeck, Gema; Bosch, Fatima; Mingrone, Gertrude; Zorzano, Antonio; Fernández-Real, José M

2013-04-01

Calgranulin B (S100A9) was recognized as a candidate type 2 diabetes (T2D) gene in the genomic profiling of muscle from a rodent model of T2D and identifying the human orthologs of genes localized in T2D susceptibility regions. Circulating and S100A9 expressions in muscle and adipose tissue, isolated fat cells, and mouse models were evaluated. A common 5'-upstream single-nucleotide polymorphism (SNP; rs3014866) for S100A9 was analyzed, as well as the effects of weight loss and treatments in vitro with recombinant S100A9. S100a9 expression was increased in muscle of diabetic mice (1.6-fold, p = 0.002), and in muscle from subjects with impaired glucose tolerance (∼4-fold, p = 0.028; n = 34). The rs3014866 SNP was associated with circulating S100A9 and the risk of T2D, having TT carriers at 28 % (p = 0.03) lower risk (n = 1,450). Indeed, increased circulating S100A9 (∼4-fold, p = 0.03; n = 206) and subcutaneous (2-fold, p = 0.01) and omental (1.4-fold, p = 0.04) S100A9 gene expressions (n = 83) in TT carriers run in parallel to decreased fasting glucose and glycated hemoglobin. Accordingly, metformin led to increased S100A9 mRNA in ex vivo-treated adipose tissue explants (n = 5/treatment). Otherwise, obese subjects showed a compensatory increase in circulating and S100A9 expressions in adipose (n = 126), as further demonstrated by decreased levels after diet- (-34 %, p = 0.002; n = 20) and surgery-induced (-58 %, p = 0.02; n = 8) weight loss. Lipopolysaccharide led to increased S100A9 in adipose from mice (n = 5/treatment) while recombinant S100A9 downregulated inflammation in adipocytes (n = 3/treatment). Current findings support the strategy of testing differentially expressed genes in mice and human orthologs associated with T2D. The increased S100A9 reported for obesity and insulin resistance may be envisioned as a compensatory mechanism for inflammation.

The Hexahistidine Motif of Host-Defense Protein Human Calprotectin Contributes to Zinc Withholding and Its Functional Versatility.

PubMed

Nakashige, Toshiki G; Stephan, Jules R; Cunden, Lisa S; Brophy, Megan Brunjes; Wommack, Andrew J; Keegan, Brenna C; Shearer, Jason M; Nolan, Elizabeth M

2016-09-21

Human calprotectin (CP, S100A8/S100A9 oligomer, MRP-8/MRP-14 oligomer) is an abundant host-defense protein that is involved in the metal-withholding innate immune response. CP coordinates a variety of divalent first-row transition metal ions, which is implicated in its antimicrobial function, and its ability to sequester nutrient Zn(II) ions from microbial pathogens has been recognized for over two decades. CP has two distinct transition-metal-binding sites formed at the S100A8/S100A9 dimer interface, including a histidine-rich site composed of S100A8 residues His17 and His27 and S100A9 residues His91 and His95. In this study, we report that CP binds Zn(II) at this site using a hexahistidine motif, completed by His103 and His105 of the S100A9 C-terminal tail and previously identified as the high-affinity Mn(II) and Fe(II) coordination site. Zn(II) binding at this unique site shields the S100A9 C-terminal tail from proteolytic degradation by proteinase K. X-ray absorption spectroscopy and Zn(II) competition titrations support the formation of a Zn(II)-His6 motif. Microbial growth studies indicate that the hexahistidine motif is important for preventing microbial Zn(II) acquisition from CP by the probiotic Lactobacillus plantarum and the opportunistic human pathogen Candida albicans. The Zn(II)-His6 site of CP expands the known biological coordination chemistry of Zn(II) and provides new insight into how the human innate immune system starves microbes of essential metal nutrients.

ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility.

PubMed

Sumardika, I Wayan; Youyi, Chen; Kondo, Eisaku; Inoue, Yusuke; Ruma, I Made Winarsa; Murata, Hitoshi; Kinoshita, Rie; Yamamoto, Ken-Ichi; Tomida, Shuta; Shien, Kazuhiko; Satoh, Hiroki; Yamauchi, Akira; Futami, Junichiro; Putranto, Endy Widya; Hibino, Toshihiko; Toyooka, Shinichi; Nishibori, Masahiro; Sakaguchi, Masakiyo

2017-09-18

We previously identified novel S100A8/A9 receptors, Extracellular Matrix Metalloproteinase Inducer (EMMPRIN), MelanomaCell Adhesion Molecule (MCAM), Activated Leukocyte Cell Adhesion Molecule (ALCAM) and Neuroplastin (NPTN) ß, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancerspecific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real time PCR. Cell migration and invasion were assessed by a using Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of GCNT3 and MCAM in melanoma tissue. We found that ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9-MCAM axis.

Identification of Biomarkers Associated with the Healing of Chronic Wounds. Addendum

DTIC Science & Technology

2009-06-01

collagenase and 8 degrades fibrin and extracellular matrix. The upregulation in chronic wounds is consistent with the role of ENO1. Also, S100A8 and...and peripheral samples from chronic wounds. S100A8 and S100A9 were upregulated in internal sites of chronic wounds only. The differences in

Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients.

PubMed

D'Amico, F; Granata, M; Skarmoutsou, E; Trovato, C; Lovero, G; Gangemi, P; Longo, V; Pettinato, M; Mazzarino, M C

2018-03-31

The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis.

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes

PubMed Central

Kraakman, Michael J.; Lee, Man K.S.; Al-Sharea, Annas; Dragoljevic, Dragana; Barrett, Tessa J.; Montenont, Emilie; Basu, Debapriya; Heywood, Sarah; Kammoun, Helene L.; Flynn, Michelle; Whillas, Alexandra; Hanssen, Nordin M.J.; Febbraio, Mark A.; Westein, Erik; Chin-Dusting, Jaye; Cooper, Mark E.; Berger, Jeffrey S.; Goldberg, Ira J.; Nagareddy, Prabhakara R.; Murphy, Andrew J.

2017-01-01

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes. PMID:28504650

SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells.

PubMed

Moz, Stefania; Basso, Daniela; Bozzato, Dania; Galozzi, Paola; Navaglia, Filippo; Negm, Ola H; Arrigoni, Giorgio; Zambon, Carlo-Federico; Padoan, Andrea; Tighe, Paddy; Todd, Ian; Franchin, Cinzia; Pedrazzoli, Sergio; Punzi, Leonardo; Plebani, Mario

2016-10-25

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor β1 (TGFβ1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGFβ1 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGFβ1 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/β-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGFβ1 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-κB and PI3K/AKT in response to TGFβ1 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/β-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGFβ1 and S100A8/A9 mainly inhibit NF-κB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner.

SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

PubMed Central

Moz, Stefania; Basso, Daniela; Bozzato, Dania; Galozzi, Paola; Navaglia, Filippo; Negm, Ola H.; Arrigoni, Giorgio; Zambon, Carlo-Federico; Padoan, Andrea; Tighe, Paddy; Todd, Ian; Franchin, Cinzia; Pedrazzoli, Sergio; Punzi, Leonardo; Plebani, Mario

2016-01-01

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor β1 (TGFβ1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGFβ1 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGFβ1 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/β-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGFβ1 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-κB and PI3K/AKT in response to TGFβ1 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/β-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGFβ1 and S100A8/A9 mainly inhibit NF-κB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner. PMID:27655713

Downregulation of Calcium-Binding Protein S100A9 Inhibits Hypopharyngeal Cancer Cell Proliferation and Invasion Ability Through Inactivation of NF-κB Signaling.

PubMed

Wu, Ping; Quan, Huatao; Kang, Jing; He, Jian; Luo, Shi; Xie, Chubo; Xu, Jing; Tang, Yaoyun; Zhao, Suping

2017-11-02

Hypopharyngeal cancer (HPC) frequently presents at an advanced stage and displays early submucosal spread, resulting in a poor prognosis. It is among the worst of all cancers in the head and neck subsites. Therefore, detection of HPC at an earlier stage would be beneficial to patients. In this study, we used differential in-gel electrophoresis (DIGE) and two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics analysis to identify the potential biomarkers for HPC. Among the differential proteins identified, calcium-binding protein S100A9 was overexpressed in HPC tissues compared with normal adjacent tissues, and S100A9 expression in metastatic tissues and advanced tumor tissues was higher than in nonmetastatic tissues and early tumor tissues. S100A9 expression was further confirmed in a large additional cohort. Our data showed that a higher S100A9 level was associated with a poor prognosis for HPC patients, and this may be an independent factor for predicting their prognosis. In addition, S100A9 protein expression was upregulated in human HPC cell lines compared with normal oral cavity epithelia. Knockdown of S100A9 induced significant inhibition of cell growth and their invasive ability. Mechanically, we found that downregulation of S100A9 significantly reduced the expression of NF-κB, phosphorylation of NF-κB and Bcl-2, as well as the expression of MMP7 and MMP2. Restoration of NF-κB expression sufficiently reversed the inhibitory effects on cell proliferation and invasion induced by S100A9 downregulation in vitro and in vivo. In conclusion, for the first time, we have identified S100A9 as an independent prognostic factor for HPC. Inhibiting S100A9 expression would be a potential novel diagnostic biomarker and therapeutic target for HPC treatment.

Impact of S100A8 expression on kidney cancer progression and molecular docking studies for kidney cancer therapeutics.

PubMed

Mirza, Zeenat; Schulten, Hans-Juergen; Farsi, Hasan Ma; Al-Maghrabi, Jaudah A; Gari, Mamdooh A; Chaudhary, Adeel Ga; Abuzenadah, Adel M; Al-Qahtani, Mohammed H; Karim, Sajjad

2014-04-01

The proinflammatory protein S100A8, which is expressed in myeloid cells under physiological conditions, is strongly expressed in human cancer tissues. Its role in tumor cell differentiation and tumor progression is largely unclear and virtually unstudied in kidney cancer. In the present study, we investigated whether S100A8 could be a potential anticancer drug target and therapeutic biomarker for kidney cancer, and the underlying molecular mechanisms by exploiting its interaction profile with drugs. Microarray-based transcriptomics experiments using Affymetrix HuGene 1.0 ST arrays were applied to renal cell carcinoma specimens from Saudi patients for identification of significant genes associated with kidney cancer. In addition, we retrieved selected expression data from the National Center for Biotechnology Information Gene Expression Omnibus database for comparative analysis and confirmation of S100A8 expression. Ingenuity Pathway Analysis (IPA) was used to elucidate significant molecular networks and pathways associated with kidney cancer. The probable polar and non-polar interactions of possible S100A8 inhibitors (aspirin, celecoxib, dexamethasone and diclofenac) were examined by performing molecular docking and binding free energy calculations. Detailed analysis of bound structures and their binding free energies was carried out for S100A8, its known partner (S100A9), and S100A8-S100A9 complex (calprotectin). In our microarray experiments, we identified 1,335 significantly differentially expressed genes, including S100A8, in kidney cancer using a cut-off of p<0.05 and fold-change of 2. Functional analysis of kidney cancer-associated genes showed overexpression of genes involved in cell-cycle progression, DNA repair, cell death, tumor morphology and tissue development. Pathway analysis showed significant disruption of pathways of atherosclerosis signaling, liver X receptor/retinoid X receptor (LXR/RXR) activation, notch signaling, and interleukin-12 (IL-12) signaling. We identified S100A8 as a prospective biomarker for kidney cancer and in silico analysis showed that aspirin, celecoxib, dexamethasone and diclofenac binds to S100A8 and may inhibit downstream signaling in kidney cancer. The present study provides an initial overview of differentially expressed genes in kidney cancer of Saudi Arabian patients using whole-transcript, high-density expression arrays. Our analysis suggests distinct transcriptomic signatures, with significantly high levels of S100A8, and underlying molecular mechanisms contributing to kidney cancer progression. Our docking-based findings shed insight into S100A8 protein as an attractive anticancer target for therapeutic intervention in kidney cancer. To our knowledge, this is the first structure-based docking study for the selected protein targets using the chosen ligands.

Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury.

PubMed

Tan, Xuexian; Zheng, Xiaohe; Huang, Zena; Lin, Jiaqiong; Xie, Chuli; Lin, Yan

2017-01-01

Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target. © 2017 The Author(s). Published by S. Karger AG, Basel.

β-Glucans in food modify colonic microflora by inducing antimicrobial protein, calprotectin, in a Dectin-1-induced-IL-17F-dependent manner.

PubMed

Kamiya, T; Tang, C; Kadoki, M; Oshima, K; Hattori, M; Saijo, S; Adachi, Y; Ohno, N; Iwakura, Y

2018-05-01

Dectin-1 (gene symbol: Clec7a) is a receptor for β-glucans that play an important role for the host defense against fungi. Recently, we showed that Clec7a -/- mice are resistant against dextran sodium sulfate (DSS)-induced colitis because of regulatory T-cell population expansion in the colon. The regulatory T-cell expansion is caused by expansion of commensal Lactobacillus murinus whose growth is suppressed by an antimicrobial protein, calprotectin S100A8/A9. In this report, we showed that S100A8 was mainly produced by mouse colonic epithelial cells. S100A8 was not induced directly by Dectin-1 but by Dectin-1-induced cytokines, especially interleukin-17F (IL-17F), that were produced by several types of innate immune cells including CD11c + /CD11b + myeloid cells in colonic lamina propria. S100A8/A9 heterodimer preferentially suppressed the growth of L. murinus that was increased in both Clec7a -/- and Il17f -/- mice. Furthermore, similar expansion of L. murinus and DSS-colitis resistance were observed in mice fed with β-glucan-free food. These observations suggest that food-derived β-glucans control the specific commensal microbiota via the Dectin-1-IL-17F-calprotectin axis to maintain the intestinal homeostasis.

Ala42S100A8 Ameliorates Psychological-Stress Impaired Cutaneous Wound Healing

PubMed Central

Sroussi, Herve Y.; Williams, Richard L.; Zhang, Qing. L.; Villines, Dana.; Marucha, Phillip. T.

2009-01-01

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation sensitive repellent of human neutrophils in-vitro. Ala42S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild type and ala42S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala42S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing. PMID:19336252

Ala42S100A8 ameliorates psychological-stress impaired cutaneous wound healing.

PubMed

Sroussi, Herve Y; Williams, Richard L; Zhang, Qing L; Villines, Dana; Marucha, Phillip T

2009-08-01

Although wound healing is generally a successful, carefully orchestrated and evolutionary sound process, it can be disregulated by extrinsic factors such as psychological-stress. In the SKH-1 restraint stress model of cutaneous wound healing, the rate of wound closure is approximately 30% slower in stressed mice. Delay in healing is associated with exaggerated acute inflammation and deficient bacterial clearance at the wound site. It has been suggested that wound hypoxia may contribute to the mechanisms of impaired cutaneous wound healing in the mouse SKH-1 model. Optimal healing of a cutaneous wound is a stepwise repair program. In its early phase, an inflammatory oxidative burst generated by neutrophils is observed. About 40% of neutrophils cytosolic protein weight is comprised of two calcium binding proteins S100A8 and S100A9. Our previous work has shown that S100A8 act as an oxidation-sensitive repellent of human neutrophils in-vitro. Ala(42)S100A8, a site-directed mutant protein is resistant to oxidative inhibition and inhibits neutrophil recruitment in-vivo. Accordingly, we tested the hypothesis that S100A8 may ameliorate wound healing in this model. We examined the effect of wild-type and ala(42)S100A8 for their ability to ameliorate wound closure rates. The data indicated that a single local application of ala(42)S100A8 ameliorated the decreased rate of wound closure resulting from stress. This occurred without significantly affecting wound bacterial clearance. Wild-type S100A8 only had a partial beneficial effect on the rate of wound closure. Those findings support further translational studies of S100 based intervention to ameliorate impaired wound healing.

Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23.

PubMed

Yan, Ling; Bowman, Marion A Hofmann

Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNFα, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic dysfunction in hBAC-S100 mice with CKD. We suggest that S100/RAGE-mediated chronic sustained systemic inflammation is linked to pathological cardiac remodeling via direct up regulation of FGF23 in cardiac fibroblasts, thereby providing a new mechanistic understanding for the common association between CKD, diabetes, metabolic syndrome, or hypertension with left ventricular hypertrophy with diastolic dysfunction.

S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy.

PubMed

Kim, W T; Kim, J; Yan, C; Jeong, P; Choi, S Y; Lee, O J; Chae, Y B; Yun, S J; Lee, S C; Kim, W J

2014-05-01

In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC. Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings. Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623-13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy. The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.

S100A9 Interaction with TLR4 Promotes Tumor Growth

PubMed Central

Källberg, Eva; Vogl, Thomas; Liberg, David; Olsson, Anders; Björk, Per; Wikström, Pernilla; Bergh, Anders; Roth, Johannes; Ivars, Fredrik; Leanderson, Tomas

2012-01-01

By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies. PMID:22470535

Elevated levels of cerebrospinal fluid neuron-specific enolase (NSE), but not S100B in major depressive disorder.

PubMed

Schmidt, Frank Martin; Mergl, Roland; Stach, Barbara; Jahn, Ina; Schönknecht, Peter

2015-02-01

Alterations in neuronal and glial integrity are considered to be of pathogenic impact on major depressive disorder (MDD). For MDD, data on cerebrospinal fluid (CSF) levels of neuron-specific enolase (NSE) are lacking and scarce for glial protein S100B. We measured CSF levels of NSE and S100B in 31 patients with MDD and 32 mentally healthy controls using electrochemiluminescence immunoassays (ECLIA). Adjusted means of NSE were significantly elevated in the MDD patients (11.73 ng/ml (9.95-13.52 95% CI) compared to the controls (6.17 ng/ml (4.55-7.78), F = 9.037, P = 0.004. Effect size for adjusted mean group difference of 5.57 ng/ml was found invariably high (Cohen's d = 1.23). Differentiating MDD from controls, a NSE cut-off of 7.94 ng/ml showed sensitivity of 81% (95% CI 63.7-90.8) and specificity of 75% (95% CI 57.9-86.7). Adjusted levels of S100B did not differ significantly between the two groups (1.12 ng/ml (0.77-1.48) in MDD, 0.97 ng/ml (0.64-1.30) in controls). Our results of elevated CSF-NSE levels support neuronal pathology in MDD and the potential use of CSF-NSE as marker in clinical diagnostics. Missing group differences in S100B do not promote a specific glial pathology in depressive disorders.

S100A8 Contributes to Drug Resistance by Promoting Autophagy in Leukemia Cells

PubMed Central

Yang, Minghua; Zeng, Pei; Kang, Rui; Yu, Yan; Yang, Liangchun; Tang, Daolin; Cao, Lizhi

2014-01-01

Autophagy is a double-edged sword in tumorigenesis and plays an important role in the resistance of cancer cells to chemotherapy. S100A8 is a member of the S100 calcium-binding protein family and plays an important role in the drug resistance of leukemia cells, with the mechanisms largely unknown. Here we report that S100A8 contributes to drug resistance in leukemia by promoting autophagy. S100A8 level was elevated in drug resistance leukemia cell lines relative to the nondrug resistant cell lines. Adriamycin and vincristine increased S100A8 in human leukemia cells, accompanied with upregulation of autophagy. RNA interference-mediated knockdown of S100A8 restored the chemosensitivity of leukemia cells, while overexpression of S100A8 enhanced drug resistance and increased autophagy. S100A8 physically interacted with the autophagy regulator BECN1 and was required for the formation of the BECN1-PI3KC3 complex. In addition, interaction between S100A8 and BECN1 relied upon the autophagic complex ULK1-mAtg13. Furthermore, we discovered that exogenous S100A8 induced autophagy, and RAGE was involved in exogenous S100A8-regulated autophagy. Our data demonstrated that S100A8 is involved in the development of chemoresistance in leukemia cells by regulating autophagy, and suggest that S100A8 may be a novel target for improving leukemia therapy. PMID:24820971

Alarmins and Clinical Outcomes After Major Abdominal Surgery-A Prospective Study.

PubMed

Máca, Jan; Burša, Filip; Ševčík, Pavel; Sklienka, Peter; Burda, Michal; Holub, Michal

2017-06-01

Tissue injury causing immune response is an integral part of surgical procedure. Evaluation of the degree of surgical trauma could help to improve postoperative management and determine the clinical outcomes. We analyzed serum levels of alarmins, including S100A5, S100A6, S100A8, S100A9, S100A11, and S100A12; high-mobility group box 1; and heat-shock protein 70, after elective major abdominal surgery (n = 82). Blood samples were collected for three consecutive days after surgery. The goals were to evaluate the relationships among the serum levels of alarmins and selected surgical characteristics and to test potential of alarmins to predict the clinical outcomes. Significant, positive correlations were found for high-mobility group box 1 with the length of surgery, blood loss, and intraoperative fluid intake for all three days of blood sampling. The protein S100A8 serum levels showed positive correlations with intensive care unit length of stay, 28-day and in-hospital mortality. The protein S100A12 serum levels had significant, positive correlations with intensive care unit length of stay, 28-day mortality, and in-hospital mortality. We did not find significant differences in alarmin levels between cancer and noncancer subjects. The high-mobility group box 1 serum levels reflect the degree of surgical injury, whereas proteins S100A8 and S100A12 might be considered good predictors of major abdominal surgery morbidity and mortality.

Potential Role of S100A8 in Cutaneous Squamous Cell Carcinoma Differentiation.

PubMed

Shin, Jung-Min; Chang, In-Kyu; Lee, Young-Ho; Yeo, Min-Kyung; Kim, Jin-Man; Sohn, Kyung-Cheol; Im, Myung; Seo, Young-Joon; Kim, Chang-Deok; Lee, Jeung-Hoon; Lee, Young

2016-04-01

S100A8 is differentially expressed in various cell types and is associated with a number of malignant disorders. S100A8 may affect tumor biology. However, its role in cutaneous squamous cell carcinoma (SCC) is not well established. This study aims to investigate the relationship between S100A8 and cutaneous SCC development. We performed immunohistochemical staining to detect S100A8 expression in facial skin specimens of premalignant actinic keratosis (AK), malignant SCC, and normal tissues. In addition, we utilized postconfluence and high calcium-induced differentiation in a culture system model. Furthermore, we constructed a recombinant adenovirus expressing GFP-tagged S100A8 to investigate the role of S100A8 in SCC cell differentiation. S100A8 was significantly overexpressed in human cutaneous SCC compared to that in normal and AK tissues. S100A8 was gradually upregulated in SCC cells in a post-confluence-induced differentiation model. Overexpression of S100A8 in SCC cells induced by adenoviral transduction led to increased expression levels of differentiation markers, such as loricrin, involucrin, and filaggrin. S100A8 overexpression also increased loricrin and involucrin luciferase activity. S100A8 regulates cutaneous SCC differentiation and induces well-differentiated SCC formation in skin.

Training Extract AFSC 51XX Computer Systems Officer AFPT 90-51X-468.

DTIC Science & Technology

1983-06-01

AUTHOIZATICN TABLES .5! S.S 9.9 2.9 .0 iBM CONDUCT MOBILITY TRAINING ,4 T.$ .0 5.? 10.0 O 20V EVALUATE STUDENT PROUPEGS .5 .7 6.1 5.7 20.0 223 SELECT... ITP TEST PUOCEOURS. PLA&S OR CRITERIA .65 5.1 7.1 1.1 5. 8.8 7.1 13.2 7.7 P 869 APR o1T OP DISAPPROVE CONFIURBTION MANAGEMENT PLANS ICMP) .6s 5.6 9.6

Fort Leavenworth, Fort Leavenworth, Kansas. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F

DTIC Science & Technology

1975-06-20

3 .71S 1 11__r_go/ 891 TD B -Tl 86/ 851 11 ’so__ 941 B-34 6 18 82/ 811 ,[L 9 ___,_ _ __ ___, _ 01 79 .... 11 -l 251 .2 5; : 1 0._ ,_ _ _ _ 7 1 74...FRQECYOFCCREC ( ) 1% 2% 30% TD 0 0 70% 0% 9% HUMIDITY 065 SEP_ 00__0_ 1000.O~ LD 0 99.8 98.6 96.3 91.0 77si 4*6 6.5 2i09 o__ 3I;05 100.0 i00.0 100.0 99.7 99.3...9,619 8.395’ 8.91S S.14a 6.005 5#65513.871 4o0161 .1 .9𔄂l4 .1 .2 HOBI TOA sl6~ l53 61A0268 6.6. 1 *6~ 6410 61881.k3. 6 .a~ ..3.3 1 268, 7354m C USAFETAC FOR 0.89.5 (OLD~ JUL 64 fj . 777 -X,.-

Day/night changes in serum S100B protein concentrations in acute paranoid schizophrenia.

PubMed

Morera-Fumero, Armando L; Díaz-Mesa, Estefanía; Abreu-Gonzalez, Pedro; Fernandez-Lopez, Lourdes; Cejas-Mendez, Maria Del Rosario

2017-04-03

There are day/night and seasonal changes in biological markers such as melatonin and cortisol. Controversial changes in serum S100B protein levels have been described in schizophrenia. We aim studying whether serum S100B levels present day/night variations in schizophrenia patients and whether S100B levels are related to psychopathology. Sixty-five paranoid schizophrenic inpatients participated in the study. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and discharge. Blood was drawn at 12:00 (midday) and 00:00 (midnight) hours at admission and discharge. Sixty-five healthy subjects matched by age, gender and season acted as control group. At admission and discharge patients had significantly higher serum S100B concentrations at midday and midnight than healthy subjects. At admission, patients showed a day/night variation of S100B levels, with higher S100B levels at 12:00 than at 00:00h (143.7±26.3pg/ml vs. 96.9±16.6pg/ml). This day/night difference was not present in the control group. Midday and midnight S100B at admission decreased when compared to S100B at discharge (midday, 143.7±26.3 vs. 83.0±12, midnight 96.9±16.6 vs. 68.6±14.5). There was a positive correlation between the PANSS positive subscale and S100B concentrations at admission. This correlation was not present at discharge. acute paranoid schizophrenia inpatients present a day/night change of S100B serum levels at admission that disappears at discharge. The correlation between serum S100B concentrations and the PANSS positive scores at admission as well as the decrease of S100B at discharge may be interpreted as an acute biological response to the clinical state of the patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Association of increased S100A8 serum protein with early pregnancy loss.

PubMed

Nair, Rohini R; Khanna, Anuradha; Singh, Kiran

2015-02-01

The contribution of systemic S100A8 protein in menstrual cycle, pregnancy, and early pregnancy loss (EPL) is not known. Altered expression of S100A8 in maternal decidua is associated with recurrent early pregnancy loss. The objective of this study was to investigate the systemic level of S100A8 in different phases of menstrual cycle, different trimester of pregnancy, and in EPL. Level of S100A8 was investigated in serum samples of the subjects through enzyme-linked immunosorbent assay (ELISA). S100A8 levels were elevated during proliferative phase of menstrual cycle. We found no statistical difference in S100A8 level in different trimester of pregnancy. S100A8 level was found to be significantly elevated in patients with EPL. This is the first study evaluating the systemic level of S100A8 predicting its role during menstrual cycle and pregnancy. It opens a new perspective in which S100A8 can be used as a prognostic marker for EPL. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Serum S100 calcium binding protein A4 improves the diagnostic accuracy of transient elastography for assessing liver fibrosis in hepatitis B.

PubMed

Yan, Li-Bo; Zhang, Qing-Bo; Zhu, Xia; He, Min; Tang, Hong

2018-02-01

The diagnostic performance of Fibroscan might be improved when combined with other serum fibrosis related markers. Previous study has demonstrated that S100A4 expression is associated with liver fibrosis in humans with hepatitis. This study aimed to clarify diagnostic accuracy of serum S100A4 levels for significant liver fibrosis in patients with chronic hepatitis B (CHB), and develop a combined algorithm of liver stiffness measurement (LSM) and S100A4 to predict significant liver fibrosis in CHB. One hundred and seventy-five CHB patients who had performed liver biopsy were consecutively included. We evaluated serum S100A4 levels, LSM values and other clinically-approved fibrosis scores. Serum S100A4 level was higher in CHB patients with significant fibrosis, compared to those without [199.58 (33.31-1971.96) vs. 107.15 (2.10-1038.94), P<0.001]. Using receiver-operating characteristic (ROC) analyses, the area under the curves (AUC), sensitivity, specificity and accuracy of S100A4 were found to be 0.749, 62.7%, 75.9% and 0.70 for significant fibrosis (≥Stage 2), respectively. Although not superior to LSM, these results were better than the fibrosis index based on the 4 factor (FIB-4) and the aspartate aminotransferase-to-platelet ratio index (APRI) for significant fibrosis detection. An algorithm consisting of S100A4 and LSM was derived. The AUC, sensitivity, specificity and accuracy of model based on serum S100A4 level and LSM were 0.866, 86.6%, 77.8% and 0.79 for significant fibrosis detection, superior to those based on LSM alone (0.834, 76.1%, 80.7% and 0.76, P=0.041). Serum S100A4 level was identified as a fibrosis marker of liver fibrosis in patients with CHB. Combining serum S100A4 with LSM improved the accuracy of transient elastography for hepatitis B significant fibrosis detection. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Purification, crystallization and preliminary X-ray diffraction of human S100A15

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boeshans, Karen M.; Wolf, Ronald; Voscopoulos, Christopher

2006-05-01

S100 proteins are differentially expressed during epithelial cell maturation, tumorigenesis and inflammation. The novel human S100A15 protein has been cloned, expressed, purified and crystallized in two crystal forms, a triclinic and a monoclinic form, which diffract to 1.7 and 2.0 Å, respectively. Human S100A15 is a novel member of the S100 family of EF-hand calcium-binding proteins and was recently identified in psoriasis, where it is significantly upregulated in lesional skin. The protein is implicated as an effector in calcium-mediated signal transduction pathways. Although its biological function is unclear, the association of the 11.2 kDa S100A15 with psoriasis suggests that itmore » contributes to the pathogenesis of the disease and could provide a molecular target for therapy. To provide insight into the function of S100A15, the protein was crystallized to visualize its structure and to further the understanding of how the many similar calcium-binding mediator proteins in the cell distinguish their cognate target molecules. The S100A15 protein has been cloned, expressed and purified to homogeneity and produced two crystal forms. Crystals of form I are triclinic, with unit-cell parameters a = 33.5, b = 44.3, c = 44.8 Å, α = 71.2, β = 68.1, γ = 67.8° and an estimated two molecules in the asymmetric unit, and diffract to 1.7 Å resolution. Crystals of form II are monoclinic, with unit-cell parameters a = 82.1, b = 33.6, c = 52.2 Å, β = 128.2° and an estimated one molecule in the asymmetric unit, and diffract to 2.0 Å resolution. This structural analysis of the human S100A15 will further aid in the phylogenic comparison between the other members of the S100 protein family, especially the highly homologous paralog S100A7.« less

Potential Role of S100A8 in Cutaneous Squamous Cell Carcinoma Differentiation

PubMed Central

Shin, Jung-Min; Chang, In-Kyu; Lee, Young-Ho; Yeo, Min-Kyung; Kim, Jin-Man; Sohn, Kyung-Cheol; Im, Myung; Seo, Young-Joon; Kim, Chang-Deok; Lee, Jeung-Hoon

2016-01-01

Background S100A8 is differentially expressed in various cell types and is associated with a number of malignant disorders. S100A8 may affect tumor biology. However, its role in cutaneous squamous cell carcinoma (SCC) is not well established. Objective This study aims to investigate the relationship between S100A8 and cutaneous SCC development. Methods We performed immunohistochemical staining to detect S100A8 expression in facial skin specimens of premalignant actinic keratosis (AK), malignant SCC, and normal tissues. In addition, we utilized postconfluence and high calcium-induced differentiation in a culture system model. Furthermore, we constructed a recombinant adenovirus expressing GFP-tagged S100A8 to investigate the role of S100A8 in SCC cell differentiation. Results S100A8 was significantly overexpressed in human cutaneous SCC compared to that in normal and AK tissues. S100A8 was gradually upregulated in SCC cells in a post-confluence-induced differentiation model. Overexpression of S100A8 in SCC cells induced by adenoviral transduction led to increased expression levels of differentiation markers, such as loricrin, involucrin, and filaggrin. S100A8 overexpression also increased loricrin and involucrin luciferase activity. Conclusion S100A8 regulates cutaneous SCC differentiation and induces well-differentiated SCC formation in skin. PMID:27081264

[Protective effect of erythropoietin on brain tissue in rats with cardiopulmonary resuscitation after asphyxia].

PubMed

Chunling, Ji; Hourong, Zhou; Xiulin, Yang; Qian, Zhang; Yuhui, Yuan; Jia, Huang

2015-12-01

To study the protective effect of erythropoietin (EPO) on brain tissue with cardiac arrest-cardiopulmonary resuscitation (CA-CPR) and its mechanism. 120 male Sprague-Dawley (SD) rats were randomly divided into three groups (each n = 40), namely: sham group, routine chest compression group, and conventional chest compression + EPO group (EPO group). The rats in each group were subdivided into CA and 6, 12, 24, 48 hours after restoration of spontaneous circulation (ROSC) five subgroups (each n = 8). The model of CA was reproduced according to the Hendrickx classical asphyxia method followed by routine chest compression, and the rats in sham group only underwent anesthesia, tracheostomy intubation and venous-puncture without asphyxia and CPR. The rats in EPO group were given the routine chest compression + EPO 5 kU/kg (2 mL/kg) after CA. Blood sample was collected at different time points of intervention for the determination the content of serum S100 β protein by enzyme linked immunosorbent assay (ELISA). All the rats were sacrificed at the corresponding time points, and the hippocampus was harvested for the calculation of the number of S100 β protein positive cells, and to examine the pathological changes and their scores at 24 hours after ROSC by light microscopy. With prolongation of ROSC time, the serum levels of S100 β protein (µg/L) in the routine chose compression group and the EPO group were significantly elevated, peaking at 24 hours (compared with CA: 305.7 ± 29.2 vs. 44.4 ± 6.2 in routine chest compression group, and 276.7 ± 28.9 vs. 44.7 ± 5.6 in the EPO group, both P < 0.05), followed by a fall. The levels of S100 β protein at each time point after ROSC in EPO group were significanthy lower than those of the routine chest compression group (83.2 ± 7.5 vs. 114.3 ± 15.3 at 6 hours, 123.9 ± 20.2 vs. 184.9 ± 22.2 at 12 hours, 276.7 ± 28.9 vs. 305.7 ± 29.2 at 24 hours, 256.3 ± 26.6 vs. 283.2 ± 23.6 at 48 hours, all P < 0.05). With the prolongation of ROSC time, the S100 β protein positive cell number in brain (cells/HP) in the routine chest compression group and the EPO group was significantly increased, peaking at 24 hours (compared with CA: 14.3 ± 2.2 vs. 6.7 ± 0.7 in the routine chest compression group, 11.3 ± 1.3 vs. 6.8 ± 0.9 in the EPO group, both P < 0.05), then it began to fall. The S100 β protein positive cell number in brain at each time point after ROSC in the EPO group was significantly lower than that of the routine chest compression group (7.0 ± 0.9 vs. 7.9 ± 1.9 at 6 hours, 8.4 ± 1.1 vs. 10.2 ± 2.2 at 12 hours, 11.3 ± 1.3 vs. 14.3 ± 2.2 at 24 hours, 8.3 ± 0.8 vs. 10.8 ± 2.0 at 48 hours, all P < 0.05). Under the light microscope, a serious brain cortex injury was found after reproduction of the model, and the degree of injury was reduced after EPO intervention. The pathological score at 24 hours after ROSC in EPO group was lower than that of routine chest compression group (3.83 ± 0.73 vs. 4.17 ± 0.75, P < 0.05). The S100 β protein level in serum and brain tissue was increased early in asphyxia CA-CPR rats. EPO intervention can reduce the expression of S100 protein and reduce the degree of brain injury.

S100A7 promotes the migration, invasion and metastasis of human cervical cancer cells through epithelial–mesenchymal transition

PubMed Central

Ma, Jianlin; Wu, Xiaowei; Liu, Zhihua; Chen, Hongyan; Cui, Zhumei

2017-01-01

S100A7 is an EF-hand calcium-binding protein that has been suggested to be implicated in cell proliferation, migration, invasion and tumor metastasis. However, its role in cervical cancer has not yet been fully clarified. The present study used immunohistochemistry analysis of S100A7 in clinical specimens of cervical cancer to show that S100A7 expression was significantly upregulated in cervical cancer tissues compared with normal cervical tissues and S100A7 expression in high grade cervical intraepithelial neoplasm (CIN) was significantly higher than cervical cancer. Statistical analysis showed that S100A7 expression was associated with tumor grade (P <0.01) and lymph node metastasis (P <0.05). Functional studies showed that overexpression of S100A7 in cervical cancer cells promoted migration, invasion and metastasis of cervical cancer cells without influencing cell proliferation. Furthermore, S100A7 was found to be secreted into the conditioned media and extracellular S100A7 enhanced cell migration and invasion. Mechanistically, S100A7 bound to RAGE and activated ERK signaling pathway. And S100A7 enhanced cell mesenchymal properties and induced epithelial–mesenchymal transition. In summary, these data reveal a crucial role for S100A7 in regulating cell migration, invasion, metastasis and EMT of cervical cancer and suggest that targeting S100A7 may offer a new targeted strategy for cervical cancer. PMID:28212564

S100A7 promotes the migration, invasion and metastasis of human cervical cancer cells through epithelial-mesenchymal transition.

PubMed

Tian, Tian; Li, Xukun; Hua, Zhen; Ma, Jianlin; Wu, Xiaowei; Liu, Zhihua; Chen, Hongyan; Cui, Zhumei

2017-04-11

S100A7 is an EF-hand calcium-binding protein that has been suggested to be implicated in cell proliferation, migration, invasion and tumor metastasis. However, its role in cervical cancer has not yet been fully clarified. The present study used immunohistochemistry analysis of S100A7 in clinical specimens of cervical cancer to show that S100A7 expression was significantly upregulated in cervical cancer tissues compared with normal cervical tissues and S100A7 expression in high grade cervical intraepithelial neoplasm (CIN) was significantly higher than cervical cancer. Statistical analysis showed that S100A7 expression was associated with tumor grade (P <0.01) and lymph node metastasis (P <0.05). Functional studies showed that overexpression of S100A7 in cervical cancer cells promoted migration, invasion and metastasis of cervical cancer cells without influencing cell proliferation. Furthermore, S100A7 was found to be secreted into the conditioned media and extracellular S100A7 enhanced cell migration and invasion. Mechanistically, S100A7 bound to RAGE and activated ERK signaling pathway. And S100A7 enhanced cell mesenchymal properties and induced epithelial-mesenchymal transition. In summary, these data reveal a crucial role for S100A7 in regulating cell migration, invasion, metastasis and EMT of cervical cancer and suggest that targeting S100A7 may offer a new targeted strategy for cervical cancer.

S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle.

PubMed

Xu, Yu-Dong; Wang, Yu; Yin, Lei-Miao; Park, Gyoung-Hee; Ulloa, Luis; Yang, Yong-Qing

2017-02-26

Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

S100A8+ stroma cells predict a good prognosis and inhibit aggressiveness in colorectal carcinoma.

PubMed

Li, Si; Xu, Fangying; Li, Hui; Zhang, Jing; Zhong, Anjing; Huang, Bin; Lai, Maode

2017-01-01

Gene microarray and bioinformatic analysis showed that S100A8 was more abundant in the stroma surrounding tumor buddings (TBs) than in the stroma surrounding primary tumor cells in colorectal carcinomas. Here, S100A8 + cells in 419 colorectal carcinoma samples were stained by immunohistochemistry and counted using Image-pro plus 6.0. TBs were also counted and biomarkers associated with the epithelial-mesenchymal transition and apoptosis were assessed by immunohistochemistry. We evaluated the association between S100A8 + cells and clinico-pathological variables as well as survival. Migration and invasion as well as biomarkers of the epithelial-mesenchymal transition and apoptosis were tested in CRC cells, treated with graded concentrations of recombinant human S100A8 protein. We found that the density of S100A8 + cells in the tumor invasive front (S100A8 + TIF ) clearly distinguished patients with 5-y survival from those who did not survive ( p = 0.01). The S100A8 + -associated tumor budding (SATB) index determined by the S100A8 + TIF and TB was an independent predictor of overall survival ( p = 0.001) other than the S100A8 + TIF or TB alone. Migration and invasion properties of CRC cells were inhibited by recombinant human S100A8 treatment. The particular S100A8 + cells in the stroma were associated with important biomarkers of the epithelial-mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2). In conclusion, S100A8 + cells in the stroma predict a good prognosis in colorectal carcinoma. An index combining S100A8 + cells and TB independently predicts survival. Recombinant human S100A8 inhibited CRC cell migration and invasion, which was involved in epithelial-mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2).

S100A8+ stroma cells predict a good prognosis and inhibit aggressiveness in colorectal carcinoma

PubMed Central

Li, Si; Xu, Fangying; Li, Hui; Zhang, Jing; Zhong, Anjing; Huang, Bin; Lai, Maode

2017-01-01

ABSTRACT Gene microarray and bioinformatic analysis showed that S100A8 was more abundant in the stroma surrounding tumor buddings (TBs) than in the stroma surrounding primary tumor cells in colorectal carcinomas. Here, S100A8+ cells in 419 colorectal carcinoma samples were stained by immunohistochemistry and counted using Image-pro plus 6.0. TBs were also counted and biomarkers associated with the epithelial–mesenchymal transition and apoptosis were assessed by immunohistochemistry. We evaluated the association between S100A8+ cells and clinico-pathological variables as well as survival. Migration and invasion as well as biomarkers of the epithelial–mesenchymal transition and apoptosis were tested in CRC cells, treated with graded concentrations of recombinant human S100A8 protein. We found that the density of S100A8+ cells in the tumor invasive front (S100A8+TIF) clearly distinguished patients with 5-y survival from those who did not survive (p = 0.01). The S100A8+-associated tumor budding (SATB) index determined by the S100A8+TIF and TB was an independent predictor of overall survival (p = 0.001) other than the S100A8+TIF or TB alone. Migration and invasion properties of CRC cells were inhibited by recombinant human S100A8 treatment. The particular S100A8+ cells in the stroma were associated with important biomarkers of the epithelial–mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2). In conclusion, S100A8+ cells in the stroma predict a good prognosis in colorectal carcinoma. An index combining S100A8+ cells and TB independently predicts survival. Recombinant human S100A8 inhibited CRC cell migration and invasion, which was involved in epithelial–mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2). PMID:28197382

Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes.

PubMed

Cluzeau, Thomas; McGraw, Kathy L; Irvine, Brittany; Masala, Erico; Ades, Lionel; Basiorka, Ashley A; Maciejewski, Jaroslaw; Auberger, Patrick; Wei, Sheng; Fenaux, Pierre; Santini, Valeria; List, Alan

2017-12-01

Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate in vitro erythropoietin elaboration. Serum samples collected from 311 patients with myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to lenalidomide therapy). Serum concentrations of S100A9, S100A8, tumor necrosis factor-α, interleukin-1β and erythropoietin were analyzed by enzyme-linked immunosorbent assay. Using erythropoietin-producing HepG2 cells, we show that S100A9, tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of erythropoietin. Pre-incubation with lenalidomide significantly diminished suppression of erythropoietin production by S100A9 or tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with myelodysplastic syndromes, lenalidomide significantly reduced steady-state S100A9 generation ( P =0.01) and lipopolysaccharide-induced tumor necrosis factor-α elaboration ( P =0.002). Enzyme-linked immunosorbent assays of serum from 316 patients with non-del(5q) myelodysplastic syndromes demonstrated a significant inverse correlation between tumor necrosis factor-α and erythropoietin concentrations ( P =0.006), and between S100A9 and erythropoietin ( P =0.01). Moreover, baseline serum tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents ( P =0.03), whereas lenalidomide responders had significantly lower tumor necrosis factor-α and higher S100A9 serum concentrations ( P =0.03). These findings suggest that S100A9 and its nuclear factor-κB transcriptional target, tumor necrosis factor-α, directly suppress erythropoietin elaboration in myelodysplastic syndromes. These cytokines may serve as rational biomarkers of response to lenalidomide and erythroid-stimulating agent treatments. Therapeutic strategies that either neutralize or suppress S100A9 may improve erythropoiesis in patients with myelodysplastic syndromes. Copyright© 2017 Ferrata Storti Foundation.

Subject-specific increases in serum S-100B distinguish sports-related concussion from sports-related exertion.

PubMed

Kiechle, Karin; Bazarian, Jeffrey J; Merchant-Borna, Kian; Stoecklein, Veit; Rozen, Eric; Blyth, Brian; Huang, Jason H; Dayawansa, Samantha; Kanz, Karl; Biberthaler, Peter

2014-01-01

The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury. To compare subject-specific changes in the astroglial protein, S100B, before and after SRC among collegiate and semi-professional contact sport athletes, and compare these changes to differences in S100B before and after non-contact exertion. Longitudinal cohort study. From 2009-2011, we performed a prospective study of athletes from Munich, Germany, and Rochester, New York, USA. Serum S100B was measured in all SRC athletes at pre-season baseline, within 3 hours of injury, and at days 2, 3 and 7 post-SRC. Among a subset of athletes, S100B was measured after non-contact exertion but before injury. All samples were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels. Forty-six athletes (30 Munich, 16 Rochester) underwent baseline testing. Thirty underwent additional post-exertion S100B testing. Twenty-two athletes (16 Rochester, 6 Munich) sustained a SRC, and 17 had S100B testing within 3 hours post-injury. The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline (0.099±0.008 µg/L vs. 0.058±0.006 µg/L, p = 0.0002). Mean post-exertion S100B was not significantly different than the preseason baseline. S100B levels at post-injury days 2, 3 and 7 were significantly lower than the 3-hour level, and not different than baseline. Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC (AUC 0.772 and 0.904, respectively). A 3-hour post-concussion S100B >0.122 µg/L and a proportional S100B increase of >45.9% over baseline were both 96.7% specific for SRC. Relative and absolute increases in serum S100B can accurately distinguish SRC from sports-related exertion, and may be a useful adjunct to the diagnosis of SRC.

Exogenous S100A8 protein inhibits PDGF-induced migration of airway smooth muscle cells in a RAGE-dependent manner.

PubMed

Xu, Yu-Dong; Wei, Ying; Wang, Yu; Yin, Lei-Miao; Park, Gyoung-Hee; Liu, Yan-Yan; Yang, Yong-Qing

2016-03-25

S100A8 is an important member of the S100 protein family, which is involved in intracellular and extracellular regulatory activities. We previously reported that the S100A8 protein was differentially expressed in the asthmatic respiratory tracts. To understand the potential role of S100A8 in asthma, we investigated the effect of recombinant S100A8 protein on the platelet-derived growth factor (PDGF)-induced migration of airway smooth muscle cells (ASMCs) and the underlying molecular mechanism by using multiple methods, such as impedance-based xCELLigence migration assay, transwell migration assays and wound-healing assays. We found that exogenous S100A8 protein significantly inhibited PDGF-induced ASMC migration. Furthermore, the migration inhibition effect of S100A8 was blocked by neutralizing antibody against the receptor for advanced glycation end-products (RAGE), a potential receptor for the S100A8 protein. These findings provide direct evidence that exogenous S100A8 protein inhibits the PDGF-induced migration of ASMCs through the membrane receptor RAGE. Our study highlights a novel role of S100A8 as a potential means of counteracting airway remodeling in chronic airway diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production

PubMed Central

Fang, Wei-Yu; Chen, Yi-Wen; Hsiao, Jenn-Ren; Liu, Chiang-Shin; Kuo, Yi-Zih; Wang, Yi-Ching; Chang, Kung-Chao; Tsai, Sen-Tien; Chang, Mei-Zhu; Lin, Siao-Han; Wu, Li-Wha

2015-01-01

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis. PMID:26315114

Elevated S100A9 expression in tumor stroma functions as an early recurrence marker for early-stage oral cancer patients through increased tumor cell invasion, angiogenesis, macrophage recruitment and interleukin-6 production.

PubMed

Fang, Wei-Yu; Chen, Yi-Wen; Hsiao, Jenn-Ren; Liu, Chiang-Shin; Kuo, Yi-Zih; Wang, Yi-Ching; Chang, Kung-Chao; Tsai, Sen-Tien; Chang, Mei-Zhu; Lin, Siao-Han; Wu, Li-Wha

2015-09-29

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.

Contraction velocity influence the magnitude and etiology of neuromuscular fatigue during repeated maximal contractions.

PubMed

Morel, B; Clémençon, M; Rota, S; Millet, G Y; Bishop, D J; Brosseau, O; Rouffet, D M; Hautier, C A

2015-10-01

This study aimed to compare the magnitude and etiology of neuromuscular fatigue during maximal repeated contractions performed in two contraction modes (concentric vs isometric) and at two contraction velocities (30/s vs 240°/s). Eleven lower limb-trained males performed 20 sets of maximal contractions at three different angular velocities: 0°/s (KE0), 30/s (KE30), and 240°/s (KE240). Cumulated work, number of contraction, duty cycle, and contraction time were controlled. Torque, superimposed and resting twitches, as well as gas exchange, were analyzed. Increasing contraction velocity was associated with greater maximal voluntary torque loss (KE0: -9.8 ± 3.9%; KE30: -16.4 ± 8.5%; KE240: -32.6 ± 6.3%; P < 0.05). Interestingly, the torque decrease was similar for a given cumulated work. Compared with KE0, KE240 generated a greater evoked torque loss (Db100: -24.3 ± 5.3% vs -5.9 ± 6.9%; P < 0.001), a higher O2 consumption (23.7 ± 6.4 mL/min/kg vs 15.7 ± 3.8 mL/min/kg; P < 0.001), but a lower voluntary activation (VA) loss (-4.3 ± 1.6% vs -11.2 ± 4.9%; P < 0.001). The neuromuscular perturbations were intermediate for KE30 (Db100: -10.0 ± 6.8%; VA: -7.2 ± 2.8%). Although the amount of mechanical work cumulated strongly determined the magnitude of torque decrease, the contraction velocity and mode influenced the origin of the neuromuscular fatigue. The metabolic stress and peripheral fatigue increased but reduction of VA is attenuated when the contraction velocity increased from 0°/s to 240°/s. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

S100 chemokines mediate bookmarking of premetastatic niches

PubMed Central

Rafii, Shahin; Lyden, David

2010-01-01

Primary tumours release soluble factors, including VEGF-A, TGFβ and TNFα, which induce expression of the chemokines S100A8 and S100A9 in the myeloid and endothelial cells within the lung before tumour metastasis. These chemokine-activated premetastatic niches support adhesion and invasion of disseminating malignant cells, thereby establishing a fertile habitat for metastatic tumours. PMID:17139281

Increased expression of TLR9 associated with pro-inflammatory S100A8 and IL-8 in diabetic wounds could lead to unresolved inflammation in type 2 diabetes mellitus (T2DM) cases with impaired wound healing.

PubMed

Singh, Kanhaiya; Agrawal, Neeraj K; Gupta, Sanjeev K; Sinha, Pratima; Singh, Kiran

2016-01-01

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which causes a chain of abrupt biochemical and physiological changes. Immune dys-regulation is the hallmark of T2DM that could contribute to prolonged inflammation causing transformation of wounds into non-healing chronic ulcers. Toll like receptor -9 (TLR9) is a major receptor involved in innate immune regulation. TLR9 activation induces release of pro-inflammatory molecules like S100A8 and interleukin-8 (IL-8) by myeloid cells causing migration of myeloid cells to the site of inflammation. We hypothesized that pro-inflammatory S100A8 and IL-8 proteins could cause persistent inflammation in chronic wounds like diabetic foot ulcer (DFU) and may contribute to impaired wound healing in T2DM patients. Expression of TLR9 and its downstream effector molecules S100A8, and IL-8 were analyzed in chronic diabetic wound and non-diabetic control wound tissue samples by semiquantitative reverse transcriptase - polymerase chain reaction (RT-PCR), quantitative RT-PCR, western blot and immunofluorescence. CD11b(+)CD33(+) myeloid cells were analyzed by flow cytometry. TLR9 message and protein were higher in diabetic wounds compared to control wounds (p=0.03, t=2.21 for TLR9 mRNA; p=<0.001, t=4.21 for TLR9 protein). TLR9 down-stream effector molecules S100A8 and IL-8 were also increased in diabetic wounds (p=0.003, t=3.1 for S100A8 mRNA; p=0.04, t=2.04 for IL-8). CD11b(+) CD33(+) myeloid cells were decreased in T2DM as compared to non-diabetic controls (p=0.001, t=3.6). DFU subjects had higher levels of CD11b(+) CD33(+) myeloid cells as compared to non-DFU T2DM control (p=0.003, t=2.8). Infection in the wound microenvironment could be the cause of increase in CD11b(+)CD33(+) myeloid cells in DFU (p=0.03, t=2.5). The up-regulation of myeloid cell-derived pro-inflammatory molecules S100A8 and IL-8 in combination with lower levels of CD11b(+) CD33(+) myeloid cells may cause the impairment of wound healing in T2DM subjects leading to chronic ulcers. Copyright © 2016 Elsevier Inc. All rights reserved.

VO2 Kinetics in All-out Arm Stroke, Leg Kick and Whole Stroke Front Crawl 100-m Swimming.

PubMed

Rodríguez, F A; Lätt, E; Jürimäe, J; Maestu, J; Purge, P; Rämson, R; Haljaste, K; Keskinen, K L; Jürimäe, T

2016-03-01

The VO2 response to extreme-intensity exercise and its relationship with sports performance are largely unexplored. This study investigated the pulmonary VO2 kinetics during all-out 100-m front crawl whole stroke swimming (S), arm stroke (A) and leg kick (L). 26 male and 10 female competitive swimmers performed an all-out S trial followed by A and L of equal duration in random order. Breath-by-breath VO2 was measured using a snorkel attached to a portable gas analyzer. Mean (±SD) primary component parameters and peak blood lactate (Lapeak) during S, A, and L were, respectively: time delay (s), 14.2 ± 4.7, 14.3 ± 4.5, 15.6 ± 5.1; amplitude (ml·kg(-1)·min(-1)), 46.8 ± 6.1, 37.3 ± 6.9, 41.0 ± 4.7; time constant (τ, s): 9.2 ± 3.2, 12.4 ± 4.7, 10.1 ± 3.2; Lapeak (mmol·l(-1)), 6.8 ± 3.1, 6.3 ± 2.5, 7.9 ± 2.8. During A and L respectively, 80% and 87% of amplitude in S was reached, whereas A+L were 68% greater than in S. 100-m performance was associated to shorter cardiodynamic phase and greater VO2 amplitude and Lapeak (accounting up to 61% of performance variance), but not to τ. We conclude that (i) VO2 gain was proportional to exercise intensity and muscle mass involved, (ii) kicking is metabolically less efficient, and (iii) the main limiting factor of peak VO2 appears to be O2 delivery and not muscle extraction. © Georg Thieme Verlag KG Stuttgart · New York.

46 CFR 282.22 - Maintenance (upkeep) and repairs.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) (Percent) Japan Japan 85 36.21 30.78 U.S 15 0 0 100 30.78 23.4 7.20 Norway Norway 15 44.72 6.71 Netherlands 20 43.23 8.65 Japan 45 36.21 16.29 U.S 20 0 0 100 31.65 31.1 9.84 United Kingdom U.K 80 19.00 15.20...

The cyst wall of Colpoda steinii. A substance rich in glutamic acid residues

PubMed Central

Tibbs, J.

1966-01-01

1. The cyst wall of Colpoda steinii has been isolated and its chemical nature examined. It had a nitrogen content 13·9±0·2% (s.d.) and an ash 8·6±1·6% (s.d.). After lipid and hot-acid extraction there was a variable residual phosphorus of 0·19–0·64%. The protein nature, indicated by infrared and ultraviolet absorption, was confirmed when 100μg. of hydrolysed wall gave a ninhydrin colour equivalent to that given by 0·88–1·01μmoles of glycine. Hexosamine, hexose, pentose, lipid and dipicolinic acid were absent. 2. Paper chromatography of hydrolysates, besides showing the presence of the usual protein amino acids and three unidentified ninhydrin-reacting spots, indicated the presence of large amounts of glutamic acid. Estimated by chromatography, the amount present was 52·9±0·6 (s.d.) g./100g. of ash-free wall; manometric estimation of l-glutamic acid with l-glutamate 1-carboxy-lyase gave 46·5±0·9 (s.d.) g./100g. 3. Free carboxyl groups were estimated by titration as 0·159±0·011 (s.d.) mole/100g. and those present as amide as 0·154±0·004 (s.d.) mole/100g., and the total was compared with the dicarboxylic acid content 0·360±0·010 (s.d.) mole/100g. 4. After treatment with 98% formic acid 25–30% of the wall material could be extracted by 0·05m-sodium carbonate solution (extract 1); after treatment of the residue with performic acid a further 62–63% based on the original weight could be extracted by 0·05m-sodium carbonate (extract 2). 5. The average values found for the glutamic acid contents were 21·7g./100g. for extract 1 and 58·0g./100g. for extract 2. The cysteic acid content of whole oxidized wall was about 5·8g./100g. and of extract 2 also about 5·8g./100g. The glutamic acid and cysteic acid contents of the final residue were also investigated. 6. The significance of these extraction experiments in relation to the wall structure is discussed. ImagesPlate 1. PMID:4957913

S100β Levels in CSF of Nonambulatory Dogs with Intervertebral Disk Disease Treated with Electroacupuncture

PubMed Central

Fonseca Pinto, Ana Carolina Brandão Campos; Cortopassi, Silvia Renata Gaido; Marvulle, Valdecir; Ruivo Maximino, Jessica; Chadi, Gerson

2013-01-01

The aim of the study was to investigate S100β levels in the cerebrospinal fluid of nonambulatory dogs with intervertebral disk disease treated with electroacupuncture: 10 dogs with thoracolumbar disk extrusion graded 3 to 5 (EA group) and 7 dogs without neurologic dysfunction (control group). All dogs regained ambulation. S100β was detected by Western blot analysis where EA group dogs were evaluated at two time points (M1 = before EA and M2 = when the dogs return ambulation) and at one time point from control group. In EA group dogs M1-S100β levels were significantly higher than in control group. EA group dogs were divided into subgroups A (n = 7—early motor recovery; 6.7 ± 7.8 days) and B (n = 3—late motor recovery; 76 ± 17.0 days). M1-S100β levels were similar between subgroups A and B. However, M2-S100β levels were significantly higher in subgroup B than in subgroup A. An elevated S100β levels were observed in dogs with late motor recovery. S100β may be associated with neuroplasticity following spinal cord injuries with intervertebral disk extrusion. Further studies with larger numbers of subjects and control group with affected dogs are necessary to investigate the relationship between neurotrophic factors and electroacupuncture stimulation. PMID:26464906

Evaluation of Postmortem Cerebrospinal Fluid S100B Protein and Serotonin Levels: Comparison of Suicidal Versus Nonsuicidal Deaths in Konya, Turkey.

PubMed

Dogan, Kamil Hakan; Unaldi, Mustafa; Demirci, Serafettin

2016-09-01

Although suicide is a preventable public health problem, objective assays for suicide risk are limited. In this study, it was aimed to determine levels of S100B protein and serotonin as a marker for risk of suicide. S100B protein and serotonin levels were investigated with ELISA method in the cerebrospinal fluid (CSF) in medicolegal autopsy cases, including those of suicide cases (n = 32) and nonsuicide cases (n = 56). The CSF S100B levels were higher (9.3 ± 2.9 ng/mL vs. 5.4 ± 2.0 ng/mL), and serotonin levels were lower (10.4 ± 4.9 ng/mL vs. 19.0 ± 5.7 ng/mL) in suicide group than nonsuicide group (p < 0.05). There was no correlation between S100B protein and serotonin levels with gender, age groups, postmortem interval, and cause of death. It is concluded that both S100B protein and serotonin in CSF may be useful for determination of suicide risk. © 2016 American Academy of Forensic Sciences.

Effects of downregulation of S100A8 protein expression on cell cycle and apoptosis of fibroblasts derived from hypertrophic scars.

PubMed

Yaundong, Lv; Dongyan, Wang; Lijun, Hao; Zhibo, Xiao

2014-01-01

Uncontrolled growth and lack of apoptosis in fibroblasts derived from a hypertrophic scar play an important role in pathology. The authors explore the contribution of S100A8 overexpression to the phenotype of cells and discuss how the downregulation of S100A8 could inhibit the growth and induce apoptosis of fibroblasts derived from hypertrophic scars. Fibroblasts were harvested from hypertrophic scar tissue in 8 patients treated with small interfering RNA against S100A8 in an in vitro culture. The effects of silencing S100A8 were analyzed by Western blot. Cellular proliferation and apoptosis were detected by flow cytometry. Fibroblasts treated with small interfering RNA targeting S100A8 showed a significant decrease in S100A8 protein 48 hours after treatment. They also proliferated significantly slower and showed more apoptosis than control fibroblasts. Inhibition of S100A8 resulted in significant growth reduction and apoptosis acceleration in fibroblasts derived from hypertrophic scars. Manipulation of S100A8 protein expression by gene silencing may represent something new in the treatment of hypertrophic scarring.

Calprotectin (S100A8/A9) and S100A12 are associated with measures of disease activity in a longitudinal study of patients with rheumatoid arthritis treated with infliximab.

PubMed

Nordal, H H; Brun, J G; Hordvik, M; Eidsheim, M; Jonsson, R; Halse, A-K

2016-07-01

The pro-inflammatory proteins calprotectin (a heterocomplex of S100A8/A9) and S100A12 have been associated with disease activity in rheumatoid arthritis (RA). The aim of this study was to compare their potential as biomarkers in a prospective study of RA patients starting with infliximab as their first biological disease-modifying anti-rheumatic drug (DMARD). Thirty-nine RA patients were examined and serum samples collected when starting with infliximab and after 3, 6, and 12 months. Calprotectin and S100A12 were analysed by enzyme-linked immunosorbent assays (ELISAs) and, together with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), measured at all time points. A disease activity score of 28 joints (DAS28) was calculated. Radiographs of the hands, wrists, and feet were taken at baseline and after 3 years, and assessed according to the modified Sharp/van der Heijde (SvH) score. Responsiveness was evaluated according to the European League of Associations for Rheumatology (EULAR) response criteria based on 28 joints. Both S100 proteins were significantly higher in seropositive than in seronegative patients (p = 0.01). Calprotectin correlated significantly with CRP (ρ = 0.51-0.75), ESR (ρ = 0.32-0.52), and DAS28 (ρ = 0.32-0.62). S100A12 correlated with calprotectin (ρ = 0.62-0.77) and CRP (ρ = 0.32-0.63). The S100 proteins, and especially calprotectin (ρ = 0.23-0.39), showed weak associations with radiographic progression, unlike CRP/ESR. None of the S100 proteins could predict responsiveness. Calprotectin showed the strongest correlation with measures of disease activity and may be better than S100A12 when evaluating disease activity in RA patients. More extensive studies are needed to further compare the predictive value of the S100 proteins relative to radiographic progression.

The Characteristic of S100A7 Induction by the Hippo-YAP Pathway in Cervical and Glossopharyngeal Squamous Cell Carcinoma.

PubMed

Kong, Fei; Li, Yunguang; Hu, Enze; Wang, Rui; Wang, Junhao; Liu, Jin; Zhang, Jinsan; He, Dacheng; Xiao, Xueyuan

2016-01-01

S100A7 is expressed in many squamous cell carcinomas (SCCs). Our previous study revealed that S100A7 was dramatically induced in several SCC cells and activation of the Hippo pathway significantly promoted S100A7 in epidermoid carcinoma cells. However, whether the Hippo pathway regulates S100A7 expression in SCCs remains largely unknown. Here, we uncover that S100A7 induction by the Hippo-YAP pathway displays different characteristic in cervical and glossopharyngeal SCC. In well differentiated HCC94 cervical cells and FaDu pharyngeal cells, S100A7 is easily induced by both suspension and dense culture, which is accompanied by an increase in YAP phosphorylation and a decrease in nuclear YAP. Strikingly, these correlations of S100A7 and YAP reverse after recovery of cell attachment or relief from dense culture. Further examination finds that S100A7 induction is significantly repressed by nuclear YAP, which is validated by activation or inhibition of the Hippo pathway via loss- and/or gain-of- LATS1 and MST1 function. Subsequently, we prove that TEAD1 is required for YAP transcriptional repression of S100A7. However, S100A7 is hardly induced in poorly differentiated SiHa cervical cells and NCI-H226 pulmonary cells even in suspension or activation of the Hippo pathway. More importantly, cervical and lingual SCC tissues array analyses show that S100A7 expression displays the positive correlation with pYAP-S127 and the negative correlation with nuclear YAP in the majority of well differentiated but not in poorly differentiated tissues. Collectively, our findings demonstrate that the different induction of S100A7 toward activation of the Hippo pathway mainly depends on the degree of cell differentiation in cervical and glossopharyngeal SCC.

S-Glutathionylation Regulates Inflammatory Activities of S100A9*

PubMed Central

Lim, Su Yin; Raftery, Mark J.; Goyette, Jesse; Geczy, Carolyn L.

2010-01-01

Reactive oxygen species generated by activated neutrophils can cause oxidative stress and tissue damage. S100A8 (A8) and S100A9 (A9), abundant in neutrophil cytoplasm, are exquisitely sensitive to oxidation, which may alter their functions. Murine A8 is a neutrophil chemoattractant, but it suppresses leukocyte transmigration in the microcirculation when S-nitrosylated. Glutathione (GSH) modulates intracellular redox, and S-glutathionylation can protect susceptible proteins from oxidative damage and regulate function. We characterized S-glutathionylation of A9; GSSG and GSNO generated S-glutathionylated A8 (A8-SSG) and A9 (A9-SSG) in vitro, whereas only A9-SSG was detected in cytosol of neutrophils activated with phorbol myristate acetate (PMA) but not with fMLP or opsonized zymosan. S-Glutathionylation exposed more hydrophobic regions in Zn2+-bound A9 but did not alter Zn2+ binding affinity. A9-SSG had reduced capacity to form heterocomplexes with A8, but the arachidonic acid binding capacities of A8/A9 and A8/A9-SSG were similar. A9 and A8/A9 bind endothelial cells; S-glutathionylation reduced binding. We found little effect of A9 or A9-SSG on neutrophil CD11b/CD18 expression or neutrophil adhesion to endothelial cells. However, A9, A9-SSG and A8/A9 promoted neutrophil adhesion to fibronectin but, in the presence of A8, A9-mediated adhesion was abrogated by glutathionylation. S-Glutathionylation of A9 may protect its oxidation to higher oligomers and reduce neutrophil binding to the extracellular matrix. This may regulate the magnitude of neutrophil migration in the extravasculature, and together with the functional changes we reported for S-nitrosylated A8, particular oxidative modifications of these proteins may limit tissue damage in acute inflammation. PMID:20223829

Environmental Assessment and Inversion Studies Based on Features of the Acoustic Vector Field in Shallow Water

DTIC Science & Technology

2008-09-30

A tte nu at io n 1 20 40 60 80 100 1.7 1.75 1.8 1.85 1.9 D en si ty 1 20 40 60 80 100 1520 1540 1560 1580 1600 S ou nd S pe ed 1 20 40 60 80 100 0...0.01 0.02 0.03 0.04 0.05 0.06 0.07 LAYER A tte nu at io n 1 20 40 60 80 100 1.3 1.35 1.4 1.45 1.5 1.55 1.6 D en si ty 1 20 40 60 80 100 1460...Hermand, ed.), no. YS-1, La Spezia, Italy: SACLANT Undersea Research Centre, Dec. 1996. 2. J.-P. Hermand, ``Broad-band geoacoustic inversion in

The Biomarker S100B and Mild Traumatic Brain Injury: A Meta-analysis.

PubMed

Oris, Charlotte; Pereira, Bruno; Durif, Julie; Simon-Pimmel, Jeanne; Castellani, Christoph; Manzano, Sergio; Sapin, Vincent; Bouvier, Damien

2018-05-01

The usefulness of S100B has been noted as a biomarker in the management of mild traumatic brain injury (mTBI) in adults. However, S100B efficacy as a biomarker in children has previously been relatively unclear. A meta-analysis is conducted to assess the prognostic value of S100B in predicting intracerebral lesions in children after mTBI. Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, and Google Scholar. Studies including children suffering mTBI who underwent S100B measurement and computed tomography (CT) scans were included. Of 1030 articles screened, 8 studies met the inclusion criteria. The overall pooled sensitivity and specificity were 100% (95% confidence interval [CI]: 98%-100%) and 34% (95% CI: 30%-38%), respectively. A second analysis was based on the collection of 373 individual data points from 4 studies. Sensitivity and specificity results, obtained from reference ranges in children with a sampling time <3 hours posttrauma, were 97% (95% CI: 84.2%-99.9%) and 37.5% (95% CI: 28.8%-46.8%), respectively. Only 1 child had a low S100B level and a positive CT scan result without clinically important traumatic brain injury. Only patients undergoing both a CT scan and S100B testing were selected for evaluation. S100B serum analysis as a part of the clinical routine could significantly reduce the number of CT scans performed on children with mTBI. Sampling should take place within 3 hours of trauma. Cutoff levels should be based on pediatric reference ranges. Copyright © 2018 by the American Academy of Pediatrics.

Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-11 study.

PubMed

Zhanel, George G; Adam, Heather J; Baxter, Melanie R; Fuller, Jeff; Nichol, Kimberly A; Denisuik, Andrew J; Lagacé-Wiens, Philippe R S; Walkty, Andrew; Karlowsky, James A; Schweizer, Frank; Hoban, Daryl J

2013-05-01

The purpose of the CANWARD study was to assess the antimicrobial activity of a variety of available agents against 22,746 pathogens isolated from patients in Canadian hospitals between 2007 and 2011. Between 2007 and 2011, 27,123 pathogens were collected from tertiary-care centres from across Canada; 22,746 underwent antimicrobial susceptibility testing using CLSI broth microdilution methods. Patient demographic data were also collected. Of the isolates collected, 45.2%, 29.6%, 14.8% and 10.4% were from blood, respiratory, urine and wound specimens, respectively. Patient demographics were as follows: 54.4%/45.6% male/female, 12.8% ≤ 17 years old, 45.1% 18-64 years old and 42.1% ≥65 years old. Isolates were obtained from patients in medical and surgical wards (37.8%), emergency rooms (25.7%), clinics (18.0%) and intensive care units (18.5%). The three most common pathogens were Escherichia coli (20.1%), Staphylococcus aureus [methicillin-susceptible S. aureus and methicillin-resistant S. aureus (MRSA)] (20.0%) and Pseudomonas aeruginosa (8.0%), which together accounted for nearly half of the isolates obtained. Susceptibility rates (SRs) for E. coli were 100% meropenem, 99.9% tigecycline, 99.7% ertapenem, 97.7% piperacillin/tazobactam, 93.7% ceftriaxone, 90.5% gentamicin, 77.9% ciprofloxacin and 73.4% trimethoprim/sulfamethoxazole. Twenty-three percent of the S. aureus were MRSA. SRs for MRSA were 100% daptomycin, 100% linezolid, 100% telavancin, 99.9% vancomycin, 99.8% tigecycline, 92.2% trimethoprim/sulfamethoxazole and 48.2% clindamycin. SRs for P. aeruginosa were 90.1% amikacin, 93.1% colistin, 84.0% piperacillin/tazobactam, 83.5% ceftazidime, 82.6% meropenem, 72.0% gentamicin and 71.9% ciprofloxacin. The CANWARD surveillance study has provided important data on the antimicrobial susceptibility of pathogens commonly causing infections in Canadian hospitals.

Review of S100A9 Biology and its Role in Cancer

PubMed Central

Markowitz, Joseph; Carson, William E.

2013-01-01

S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe S100A9 structural elements important for its biological activity, 2) describe S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes. PMID:23123827

S100A8 contributes to postoperative cognitive dysfunction in mice undergoing tibial fracture surgery by activating the TLR4/MyD88 pathway.

PubMed

Lu, Shun-Mei; Yu, Chan-Juan; Liu, Ya-Hua; Dong, Hong-Quan; Zhang, Xiang; Zhang, Su-Su; Hu, Liu-Qing; Zhang, Feng; Qian, Yan-Ning; Gui, Bo

2015-02-01

Neuro-inflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Although S100A8 and Toll-like receptor 4 (TLR4) have been increasingly recognized to contribute to neuro-inflammation, little is known about the interaction between S100A8 and TLR4/MyD88 signaling in the process of systemic inflammation that leads to neuro-inflammation. Firstly, we demonstrated that C57BL/6 wide-type mice exhibit cognitive deficit 24h after the tibial fracture surgery. Subsequently, increased S100A8 and S100A9 expression was found in the peripheral blood mononuclear cells (PBMCs), spleen, and hippocampus of C57BL/6 wide-type mice within 48h after the surgery. Pre-operative administration of S100A8 antibody significantly inhibited hippocampal microgliosis and improved cognitive function 24h after the surgery. Secondly, we also observed TLR4/MyD88 activation in the PBMCs, spleen, and hippocampus after the surgery. Compared with those in their corresponding wide-type mice, TLR4(-/-) and MyD88(-/-) mice showed lower immunoreactive area of microglia in the hippocampal CA3 region after operation. TLR4 deficiency also led to reduction of CD45(hi)CD11b(+) cells in the brain and better performance in both Y maze and open field test after surgery, suggesting a new regulatory mechanism of TLR4-dependent POCD. At last, the co-location of S100A8 and TLR4 expression in spleen after operation suggested a close relationship between them. On the one hand, S100A8 could induce TLR4 activation of CD11b(+) cells in the blood and hippocampus via intraperitoneal or intracerebroventricular injection. On the other hand, TLR4 deficiency conversely alleviated S100A8 protein-induced hippocampal microgliosis. Furthermore, the increased expression of S100A8 protein in the hippocampus induced by surgery sharply decreased in both TLR4 and MyD88 genetically deficient mice. Taken together, these data suggest that S100A8 exerts pro-inflammatory effect on the occurrence and development of neuro-inflammation and POCD by activating TLR4/MyD88 signaling in the early pathological process of the postoperative stage. Copyright © 2014 Elsevier Inc. All rights reserved.

Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome.

PubMed

Miller, P; Kidwell, K M; Thomas, D; Sabel, M; Rae, J M; Hayes, D F; Hudson, B I; El-Ashry, D; Lippman, M E

2017-11-01

Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients. Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I-III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan-Meier method and Cox proportional hazard models. High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00-1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status. Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers.

Distribution of Personnel by State-by Installation, FY-62

DTIC Science & Technology

1962-06-30

Strategic-Air Defense) 6,125 46 5,693 46 432 43 Presque Isle AFB (Missile) 59 * 13 * 46 4 Subtotal 1,832 11,023 890 STATE TOTAL 1332 100 12&326 100...49 eOklahoa . . . . . . . . . . . .......... . . . 52 e Oregon s . . . . . . . . . . . . . . . . . 53 Pennsylvania ...631 6 631 33 0 0 Subtotal 9 A 1,705 7,594 91 STATE TOTAL 10.234 100 1,914 100 8lo010 ___ I 0___ io l~O - NAVY Grosse Isle NAS 732 60 644 56 88 68

S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis

PubMed Central

Wang, Yuqin; Zhang, Zuhui; Zhang, Laihe; Li, Xinxin; Lu, Rui; Xu, Peipei; Zhang, Xuhong; Dai, Mali; Dai, Xiaodan; Qu, Jia; Lu, Fan; Chi, Zailong

2016-01-01

Uveitis, the pathologic condition of inflammation of the uvea, frequently leads to severe vision loss and blindness. S100A8 is a calcium-binding protein which mainly expresses in granulocytes and monocytes and plays a prominent role in the regulation of inflammatory processes and immune response. Here, we determined the role of S100A8-positive cells in acute anterior uveitis (AAU) and keratitis. In rat models of endotoxin (lipopolisaccharide, LPS) -induced uveitis (EIU) and keratitis, S100A8-positive granulocytes and monocytes increased significantly in the iris-ciliary body and cornea as well as in the blood. Interestingly, Glucocorticoids slightly increased S100A8 levels in leukocytes, but reduced its presence significantly in the iris-ciliary body after LPS injection. Moreover, inhibition of NF-kB activation remarkably suppressed both progression of AAU and total S100A8 levels in leukocytes and the iris-ciliary body after LPS administration. Additionally, S100A8 protein level was also found to be elevated in the serum of AAU patients parallel with the progression of AAU through the designated clinical stages. Thus, S100A8 plays a pivotal role in the processes of AAU through involvement in migration and infiltration of S100A8-positive cells. Our findings suggest that serum levels of S100A8 protein can be used to monitor inflammatory activity in AAU. PMID:27786310

S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis.

PubMed

Wang, Yuqin; Zhang, Zuhui; Zhang, Laihe; Li, Xinxin; Lu, Rui; Xu, Peipei; Zhang, Xuhong; Dai, Mali; Dai, Xiaodan; Qu, Jia; Lu, Fan; Chi, Zailong

2016-10-27

Uveitis, the pathologic condition of inflammation of the uvea, frequently leads to severe vision loss and blindness. S100A8 is a calcium-binding protein which mainly expresses in granulocytes and monocytes and plays a prominent role in the regulation of inflammatory processes and immune response. Here, we determined the role of S100A8-positive cells in acute anterior uveitis (AAU) and keratitis. In rat models of endotoxin (lipopolisaccharide, LPS) -induced uveitis (EIU) and keratitis, S100A8-positive granulocytes and monocytes increased significantly in the iris-ciliary body and cornea as well as in the blood. Interestingly, Glucocorticoids slightly increased S100A8 levels in leukocytes, but reduced its presence significantly in the iris-ciliary body after LPS injection. Moreover, inhibition of NF-kB activation remarkably suppressed both progression of AAU and total S100A8 levels in leukocytes and the iris-ciliary body after LPS administration. Additionally, S100A8 protein level was also found to be elevated in the serum of AAU patients parallel with the progression of AAU through the designated clinical stages. Thus, S100A8 plays a pivotal role in the processes of AAU through involvement in migration and infiltration of S100A8-positive cells. Our findings suggest that serum levels of S100A8 protein can be used to monitor inflammatory activity in AAU.

High expression of S100A8 gene is associated with drug resistance to etoposide and poor prognosis in acute myeloid leukemia through influencing the apoptosis pathway.

PubMed

Yang, Xiao-Yan; Zhang, Ming-Ying; Zhou, Qi; Wu, Shui-Yan; Zhao, Ye; Gu, Wei-Ying; Pan, Jian; Cen, Jian-Nong; Chen, Zi-Xing; Guo, Wen-Ge; Chen, Chien-Shing; Yan, Wen-Hua; Hu, Shao-Yan

2016-01-01

S100A8 has been increasingly recognized as a biomarker in multiple solid tumors and has played pivotal roles in hematological malignancies. S100A8 is potentially an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. In this study, we investigated the correlation of S100A8 at the transcription level with clinical parameters in 91 de novo AML patients and explored its mechanisms of chemoresistance to etoposide in vitro. The transcription level of S100A8 was significantly lower at initial and relapse stages of AML samples than at complete remission (P<0.001) and than in the control group (P=0.0078), while no significant difference could be found between initial and relapse stages (P=0.257). Patients with high transcription levels of S100A8 exhibited a shorter overall survival (P=0.0012). HL-60 cells transfected with S100A8 showed resistance to etoposide with a higher level IC50 value and lower apoptosis rate compared with HL-60 cells transfected with empty vector. Thirty-six genes were significantly downregulated and 12 genes were significantly upregulated in S100A8 overexpression group compared with control group in which 360 genes involved in apoptotic genes array were performed by real-time reverse transcriptase polymerase chain reaction. Among them, the caspase-3, Bcl-2, and Bax were verified by Western blot analysis which indicated that the role of S100A8 in resistance to chemotherapy was closely related with antiapoptosis. In conclusion, critical S100A8 provided useful clinical information in predicting the outcome of AML. The main mechanism of S100A8 which promoted chemoresistance was antiapoptosis.

High expression of S100A8 gene is associated with drug resistance to etoposide and poor prognosis in acute myeloid leukemia through influencing the apoptosis pathway

PubMed Central

Yang, Xiao-yan; Zhang, Ming-ying; Zhou, Qi; Wu, Shui-yan; Zhao, Ye; Gu, Wei-ying; Pan, Jian; Cen, Jian-nong; Chen, Zi-xing; Guo, Wen-ge; Chen, Chien-shing; Yan, Wen-hua; Hu, Shao-yan

2016-01-01

S100A8 has been increasingly recognized as a biomarker in multiple solid tumors and has played pivotal roles in hematological malignancies. S100A8 is potentially an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. In this study, we investigated the correlation of S100A8 at the transcription level with clinical parameters in 91 de novo AML patients and explored its mechanisms of chemoresistance to etoposide in vitro. The transcription level of S100A8 was significantly lower at initial and relapse stages of AML samples than at complete remission (P<0.001) and than in the control group (P=0.0078), while no significant difference could be found between initial and relapse stages (P=0.257). Patients with high transcription levels of S100A8 exhibited a shorter overall survival (P=0.0012). HL-60 cells transfected with S100A8 showed resistance to etoposide with a higher level IC50 value and lower apoptosis rate compared with HL-60 cells transfected with empty vector. Thirty-six genes were significantly downregulated and 12 genes were significantly upregulated in S100A8 overexpression group compared with control group in which 360 genes involved in apoptotic genes array were performed by real-time reverse transcriptase polymerase chain reaction. Among them, the caspase-3, Bcl-2, and Bax were verified by Western blot analysis which indicated that the role of S100A8 in resistance to chemotherapy was closely related with antiapoptosis. In conclusion, critical S100A8 provided useful clinical information in predicting the outcome of AML. The main mechanism of S100A8 which promoted chemoresistance was antiapoptosis. PMID:27540302

Time course of defense mechanisms in bovine endometrium in response to lipopolysaccharide.

PubMed

Swangchan-Uthai, Theerawat; Lavender, Chloe R M; Cheng, Zhangrui; Fouladi-Nashta, Ali A; Wathes, D Claire

2012-06-01

Endometritis caused by uterine infection after calving reduces fertility and causes major economic losses to the dairy industry. This study investigated the time course of an inflammatory response in bovine endometrium triggered by exposure to bacterial endotoxin lipopolysaccharide (LPS). Mixed endometrial epithelial and stromal cells (9:1 ratio) were grown to confluence as a model system and treated with an optimized dose of 100 ng/ml LPS in vitro. Gene expression responses were measured using quantitative PCR, and gene products were investigated using assays of culture medium and Western blotting. Of 17 candidate genes tested initially, LPS treatment for 24 h up-regulated mRNA expression of TLR4 signaling (TLR4, CD14), cytokines (IL1B, TNF), chemokines (IL8, CXCL5), antimicrobial peptides (LAP, S100A8, S100A9, S100A12), and matrix metalloproteinases (MMP1, MMP13). A 48 h, LPS time course study showed that TNF increased first at 1 h, followed by peak expression of IL1B at 6 h, and those of S100A8, S100A12, and LAP at 12 h. The intracellular S100A8 protein content doubled at 12-24 h but with little excretion into the medium. Regarding prostaglandin biosynthesis, PTGES mRNA was slightly higher after LPS exposure, whereas expression of the PGF synthase AKR1B1 was inhibited. Despite this, LPS treatment stimulated the secretion of both PGE₂ and PGF₂(alpha) to a similar extent. These results suggest that the family of S100 Ca²⁺ binding proteins are released from damaged endometrial cells and may play a major antimicrobial role. Prostaglandin synthesis increased during the uterine infection, but we found no evidence that this was associated with a change in the PGE:PGF ratio.

Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide

PubMed Central

Hein, Kyaw Zaw; Takahashi, Hitoshi; Tsumori, Toshiko; Yasui, Yukihiko; Nanjoh, Yasuko; Toga, Tetsuo; Wu, Zhihong; Grötzinger, Joachim; Jung, Sascha; Wehkamp, Jan; Schroeder, Bjoern O.; Schroeder, Jens M.; Morita, Eishin

2015-01-01

The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum-inhibiting activity from lesional psoriasis scale extracts and identified the Cys-reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn2+, suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7-mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn2+-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn2+-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn2+-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi. PMID:26438863

S100A8 inhibits PDGF-induced proliferation of airway smooth muscle cells dependent on the receptor for advanced glycation end-products.

PubMed

Xu, Yu-Dong; Wang, Yu; Yin, Lei-Miao; Peng, Ling-Ling; Park, Gyoung-Hee; Yang, Yong-Qing

2017-06-21

Airway remodeling is a key feature of asthma, characterized by increased proliferation of airway smooth muscle cells (ASMCs). S100A8 is a calcium-binding protein with a potential to regulate cell proliferation. Here, the effect of exogenous S100A8 protein on the proliferation of ASMCs induced by platelet-derived growth factor (PDGF) and the underlying molecular mechanism was investigated. Rat ASMCs were cultured with or without a neutralizing antibody to the receptor for advanced glycation end-products (RAGE), a potential receptor for S100A8 protein. Purified recombinant rat S100A8 protein was then added into the cultured cells, and the proliferation of ASMCs induced by PDGF was detected by colorimetric-based WST-8 assay and ampedance-based xCELLigence proliferation assay. The expression levels of RAGE in ASMCs were analyzed using western blotting assay. Results showed that exogenous S100A8 inhibited the PDGF-induced proliferation of rat ASMCs in a dose-dependent manner with the maximal effect at 1 μg/ml in vitro. Furthermore, when ASMCs was pre-treated with anti-RAGE neutralizing antibody, the inhibitory effect of S100A8 on PDGF-induced proliferation was significantly suppressed. In addition, neither the treatment with S100A8 or PDGF alone nor the pre-treatment with rS100A8 followed by PDGF stimulation affected the expression levels of RAGE. Our study demonstrated that S100A8 inhibits PDGF-induced ASMCs proliferation in a manner dependent on membrane receptor RAGE.

Decontamination System Utilizing Hydrogen Peroxide, UV Light and Catalytic Surfaces

DTIC Science & Technology

1992-02-01

Min %DMO RecoveredDisk# Catalyst (relative to control) 1 Ag 2 0 5.4 2 Ag2 0 10.1 4 FeTiO3 56 5 FeTio3 48 7 None 558 None 56 Control None 100 Ag 2 0...Std. Ag2 0 44 FeTiO3 Std. FeTiO3 100 Reference 87 - 36 - Table 9g. Experiment U, 1-09-91, 50% H2 02 , No UV Light, Run Time - 40 Min % DMO...Ag 2 0 2 7.8 44 1-09 T FeTiO3 2 52 100 1-09 U MnO 2 59 921-09 U Mn304 2 62 89 1-21 Y Ag 2 S/CaCO3 2 36 103 1-21 Y Ag 2 S 2 39 100 1-21 Z FeS2 2 6.0

Accuracy of Mobile Phone and Handheld Light Microscopy for the Diagnosis of Schistosomiasis and Intestinal Protozoa Infections in Côte d'Ivoire.

PubMed

Coulibaly, Jean T; Ouattara, Mamadou; D'Ambrosio, Michael V; Fletcher, Daniel A; Keiser, Jennifer; Utzinger, Jürg; N'Goran, Eliézer K; Andrews, Jason R; Bogoch, Isaac I

2016-06-01

Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis. Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope). The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d'Ivoire. One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy. Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa. The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively. The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8-99.6%) and 81.1% (95% CI 71.2-88.3%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 97.1% (95% CI 92.2-99.1%), respectively. The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4-74.6%) and 35.6% (95% CI 25.9-46.4%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 100% (95% CI 86.7-100%), respectively. For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1-94.7%) and 83.3% (95% CI 36.5-99.1%), respectively, and 100% specificity. Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites.

Enantioselective hydrolysis of racemic styrene oxide and its substituted derivatives using newly-isolated Sphingopyxis sp. exhibiting a novel epoxide hydrolase activity.

PubMed

Woo, Jung-Hee; Lee, Eun Yeol

2014-02-01

(S)-Styrene oxide, (S)-2-chlorostyrene oxide (CSO), (S)-3-CSO and (S)-4-CSO with 99.9 %ee were obtained with a yield of 20.6, 39.3, 28.7 and 26.8 % from 4 mM corresponding racemic substrates using 10 mg cells of a newly-isolated Sphingopyxis sp. at pH 8.0 and 25 °C in 1 ml 100 mM Tris/HCl buffer after 420, 100, 120 and 55 min, respectively. For racemic 2CSO, well-known for one of the racemates that is difficult to obtained in enantiomerically pure form, (S)-2-CSO with 99.9 %ee, 39.3 % yield (theoretical yield 50 %) and enantiomeric ratio of 42.1 was obtained. The newly-isolated strain can thus be used as whole-cell biocatalyst in the production of various (S)-CSO with a chlorine group at different positions.

Location-specific expression of chemokines, TNF-α and S100 proteins in a teat explant model.

PubMed

Lind, Monique; Sipka, Anja S; Schuberth, Hans-Joachim; Blutke, Andreas; Wanke, Rüdiger; Sauter-Louis, Carola; Duda, Katarzyna A; Holst, Otto; Rainard, Pascal; Germon, Pierre; Zerbe, Holm; Petzl, Wolfram

2015-04-01

The distal compartments of the udder are the first to interact with invading pathogens. The regulatory and effector functions of two major teat regions [Fürstenberg's rosette (FR); teat cistern (TC)] are largely unknown. The objective of this study was to establish an in vitro model with explants of the FR and the TC to analyse their response towards Escherichia coli LPS and Staphylococcus aureus lipoteichoic acid (LTA). Quantitative stereological analysis confirmed differences in the cellular composition of FR and TC explants. Chemokine (CXCL8, CCL5, CCL20) and TNF-α mRNA were expressed at low levels in both locations. Explant stimulation with LPS increased the mRNA abundance of all tested chemokines and TNF-α. Stimulation with LTA only induced CCL20 and CXCL8. LPS- and LTA-stimulated explant supernatants contained CXCL8 and CXCL3. Supernatants significantly attracted neutrophils in vitro. Compared with TC, the FR showed high constitutive mRNA expression of S100 proteins (A8, A9, A12). In the TC, both LPS and LTA significantly induced S100A8, whereas S100A9 and S100A12 expression was only induced by LPS. The novel model system underpins the role of the teat for recognising pathogens and shaping a pathogen- and location-specific immune response. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection.

PubMed

Clark, Heather L; Jhingran, Anupam; Sun, Yan; Vareechon, Chairut; de Jesus Carrion, Steven; Skaar, Eric P; Chazin, Walter J; Calera, José Antonio; Hohl, Tobias M; Pearlman, Eric

2016-01-01

Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ∆zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin. Copyright © 2015 by The American Association of Immunologists, Inc.

Increased Plasma Levels of Danger-Associated Molecular Patterns Are Associated With Immune Suppression and Postoperative Infections in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

PubMed

Leijte, Guus P; Custers, Hettie; Gerretsen, Jelle; Heijne, Amon; Roth, Johannes; Vogl, Thomas; Scheffer, Gert J; Pickkers, Peter; Kox, Matthijs

2018-01-01

Danger-associated molecular patterns (DAMPs) can elicit immune responses and may subsequently induce an immune-suppressed state. Previous work showed that increased plasma levels of DAMPs are associated with immune suppression and increased susceptibility toward infections in trauma patients. Like trauma, major surgical procedures, such as cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC), are also thought to cause profound DAMP release. Furthermore, the incidence of postoperative infections in these patients, ranging from 10 to 36%, is very high compared to that observed in patients undergoing other major surgical procedures. We hypothesized that the double hit of surgical trauma (CRS) in combination with HIPEC causes excessive DAMP release, which in turn contributes to the development of immune suppression. To investigate this, we assessed DAMP release in patients undergoing CRS-HIPEC, and investigated its relationship with immune suppression and postoperative infections. In 20 patients undergoing CRS-HIPEC, blood was obtained at five time points: just before surgery (baseline), after CRS, after HIPEC, at ICU admission, and 1 day after surgery. Circulating levels of DAMPs [heat shock protein (HSP)70, high mobility group box (HMGB)1, S100A12, S100A8/S100A9, nuclear (n)DNA, mitochondrial (mt)DNA, lactate dehydrogenase (LDH), a marker of unscheduled cell death], and cytokines [tumor necrosis factor (TNF)α, IL-6, IL-8, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and MCP-1] were measured. The extent of immune suppression was determined by measuring HLA-DR gene expression and ex vivo leukocytic cytokine production capacity. Plasma levels of DAMPs (maximum fold increases of HSP70: 2.1 [1.5-2.8], HMGB1: 5.9 [3.2-9.8], S100A8/S100A9: 3.6 [1.8-5.6], S100A12: 2.6 [1.8-4.3], nDNA 3.9 [1.0-10.8], LDH 1.7 [1.2-2.5]), and all measured cytokines increased profoundly following CRS-HIPEC. Evidence of immune suppression was already apparent during the procedure, illustrated by a decrease of HLA-DR expression compared with baseline (0.5-fold [0.3-0.9]) and diminished ex vivo pro-inflammatory cytokine production capacity. The increase in HMGB1 levels correlated with the decrease in HLA-DR expression ( r  = -0.46, p  = 0.04), and peak HMGB1 concentrations were significantly higher in the five patients who went on to develop a postoperative infection (p = 0.04). CRS-HIPEC is associated with profound DAMP release and immune suppression, and plasma HMGB1 levels are related with the occurrence of postoperative infections in these patients.

Increased Levels of Calprotectin in Obesity Are Related to Macrophage Content: Impact on Inflammation and Effect of Weight Loss

PubMed Central

Catalán, Victoria; Gómez-Ambrosi, Javier; Rodríguez, Amaia; Ramírez, Beatriz; Rotellar, Fernando; Valentí, Victor; Silva, Camilo; Gil, María J; Fernández-Real, José Manuel; Salvador, Javier; Frühbeck, Gema

2011-01-01

Calprotectin has been recently described as a novel marker of obesity. The aim of this study was to determine the circulating concentrations and expression levels of calprotectin subunits (S100A8 and S100A9) in visceral adipose tissue (VAT), exploring its impact on insulin resistance and inflammation and the effect of weight loss. We included 53 subjects in the study. Gene expression levels of the S100A8/A9 complex were analyzed in VAT as well as in both adipocytes and stromovascular fraction cells (SVFCs). In addition, circulating calprotectin and soluble receptor for the advanced glycation end product (sRAGE) concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 26). Circulating concentrations and VAT expression of S100A8/A9 complex were increased in normoglycemic and type 2 diabetic obese patients (P < 0.01) and associated with markers of inflammation (P < 0.01). Oppositely, concentrations of sRAGE were significantly lower (P < 0.001) in both obese groups compared to lean volunteers. Elevated calprotectin levels in obese patients decreased (P < 0.00001) after RYGB, whereas sRAGE concentrations tended to increase. Calprotectin was mainly expressed by SVFCs, and its expression was significantly correlated (P < 0.01) with mRNA levels of the monocyte-macrophage–related molecules macrophage-specific antigen CD68 (CD68), monocyte chemotactic protein 1 (MCP1), integrin α-M (CD11B), and NADPH oxidase 2 (NOX2). Tumor necrosis factor-α treatment significantly enhanced (P < 0.05) the mRNA levels of S100 calcium-binding protein A8 (S100A8) of human visceral adipocytes. The increased levels of calprotectin in obesity and obesity-associated type 2 diabetes, its positive association with inflammation as well as the higher expression levels in the SVFCs in VAT suggests a potential role of this protein as a chemotactic factor in the recruitment of macrophages to VAT, increasing inflammation and the development of obesity-associated comorbidities. PMID:21738950

Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI

NASA Astrophysics Data System (ADS)

Chouhan, Manil D.; Bainbridge, Alan; Atkinson, David; Punwani, Shonit; Mookerjee, Rajeshwar P.; Lythgoe, Mark F.; Taylor, Stuart A.

2017-02-01

Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver DCE MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7  ±  1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n  =  9) measured at 7 d. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and 7 d reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p  =  0.066), total liver blood flow (TLBF) (p  =  0.101), hepatic arterial (HA) fraction (p  =  0.895), mean transit time (MTT) (p  =  0.646), distribution volume (DV) (p  =  0.890) were not significantly different. Seven day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% limits-of-agreement (BA95%LoA)  ±27.9%, coefficient of variation (CoV) 61.4% versus 9.3%, ±35.5%, 81.7% respectively without correction). Seven day uncorrected PV perfusion was also improved (mean difference 9.3 ml min-1/100 g, BA95%LoA  ±506.1 ml min-1/100 g, CoV 64.1% versus 0.9 ml min-1/100 g, ±562.8 ml min-1/100 g, 65.1% respectively with correction) as was uncorrected TLBF (mean difference 43.8 ml min-1/100 g, BA95%LoA  ±586.7 ml min-1/ 100 g, CoV 58.3% versus 13.3 ml min-1/100 g, ±661.5 ml min-1/100 g, 60.9% respectively with correction). Reproducibility of uncorrected MTT was similar (uncorrected mean difference 2.4 s, BA95%LoA  ±26.7 s, CoV 60.8% uncorrected versus 3.7 s, ±27.8 s, 62.0% respectively with correction), as was and DV (uncorrected mean difference 14.1%, BA95%LoA  ±48.2%, CoV 24.7% versus 10.3%, ±46.0%, 23.9% respectively with correction). Cardiac output AIF correction does not significantly affect the estimation of hepatic perfusion parameters but demonstrates improvements in normal volunteer 7 d HA fraction reproducibility, but deterioration in PV perfusion and TLBF reproducibility. Improved HA fraction reproducibility maybe important as arterialisation of liver perfusion is increased in chronic liver disease and within malignant liver lesions.

The Surprising Composition of the Salivary Proteome of Preterm Human Newborn

PubMed Central

Castagnola, Massimo; Inzitari, Rosanna; Fanali, Chiara; Iavarone, Federica; Vitali, Alberto; Desiderio, Claudia; Vento, Giovanni; Tirone, Chiara; Romagnoli, Costantino; Cabras, Tiziana; Manconi, Barbara; Teresa Sanna, Maria; Boi, Roberto; Pisano, Elisabetta; Olianas, Alessandra; Pellegrini, Mariagiuseppina; Nemolato, Sonia; Wilhelm Heizmann, Claus; Faa, Gavino; Messana, Irene

2011-01-01

Saliva is a body fluid of a unique composition devoted to protect the mouth cavity and the digestive tract. Our high performance liquid chromatography (HPLC)-electrospray ionization-MS analysis of the acidic soluble fraction of saliva from preterm human newborn surprisingly revealed more than 40 protein masses often undetected in adult saliva. We were able to identify the following proteins: stefin A and stefin B, S100A7 (two isoforms), S100A8, S100A9 (four isoforms), S100A11, S100A12, small proline-rich protein 3 (two isoforms), lysozyme C, thymosins β4 and β10, antileukoproteinase, histone H1c, and α and γ globins. The average mass value reported in international data banks was often incongruent with our experimental results mostly because of post-translational modifications of the proteins, e.g. acetylation of the N-terminal residue. A quantitative label-free MS analysis showed protein levels altered in relation to the postconceptional age and suggested coordinate and hierarchical functions for these proteins during development. In summary, this study shows for the first time that analysis of these proteins in saliva of preterm newborns might represent a noninvasive way to obtain precious information of the molecular mechanisms of development of human fetal oral structures. PMID:20943598

Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats.

PubMed

Pepple, Kathryn L; Rotkis, Lauren; Wilson, Leslie; Sandt, Angela; Van Gelder, Russell N

2015-12-01

Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2-crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2-crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation.

Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats

PubMed Central

Pepple, Kathryn L.; Rotkis, Lauren; Wilson, Leslie; Sandt, Angela; Van Gelder, Russell N.

2015-01-01

Purpose Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. Methods Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization–time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. Results The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2–crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. Conclusions The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2–crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation. PMID:26747776

[Effects of calcipotriol on the expression of S100A8 in human keratinocytes].

PubMed

Wu, Dawei; Wu, Chao; Jin, Hongzhong

2015-04-28

To explore the effects of calcipotriol on the expression of S100A8 in human keratinocytes. Cultured HaCaT cells were divided into 4 groups of blank without interventions, tumor necrosis factor-alpha (TNF-α) 24 h stimulation with 100 ng/ml TNF-α, calcipotriol 24 h stimulation with 10⁻⁵ -10⁻⁹ mol/L calcipotriol and calcipotriol+TNF-α 24 h stimulation. The relative expression of S100A8 mRNA was detected and calculated by real-time quantitative polymerase chain reaction (PCR). The relative expression of S100A8 mRNA was up-regulated to (19.623 ± 3.486) folds (P < 0.01) under a 24 h stimulation of 100 ng/ml TNF-α versus blank. The expression of S100A8 was up-regulated to (5.029 ± 1.056) and (2.848 ± 0.612) folds (both P < 0.01) when cultured for 24 h with 10⁻⁷, 10⁻⁸ mol/L calcipotriol versus blank respectively. And the expression of S100A8 was down-regulated to (59.51 ± 3.31)% (P < 0.05) when cultured with 10⁻⁵ mol/L calcipotriol+TNF-α versus TNF-α-stimulated cells. The expression of S100A8 was up-regulated to (1.873 ± 0.153) folds (P < 0.01) when cultured with 10⁻⁷ mol/L calcipotriol+TNF-α versus TNF-α-stimulated cells. TNF-α induces a high expression of S100A8 in cultured human keratinocytes in vitro. Calcipotriol bi-directionally affects the expression of S100A8: A high concentration (10⁻⁵ mol/L) calcipotriol down-regulates while a low concentration (10⁻⁷ - 10⁻⁸ mol/L) calcipotriol up-regulates the expression of S100A8.

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma.

PubMed

Liu, Kun; Zhang, Yuening; Zhang, Chengdong; Zhang, Qinle; Li, Jiatong; Xiao, Feifan; Li, Yingfang; Zhang, Ruoheng; Dou, Dongwei; Liang, Jiezhen; Qin, Jian; Lin, Zhidi; Zhao, Dong; Jiang, Min; Liang, Zhenxin; Su, Jie; Gupta, Vanaparthy Pranay; He, Min; Yang, Xiaoli

2016-08-30

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127-2.591) and PFS (HR, 1.767; 95 % CI, 1.168-2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma

PubMed Central

Xiao, Feifan; Li, Yingfang; Zhang, Ruoheng; Dou, Dongwei; Liang, Jiezhen; Qin, Jian; Lin, Zhidi; Zhao, Dong; Jiang, Min; Liang, Zhenxin; Su, Jie; Gupta, Vanaparthy Pranay; He, Min; Yang, Xiaoli

2016-01-01

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC. Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127–2.591) and PFS (HR, 1.767; 95 % CI, 1.168–2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC. PMID:27462864

The Human Antimicrobial Protein Calgranulin C Participates in Control of Helicobacter pylori Growth and Regulation of Virulence.

PubMed

Haley, Kathryn P; Delgado, Alberto G; Piazuelo, M Blanca; Mortensen, Brittany L; Correa, Pelayo; Damo, Steven M; Chazin, Walter J; Skaar, Eric P; Gaddy, Jennifer A

2015-07-01

During infectious processes, antimicrobial proteins are produced by both epithelial cells and innate immune cells. Some of these antimicrobial molecules function by targeting transition metals and sequestering these metals in a process referred to as "nutritional immunity." This chelation strategy ultimately starves invading pathogens, limiting their growth within the vertebrate host. Recent evidence suggests that these metal-binding antimicrobial molecules have the capacity to affect bacterial virulence, including toxin secretion systems. Our previous work showed that the S100A8/S100A9 heterodimer (calprotectin, or calgranulin A/B) binds zinc and represses the elaboration of the H. pylori cag type IV secretion system (T4SS). However, there are several other S100 proteins that are produced in response to infection. We hypothesized that the zinc-binding protein S100A12 (calgranulin C) is induced in response to H. pylori infection and also plays a role in controlling H. pylori growth and virulence. To test this, we analyzed gastric biopsy specimens from H. pylori-positive and -negative patients for S100A12 expression. These assays showed that S100A12 is induced in response to H. pylori infection and inhibits bacterial growth and viability in vitro by binding nutrient zinc. Furthermore, the data establish that the zinc-binding activity of the S100A12 protein represses the activity of the cag T4SS, as evidenced by the gastric cell "hummingbird" phenotype, interleukin 8 (IL-8) secretion, and CagA translocation assays. In addition, high-resolution field emission gun scanning electron microscopy (FEG-SEM) was used to demonstrate that S100A12 represses biogenesis of the cag T4SS. Together with our previous work, these data reveal that multiple S100 proteins can repress the elaboration of an oncogenic bacterial surface organelle. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Anti-atherogenic properties of resveratrol: 4-week resveratrol administration associated with serum concentrations of SIRT1, adiponectin, S100A8/A9 and VSMCs contractility in a rat model.

PubMed

Wiciński, Michał; Malinowski, Bartosz; Węclewicz, Mateusz M; Grześk, Elżbieta; Grześk, Grzegorz

2017-05-01

Resveratrol (3, 4', 5-trihydroxy-trans-stilbene) is a natural, non-flavonoid polyphenol that exerts protective properties against atherosclerosis-associated endothelial dysfunction and senescence. The present study aimed to assess the influence of resveratrol on vascular contractility and molecular factors including sirtuin-1 (SIRT1), adiponectin and calprotectin (S100A8/A9) that are considered to be important elements of atherogenesis. A total of 17 male rats were divided into a control and treatment group and administered resveratrol or a placebo. Pharmacometrics were performed on an isolated and perfused tail artery. Serum SIRT1, adiponectin and S100A8/A9 levels were quantified using an ELISA assay. The level of SIRT1 in the control and treatment groups at time 0 was 4.26 and 4.45 ng/ml, respectively. SIRT1 in the control and treatment groups following 2 weeks of treatment was 4.59 and 6.86 ng/ml, respectively (P<0.05) and following 4 weeks of treatment was 4.15 and 6.38 ng/ml, respectively (P<0.05). The level of adiponectin in the control and treatment groups at time 0 was 1.24 and 1.21 ng/ml, respectively. Following 2 weeks of treatment, the level of adiponectin in the control and treatment groups was 1.22 and 1.2 ng/ml, respectively (P>0.05) and following 4 weeks of treatment was 1.26 and 1.58 ng/ml, respectively (P<0.05). The S100A8/A9 level in control and treatment groups at time 0 was 0.39 and 0.33 ng/ml, respectively. The level of S100A8/A9 in control and treatment groups following 2 weeks of treatment was 0.37 and 0.35 ng/ml, respectively (P>0.05) and following 4 weeks of treatment was 0.34 and 0.32 ng/ml, respectively (P>0.05). EC 50 values obtained for phenylephrine in resveratrol-pretreated arteries were significantly higher than controls in the presence and absence of A7-hydrochloride (P<0.05). The results of the present study indicate a significant increase in the concentration of SIRT1 and adiponectin in the resveratrol-pretreated group (P<0.05). S100A8/A9 serum concentrations remained unchanged. Reactivity of resistant arteries was significantly reduced for resveratrol-pretreated vessels and this effect was partially independent of phosphodiesterase (PDE1). Additionally, there was a synergistic interaction observed between resveratrol and the PDE1 inhibitor.

Role of Seprase in Breast Cancer Invasion

DTIC Science & Technology

1998-09-01

Jr., Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS( ES ) 8. PERFORMING ORGANIZATION University of Arkansas REPORT NUMBER Little Rock, Arkansas 7...2 2 0 5 - 7 19 9 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS( ES ) 10. SPONSORING / MONITORING U.S. Army Medical Research and Materiel Command...in 0.20- -1.00 24 26 283i204 3 0 4 C N- L 05 K----QYYT SERS S0 95I • _._.-.m..,,2 Untitledl Protein Toolbox Plot Figure 7. Ti.iesday, April 28, 1998

Is 10-second electrocardiogram recording enough for accurately estimating heart rate in atrial fibrillation.

PubMed

Shuai, Wei; Wang, Xi-Xing; Hong, Kui; Peng, Qiang; Li, Ju-Xiang; Li, Ping; Chen, Jing; Cheng, Xiao-Shu; Su, Hai

2016-07-15

At present, the estimation of rest heart rate (HR) in atrial fibrillation (AF) is obtained by apical auscultation for 1min or on the surface electrocardiogram (ECG) by multiplying the number of RR intervals on the 10second recording by six. But the reasonability of 10second ECG recording is controversial. ECG was continuously recorded at rest for 60s to calculate the real rest HR (HR60s). Meanwhile, the first 10s and 30s ECG recordings were used for calculating HR10s (sixfold) and HR30s (twofold). The differences of HR10s or HR30s with the HR60s were compared. The patients were divided into three sub-groups on the HR60s <80, 80-100 and >100bpm. No significant difference among the mean HR10s, HR30s and HR60s was found. A positive correlation existed between HR10s and HR60s or HR30s and HR60s. Bland-Altman plot showed that the 95% reference limits were high as -11.0 to 16.0bpm for HR10s, but for HR30s these values were only -4.5 to 5.2bpm. Among the three subgroups with HR60s <80, 80-100 and >100bpm, the 95% reference limits with HR60s were -8.9 to 10.6, -10.5 to 14.0 and -11.3 to 21.7bpm for HR10s, but these values were -3.9 to 4.3, -4.1 to 4.6 and -5.3 to 6.7bpm for HR30s. As 10s ECG recording could not provide clinically accepted estimation HR, ECG should be recorded at least for 30s in the patients with AF. It is better to record ECG for 60s when the HR is rapid. Copyright © 2016. Published by Elsevier Ireland Ltd.

The effect of vitamin D supplementation on arterial stiffness in an elderly community-based population.

PubMed

McGreevy, Cora; Barry, Miriam; Davenport, Colin; Byrne, Brendan; Donaghy, Caroline; Collier, Geraldine; Tormey, William; Smith, Diarmuid; Bennett, Kathleen; Williams, David

2015-03-01

Vitamin D deficiency may lead to impaired vascular function and abnormalities in central arterial stiffness. We compared the effects of two different doses of vitamin D3 on arterial stiffness in an elderly population with deficient serum 25-hydroxy-vitamin D levels. A total of 119 known vitamin D deficient (<50 nmol/L) subjects were randomized to receive either 50,000 international units (IU) or 100,000 IU single intramuscular vitamin D3. In the group that received 100,000 IU vitamin D, median pulse wave velocity decreased from 12.2 m/s (range, 5.1-40.3 m/s) to 11.59 m/s (range, 4.3-14.9 m/s) after 8 weeks (P = .22). A mean decrease of 3.803 ± 1.7 (P = .032) in augmentation index (a measure of systemic stiffness) was noted. Only 3/51 (5.8%) who received 100,000 IU vitamin D reached levels of sufficiency (>75 nmol/L). A significant decrease in augmentation index was seen in the group that received 100,000 IU vitamin D. Serum levels of 25-hydroxy-vitamin D were still deficient at 8 weeks in the majority of patients, which may be attributable to impaired bioavailability. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Maintenance Resources by Building Use for U.S. Army Installations. Volume 2. Appendices A through H

DTIC Science & Technology

1991-05-01

Installations, Volume II: Appendices A Through H RDTE dated 1980REIMB 1984 6 . AUTHOR(S) Edgar S. Neely and Robert D. Neathammer 7 . PERFORML’JG...Recurring Maintenance Factor 1.10 MRT For Major Cost Tasks and Replacement Tasks Decade 1 2 3 4 6 7 8 9 10 0 .000 .000 .000 .000 .000 .050 .190 .240 .300 .280...Special Condition Multiplier 1.00 Annual Recurring Maintenance Factor .79 MRT For Major Cost Tasks and Replacement Tasks Decade 1 2 3 4 6 7 8 9 10 0

Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo.

PubMed

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.

Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo

PubMed Central

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U.; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe -/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe -/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe -/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH. PMID:25880808

Effect of Microgravity on Afferent Innervation

NASA Technical Reports Server (NTRS)

1998-01-01

Presentations and publications are: (1) an audiovisual summary web presentation on results from SLM-MIR avian experiments. A color presentation summarizing results from the SLM-MIR and STS-29 avian experiments; (2) color threshold and ratio of S 100B MAP5, NF68/200, GABA and GAD; (3) chicken (Gallus domesticus) inner ear afferents; (4) microgravity in the STS-29 Space Shuttle Discovery affected the vestibular system of chick embryos; (5) expression of S 100B in sensory and secretory cells of the vertebrate inner ear; (6) otoconia biogenesis, phylogeny, composition and functional attributes;(7) the glycan keratin sulfate in inner ear crystals; (8) elliptical-P cells in the avian perilymphatic interface of the tegmentum vasculosum; and (9) LAMP2c and S100B upregulation in brain stem after VIIIth nerve deafferentation.

Cardiac AAV9-S100A1 gene therapy rescues postischemic heart failure in a preclinical large animal model

PubMed Central

Pleger, Sven T.; Shan, Changguang; Ksienzyk, Jan; Bekeredjian, Raffi; Boekstegers, Peter; Hinkel, Rabea; Schinkel, Stefanie; Leuchs, Barbara; Ludwig, Jochen; Qiu, Gang; Weber, Christophe; Kleinschmidt, Jürgen A.; Raake, Philip; Koch, Walter J.; Katus, Hugo A.; Müller, Oliver J.; Most, Patrick

2014-01-01

As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the pre-clinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure. PMID:21775667

Increased mRNA expression of selected antimicrobial peptides around ovulation and during inflammatory processes in the bovine endometrium postpartum.

PubMed

Ibrahim, M; Peter, S; Gärtner, M A; Michel, G; Jung, M; Einspanier, R; Gabler, C

2016-11-01

In the uterus, the first pathogen confrontations take place at the luminal endometrial epithelium. Therefore, it is required that these cells have the potential to recognize and respond to a bacterial infection. Antimicrobial peptides (AMP), part of the innate immune system in addition to cytokines, are principal effector molecules of mucosal immunity against pathogens. One important family of AMP that can permeabilize bacterial membranes is the beta-defensin (DEFB) family, which includes the following members: DEFB1, DEFB4A, and DEFB5, lingual AMP, and tracheal AMP. The bactericidal/permeability-increasing protein is also a cationic AMP that results in the death of bacteria. Another AMP family is the S100 calcium-binding protein (S100A) family including the following members: S100A8, S100A9, S100A11, and S100A12. These AMP exert their antimicrobial action through chelation of several ions. The aim of the present study was to evaluate mRNA expression patterns of selected AMP in bovine endometrial cells collected (1) at different stages of the estrous cycle (postovulatory, early-to-mid luteal, late luteal, and pre-ovulatory phase); (2) during the puerperium depending on uterine health status (healthy, subclinical, or clinical endometritis) starting on Day 24 to 30 postpartum for 3 weeks on a weekly basis; and (3) in vitro after co-culturing with Bacillus pumilus at three different multiplicities of infection (MOI 1, 5, and 10) up to 6 hours. The results reported that the mRNA expression of all candidate AMP, except DEFB1, S100A8, and S100A9, was estrous cycle dependent. In particular, around the time of ovulation, the transcription level of most AMP was higher (P < 0.05) compared with the luteal phase. Almost all candidate AMP mRNA expression was dependent on uterine health status, with a higher transcription level (P < 0.05) in inflamed endometrial tissues, especially during the late stage of the puerperium (Day 45-51 postpartum). Members of the DEFB family were nearly unaffected in their mRNA expression in primary endometrial cells co-incubated with B. pumilus. However, S100A8 and S100A9 mRNA contents were higher after 4 and 6 hours of co-incubation with B. pumilus compared with untreated controls. In conclusion, higher mRNA expression of the candidate AMP around ovulation or in inflamed endometrial tissue during the puerperium suggests their crucial role in uterine innate immunity in the defense against invading bacteria. Copyright © 2016 Elsevier Inc. All rights reserved.

Protein tyrosine phosphatase 1B negatively regulates S100A9-mediated lung damage during respiratory syncytial virus exacerbations.

PubMed

Foronjy, R F; Ochieng, P O; Salathe, M A; Dabo, A J; Eden, E; Baumlin, N; Cummins, N; Barik, S; Campos, M; Thorp, E B; Geraghty, P

2016-09-01

Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B expression affects lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production, and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection. Utilizing a neutralizing anti-S100A9 IgG antibody, it was determined that extracellular S100A9 signaling significantly affects lung damage during RSV infection. Preexposure to cigarette smoke desensitized PTP1B activity that coincided with enhanced S100A9 secretion and inflammation in wild-type animals during RSV infection. S100A9 levels in human bronchoalveolar lavage fluid had an inverse relationship with lung function in healthy subjects, smokers, and COPD subjects. Fully differentiated human bronchial epithelial cells isolated from COPD donors cultured at the air liquid interface secreted more S100A9 than cells from healthy donors or smokers following RSV infection. Together, these findings show that reduced PTP1B responses contribute to disease symptoms in part by enhancing S100A9 expression during viral-associated COPD exacerbations.

Essential oils from Schinus species of northwest Argentina: Composition and antifungal activity.

PubMed

Sampietro, Diego A; Belizana, Maria Melina E; Baptista, Zareath P Terán; Vattuone, Marta A; Catalán, Cesar A N

2014-07-01

The composition of the essential oils from leaves (Sal) and fruits of S. areira (Saf), and fruits of S. fasciculatus (Sff) and S. gracilipes (Sgf) were analyzed by GC/MS. The major compounds identified were sabinene (26.0 +/- 0.5%), bicyclogermacrene (14.5 +/- 0.4%), and E-citral (6.7+/- 0.2%) in Sal oil, limonene (27.7 +/- 0.7%), sabinene (16.0+/- 0.5%), beta-phellandrene (14.6 +/- 0.8%) and bicyclogermacrene (8.1 +/- 0.2%) in Saf oil, sabinene (22.7 +/- 0.6%), alpha-phellandrene (18.7 +/- 0.3%), beta-phellandrene (15.7 +/- 0.4%), and bicyclogermacrene (8.1 +/- 0.2%) in Sff oil and beta-pinene (25.4 +/- 0.8%), alpha-pinene (24.7 +/- 0.7%), and sabinene (13.6 +/- 0.4%) in Sgf oil.The antifungal activity of the four oils was evaluated on strains of Fusarium verticillioides and F. graminearum, and the results compared with the effect of epoxyconazole, pyraclostrobin and thyme oil. The Sff oil had the highest antifungal activity among the Schinus oils tested, with MIC100 (F. graminearum) = 6 per thousand and MIC100 (F. verticillioides) = 12 per thousand. A principal component analysis suggests that 9 constituents (alpha-thujene, alpha-terpinene, p-cymene, gamma-terpinene, terpinolene, 1-terpineol, alpha-calacorene, alpha-phellandrene, and terpinen-4-ol) explain the higher antifungal effect of Sff. The MIC100s of Schinus oils were on average 30-60 and 8.5-17 fold lower than those obtained for thyme oil on F. verticillioides and F. graminearum, respectively. In the case of commercial fungicides, their MIC100s were three orders of magnitude lower than those of Schinus oils. The last ones showed an additive interaction when assayed in mixtures with the commecial fungicides and thyme oil. The results suggest that the doses of fungicides required for control of the Fusarium species can be reduced when they are assayed in mixtures with the Schinus oils.

Frozen section analysis and sentinel lymph node biopsy in well differentiated thyroid cancer

PubMed Central

2013-01-01

Background The aim of this study is to prospectively review the role of sentinel lymph node (SLN) biopsy in the management of well differentiated thyroid carcinoma (WDTC), and to determine the efficacy of intraoperative frozen section analysis at detecting SLN metastasis and central compartment involvement. Methods The SLN biopsy protocol using 1% methylene blue was performed in 300 patients undergoing thyroidectomy for WDTC. A limited pretracheal central compartment neck dissection (CCND) was performed on all patients. Lymph nodes staining blue were considered as SLN’s. Both frozen and permanent section analyses were performed. Results SLN’s with metastasis were found in 14.3% (43/300) of cases. Of this, 11% (33/300) were positive on intraoperative frozen section analysis. Frozen section results failed in predicting central compartment involvement in 15 cases (5%) whereas central neck compartment involvement was missed in 5 cases (1.7%) when based on permanent section results. On frozen section analysis, the sensitivity, specificity, positive predictive value and negative predictive value (95% CI) of our SLN biopsy technique aiming to remove all disease from the central compartment was 68.8% (53.6-80.9), 100% (98.1-100), 100% (87.0-100) and 94.4% (90.7-96.7) respectively with P < 0.0001. On permanent section analysis, the values were 89.6% (76.6-96.1), 100% (98.1-100), 100% (89.8-100), and 98.1% (95.3-99.3) with P < 0.0001. Conclusion This data series demonstrates that patients with WDTC have positive SLN’s in 14.3% of cases. Moreover, when the SLN’s are negative for metastasis on frozen section, the central compartment was disease-free in 94.4% of cases. Finally, this study shows that 23.3% of positive SLN’s were false negatives on intraoperative frozen section. According to this data, SLN involvement is an accurate predictor of central compartment metastasis, however surgeons should use caution when relying on intraoperative frozen section to determine whether to perform a CCND. PMID:24025621

Effects of altitude on the energetics of human best performances in 100 m running: a theoretical analysis.

PubMed

Arsac, Laurent M

2002-05-01

The present study was designed to investigate the role of reduced air density on the energetics of 100 m running at altitude. A mathematical supply-demand model was used where supply had two components, aerobic and anaerobic and demand had three components: the cost of overcoming non-aerodynamic forces (C(na)), the cost of overcoming air resistance (C(aero)), and the cost due to changes in the runner's kinetic energy (C(kin)). Actual instantaneous-speed curves recorded in 100 m world champions were modelled at sea level. Then I calculated improvements in 100 m running times and changes in the components of the energy cost with changes in altitude from 0 m to 4,000 m. For the 100 m world championship for men, the model predicted times of 9.88 s at sea level, 9.80 s at 1,000 m, 9.73 s at 2,000 m, 9.64 s at 4,000 m and 9.15 s in the hypothetical situation where the air resistance was nil. In the counterpart for women the corresponding times were 10.85 s, 10.76 s, 10.70 s, 10.60 s and 10.04 s. The C(aero) was 12%-13% of demand at sea level, 10%-11% at 2,000 m and 8%-9% at 4,000 m. When C(aero) decreased this led to better performance by making more energy available for acceleration. Accordingly, C(kin) increased from 20%-24% at sea level to 23%-27% at 4,000 m. There was no effect of altitude specific to body size.

A Primal DPG Method Without a First Order Reformulation

DTIC Science & Technology

2013-05-01

PERFORMING ORGANIZATION NAME(S) AND ADDRESS( ES ) University of Texas at Austin,Institute for Computational Engineering and Sciences,Austin,TX,78712 8...PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS( ES ) 10. SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR...J. GOPALAKRISHNAN 100 102 104 106 10−8 10−6 10−4 10−2 100 102 Square domain: h and p convergence # Degrees of Freedom R el at iv e er ro r i n H1

Aggregation of the Inflammatory S100A8 Precedes Aβ Plaque Formation in Transgenic APP Mice: Positive Feedback for S100A8 and Aβ Productions.

PubMed

Lodeiro, Maria; Puerta, Elena; Ismail, Muhammad-Al-Mustafa; Rodriguez-Rodriguez, Patricia; Rönnbäck, Annica; Codita, Alina; Parrado-Fernandez, Cristina; Maioli, Silvia; Gil-Bea, Francisco; Merino-Serrais, Paula; Cedazo-Minguez, Angel

2017-03-01

Inflammation plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Although chronic inflammation in later stages of AD is well described, little is known about the inflammatory processes in preclinical or early stages of the disease prior to plaque deposition. In this study, we report that the inflammatory mediator S100A8 is increased with aging in the mouse brain. It is observed as extracellular aggregates, which do not correspond to corpora amylacea. S100A8 aggregation is enhanced in the hippocampi of two different mouse models for amyloid-β (Aβ) overproduction (Tg2576 and TgAPParctic mice). S100A8 aggregates are seen prior the formation of Aβ plaques and do not colocalize. In vitro treatment of glial cells from primary cultures with Aβ42 resulted in an increased production of S100A8. In parallel, treatment of a neuronal cell line with recombinant S100A8 protein resulted in enhanced Aβ42 and decreased Aβ40 production. Our results suggest that important inflammatory processes are occurring prior to Aβ deposition and the existence of a positive feedback between S100A8 and Aβ productions. The possible relevance of aging- or AD-dependent formation of S100A8 aggregates in the hippocampus thus affecting learning and memory processes is discussed. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A pilot study of S-1 plus cisplatin versus 5-fluorouracil plus cisplatin for postoperative chemotherapy in histological stage IIIB-IV (M0) gastric cancer.

PubMed

Lee, Sung Sook; Jeung, Hei-Cheul; Chung, Hyun Cheol; Noh, Sung Hoon; Hyung, Woo Jin; Ahn, Ji Yeong; Rha, Sun Young

2012-02-01

Although its efficacy is unproven, 5-fluorouracil plus cisplatin (FP) is used to prevent postoperative relapse in gastric cancer. We investigated the safety and feasibility of S-1 plus cisplatin (SP) vs. FP for stage IIIB-IV (M0) gastric cancer. Following curative resection, 41 stage IIIB-IV (M0) gastric cancer patients were assigned to SP (eight 14-day cycles of S-1 [40 mg/m(2) twice daily] plus cisplatin [60 mg/m(2) day 1] administered every 3 weeks) or FP (six 3-day cycles of FU [1 g/m(2) per day] plus cisplatin [80 mg/m(2) day 1] every 4 weeks). Doses were reduced based on predefined criteria. Patient characteristics were balanced between the two arms. In total, 124 cycles of SP (N = 20, median = 7, range 1-8) and 113 cycles of FP (N = 21, median 6, range 1-6) were administered. The median relative dose intensity per patient was 75% (49.99-100%) for S-1, 100% (75-100%) for cisplatin in SP, and 100% (64-100%) for 5-FU, 100% (60-100%) for cisplatin in FP. The relative dose intensity of FP was stable, while that of SP decreased during treatment. After median follow-up of 7.9 months (3.8-14.55), the median RFS was not reached. Relapse occurred in two (10%) patients on SP and five (23.8%) in the FP arm (P = 0.24). The incidence of grade 3-4 granulocytopenia was 36.8% with SP and 14.3% with FP. Grade 3-4 non-hematologic toxicities included fatigue (5.2% with SP vs. 4.8% with FP), vomiting (10.5% with SP vs. 0% with FP), and infection (5.2% with SP vs. 0% FP). S-1 plus cisplatin was feasible and tolerable as adjuvant treatment for stage IIIB-IV (M0) gastric cancer. However, because of decreased relative dose intensity during treatment, further study is warranted to determine optimal dosage and combination.

JPRS Report, Science & Technology, Japan, Fine Ceramics Industry Basic Issues Forum

DTIC Science & Technology

1990-10-12

Department, Nagoya Industrial Technology Testing Station, Agency of Industrial Science & Technology Tetsuya Uchino Director, Asahi Glass Co, Ltd...12.5) (100) Steel 15 3 30 75 16 8 132 (22.7) (56.8) (12.2) (100) Glass , 12 13 73 2 16 15 119 Earth & Rock (10.9) (61.3) (13.4) (100) Share, by...fil- ters, burners Nuclear Power Equipment P&S Materials used in nuclear fusion reactors R&D Materials used to fix waste products in glass , materials

Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury

PubMed Central

Kim, Ae Jin; Ro, Han; Kim, Hyunsook; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Jung, Ji Yong

2016-01-01

Early detection and accurate differentiation of the cause of AKI may improve the prognosis of the patient. However, to date, there are few reliable biomarkers that can discriminate between pre-renal and intrinsic AKI. In this study, we determined whether AKI is associated with altered serum and urinary levels of Klotho, S100A8/A9 (an endogenous ligand of toll-like receptor 4), and neutrophil gelatinase-associated lipocalin (NGAL), which may allow differentiation between pre-renal and intrinsic AKI. A volume-depleted pre-renal AKI model was induced in male Sprague Dawley rats fed a low-salt diet (0.03%) without water 96 h before two intraperitoneal (IP) injections of furosemide (20 mg/kg) at a 24 h interval. In contrast, in the cisplatin-induced intrinsic AKI model, animals were given a single IP injection of cisplatin (5 mg/kg). All of the animals were euthanized 72 h after the first IP injection. Serum and urinary levels of Klotho, S100A8/A9, and NGAL were measured using an enzyme-linked immunosorbent assay. We also performed a proof-of-concept cross-sectional study to measure serum and urinary biomarkers in 61 hospitalized patients with established AKI. Compared to the intrinsic AKI group, the pre-renal AKI group showed a marked depression in urinary Klotho levels (13.21±17.32 vs. 72.97±17.96 pg/mL; P = 0.002). In addition, the intrinsic AKI group showed marked elevation of S100A8/A9 levels compared to the pre-renal AKI group (2629.97±598.05 ng/mL vs. 685.09±111.65 ng/mL; P = 0.002 in serum; 3361.11±250.86 ng/mL vs. 741.72±101.96 ng/mL; P = 0.003 in urine). There was no difference in serum and urinary NGAL levels between the pre-renal and intrinsic AKI groups. The proof-of-concept study with the hospitalized AKI patients also demonstrated decreased urinary Klotho in pre-renal AKI patients and increased urinary S100A8/A9 concentrations in intrinsic AKI patients. The attenuation of urinary Klotho and increase in urinary S100A8/A9 may allow differentiation between pre-renal and intrinsic AKI. PMID:26799323

The Effect of Diode Laser With Different Parameters on Root Fracture During Irrigation Procedure.

PubMed

Karataş, Ertuğrul; Arslan, Hakan; Topçuoğlu, Hüseyin Sinan; Yılmaz, Cenk Burak; Yeter, Kübra Yesildal; Ayrancı, Leyla Benan

2016-06-01

The aim of this study is to compare the effect of a single diode laser application and agitation of EDTA with diode laser with different parameters at different time intervals on root fracture. Ninety mandibular incisors were instrumented except the negative control group. The specimens were divided randomly into 10 groups according to final irrigation procedure: (G1) non-instrumented; (G2) distilled water; (G3) 15% EDTA; (G4) ultrasonically agitated EDTA; (G5) single 1.5W/100 Hz Diode laser; (G6) single 3W/100 Hz Diode laser; (G7) 1.5W/100 Hz Diode laser agitation of EDTA for 20 s; (G8) 1.5W/100 Hz Diode laser agitation of EDTA for 40 s; (G9) 3W/100 Hz Diode laser agitation of EDTA for 20 s; and (G10) 3W/100 Hz Diode laser agitation of EDTA for 40 s. The specimens were filled, mounted in acrylic resin, and compression strength test was performed on each specimen. Statistical analysis was carried out using one way ANOVA and Tukey's post hoc tests (P = 0.05). The statistical analysis revealed that there were statistically significant differences among the groups (P < 0.05). Laser-agitated irrigation with a 3W/100 Hz Diode laser for both 20 s and 40 s decreased the fracture resistance of teeth. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Manufacturing Information System.

DTIC Science & Technology

1984-12-26

K 21S Nf -J a4 1 *rNJ 4j’ ~a ~ %~a L~’ ~z Q .4 I :1J I In tLj 100. , AID - %-- -7 ,~ ku’ ’.8j pkK4 ~u Ko , jkh~ 9 -j u - 7 Inv A". " .. .Cr . .. "C...space bar to continue’ 7-0 POK.E 1069 0 ’~( 7S0 CMOS = !Nt.EY$ 700 IF CMD$ z 16 THEN 0010 780 - 13’:o IF ChItS =CHRS(271 THEN 010 840 810 IF CMI’S

Color threshold and ratio of S100 beta, MAP5, NF68/200, GABA & GAD. I. Distribution in inner ear afferents

NASA Technical Reports Server (NTRS)

Fermin, C. D.; Martin, D. S.; Hara, H.

1997-01-01

Afferents of chick embryos (Gallus domesticus) VIIIth nerve were examined at E3, E6, E9, E13, El7, and hatching (NH) for anti-S100 beta, anti-MAP5, anti-GABA, anti-GAD and anti-NF68/200 stain. Different ages were processed together to determine if the distribution of these antibodies changed during synaptogenesis and myelination. Color thresholding showed that saturation of pixels changed for S100 beta only 5%, for NF68/200 10%, and for MAP5, 10%, between E9-NH. Color ratio of NF68/200 over MAP5 was 1.00 at E13 and 0.25 at E16 and NH. S100 beta, GABA and GAD were co-expressed on nerve endings at the edge of the maculae and center of the cristae, whereas hair cells in the center of the maculae expressed either S100 beta or GABA, but not both. S100 beta/NF68/200 shared antigenic sites on the chalices, but NF68/200 expression was higher than S100 beta in the chalices at hatching. MAP5 was expressed in more neurons than NF68/200 at E11, whereas NF68/200 was more abundant than MAP5 at hatching. The results suggest that: 1) the immunoexpression of these neuronal proteins is modulated concomitantly with the establishment of afferent synapses and myelination; 2) S100 beta may serve a neurotrophic function in the chalices where it is co-expressed with the neurotransmitter GABA and its synthesizing enzyme GAD.

Thermal transport properties, magnetic susceptibility and neutron diffraction studies of the (Cr100-xAlx)95Mo5 alloy system

NASA Astrophysics Data System (ADS)

Muchono, B.; Sheppard, C. J.; Venter, A. M.; Prinsloo, A. R. E.

2018-05-01

The Seebeck coefficient has been used to investigate QCB in Cr alloys [8,9]. Plots of d S /d T (in the limit T → 2 K) as function of concentration for the (Cr97.8Si2.2)100-yMoy [8] and the (Cr84Re16)100-zVz [9] alloy systems depicted anomalies at the QCP. The possibility of QCB in the (Cr100-xAlx)95Mo5 alloy system is explored by analysing the S(T) data of Fig. 1 by performing a linear-least-squares fit through the 2 K < T < 6.5 K data points. The gradient was taken as dS / dT|T → 2K . Fig. 8 shows dS / dT|T → 2K for concentrations in the range 0.5 ≤ x ≤ 8.6. It increases rapidly to a maximum at x = 1.0, then decreases on further Al addition and displays a minimum just above x = 1.4. This is the concentration where magnetism is seen to disappear on the TN(x) magnetic phase diagram. dS / dT|T → 2K shows a second minimum just above x = 4.4, i.e. corresponding to the concentration where magnetism reappears on the TN(x) magnetic phase diagram (see Fig. 17). Similar minima were also observed at the QCP in the (Cr84Re16)100-zVz [9] and (Cr86Ru14)100-rVr [13] alloy systems. The relatively large error bars in Fig. 8 originate from the large errors in the fitting routine due to a significant scatter in the original Seebeck coefficient data at low temperatures. The solid line through the dS / dT|T → 2K data points is a guide to the eye, while the dotted vertical lines indicate the boundaries between the ISDW, P and CSDW phases. The minima observed in the dS / dT|T → 2K curve correlate to these boundaries.

Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma.

PubMed

Chuang, Ai-Ying; DeMarzo, Angelo M; Veltri, Robert W; Sharma, Rajni B; Bieberich, Charles J; Epstein, Jonathan I

2007-08-01

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial markers were relatively specific with only a few prostate cancers showing scattered (

NASA Astrophysics Data System (ADS)

2018-05-01

The Seebeck coefficient has been used to investigate QCB in Cr alloys [8,9]. Plots of d S /d T (in the limit T → 2 K) as function of concentration for the (Cr97.8Si2.2)100-yMoy [8] and the (Cr84Re16)100-zVz [9] alloy systems depicted anomalies at the QCP. The possibility of QCB in the (Cr100-xAlx)95Mo5 alloy system is explored by analysing the S(T) data of Fig. 1 by performing a linear-least-squares fit through the 2 K < T < 6.5 K data points. The gradient was taken as dS / dT|T → 2K . Fig. 8 shows dS / dT|T → 2K for concentrations in the range 0.5 ≤ x ≤ 8.6. It increases rapidly to a maximum at x = 1.0, then decreases on further Al addition and displays a minimum just above x = 1.4. This is the concentration where magnetism is seen to disappear on the TN(x) magnetic phase diagram. dS / dT|T → 2K shows a second minimum just above x = 4.4, i.e. corresponding to the concentration where magnetism reappears on the TN(x) magnetic phase diagram (see Fig. 17). Similar minima were also observed at the QCP in the (Cr84Re16)100-zVz [9] and (Cr86Ru14)100-rVr [13] alloy systems. The relatively large error bars in Fig. 8 originate from the large errors in the fitting routine due to a significant scatter in the original Seebeck coefficient data at low temperatures. The solid line through the dS / dT|T → 2K data points is a guide to the eye, while the dotted vertical lines indicate the boundaries between the ISDW, P and CSDW phases. The minima observed in the dS / dT|T → 2K curve correlate to these boundaries.

High Productivity Aluminum Manufacturing

DTIC Science & Technology

2013-07-01

D. J. Spinella Alcoa Inc. Alcoa Technical Center 100 Technical Drive Alcoa Center, PA 15069 July 2013 CNST Base Task Order...Myers, Kirit Shah, D. J. Spinella 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Alcoa , Inc...8. PERFORMING ORGANIZATION REPORT NUMBER 100 Technical Drive Alcoa Center, PA 15069 9

Recurrence of intestinal metaplasia and early neoplasia after endoscopic eradication therapy for Barrett’s esophagus: a systematic review and meta-analysis *

PubMed Central

Fujii-Lau, Larissa L.; Cinnor, Birtukan; Shaheen, Nicholas; Gaddam, Srinivas; Komanduri, Srinadh; Muthusamy, V. Raman; Das, Ananya; Wilson, Robert; Simon, Violette C.; Kushnir, Vladimir; Mullady, Daniel; Edmundowicz, Steven A.; Early, Dayna S.; Wani, Sachin

2017-01-01

Background  Conflicting data exist with regard to recurrence rates of intestinal metaplasia (IM) and dysplasia after achieving complete eradication of intestinal metaplasia (CE-IM) in Barrett’s esophagus (BE) patients. Aim  (i) To determine the incidence of recurrent IM and dysplasia achieving CE-IM and (ii) to compare recurrence rates between treatment modalities [radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) vs stepwise complete EMR (SRER)]. Methods  A systematic search was performed for studies reporting on outcomes and estimates of recurrence rates after achieving CE-IM. Pooled incidence [per 100-patient-years (PY)] and risk ratios with 95 %CI were obtained. Heterogeneity was measured using the I 2 statistic. Subgroup analyses, decided a priori, were performed to explore heterogeneity in results. Results  A total of 39 studies were identified (25-RFA, 13-SRER, and 2 combined). The pooled incidence of any recurrence was 7.5 (95 %CI 6.1 – 9.0)/100 PY with a pooled incidence of IM recurrence rate of 4.8 (95 %CI 3.8 – 5.9)/100 PY, and dysplasia recurrence rate of 2.0 (95 %CI 1.5 – 2.5)/100 PY. Compared to the SRER group, the RFA group had significantly higher overall [8.6 (6.7 – 10.5)/100 PY vs. 5.1 (3.1 – 7)/100 PY, P  = 0.01] and IM recurrence rates [5.8 (4.3 – 7.3)/100 PY vs. 3.1 (1.7 – 4)/100 PY, P  < 0.01] with no difference in recurrence rates of dysplasia. Significant heterogeneity between studies was identified. The majority of recurrences were amenable to repeat endoscopic eradication therapy (EET). Conclusion  The results of this study demonstrate that the incidence rates of overall, IM, and dysplasia recurrence rates post-EET are not inconsiderable and reinforce the importance of close surveillance after achieving CE-IM. PMID:28573176

DAMP Molecule S100A9 Acts as a Molecular Pattern to Enhance Inflammation during Influenza A Virus Infection: Role of DDX21-TRIF-TLR4-MyD88 Pathway

PubMed Central

Tsai, Su-Yu; Segovia, Jesus A.; Chang, Te-Hung; Morris, Ian R.; Berton, Michael T.; Tessier, Philippe A.; Tardif, Mélanie R.; Cesaro, Annabelle; Bose, Santanu

2014-01-01

Pathogen-associated molecular patterns (PAMPs) trigger host immune response by activating pattern recognition receptors like toll-like receptors (TLRs). However, the mechanism whereby several pathogens, including viruses, activate TLRs via a non-PAMP mechanism is unclear. Endogenous “inflammatory mediators” called damage-associated molecular patterns (DAMPs) have been implicated in regulating immune response and inflammation. However, the role of DAMPs in inflammation/immunity during virus infection has not been studied. We have identified a DAMP molecule, S100A9 (also known as Calgranulin B or MRP-14), as an endogenous non-PAMP activator of TLR signaling during influenza A virus (IAV) infection. S100A9 was released from undamaged IAV-infected cells and extracellular S100A9 acted as a critical host-derived molecular pattern to regulate inflammatory response outcome and disease during infection by exaggerating pro-inflammatory response, cell-death and virus pathogenesis. Genetic studies showed that the DDX21-TRIF signaling pathway is required for S100A9 gene expression/production during infection. Furthermore, the inflammatory activity of extracellular S100A9 was mediated by activation of the TLR4-MyD88 pathway. Our studies have thus, underscored the role of a DAMP molecule (i.e. extracellular S100A9) in regulating virus-associated inflammation and uncovered a previously unknown function of the DDX21-TRIF-S100A9-TLR4-MyD88 signaling network in regulating inflammation during infection. PMID:24391503

Differential behavior between S100A9 and adiponectin in coronary artery disease. Plasma or epicardial fat.

PubMed

Agra, Rosa María; Teijeira-Fernández, Elvis; Pascual-Figal, Domingo; Jesús, Sánchez-Más; Fernández-Trasancos, Angel; Sierra, Juan; González-Juanatey, José Ramón; Eiras, Sonia

2014-04-01

S100A9 is a new inflammatory marker associated with obesity and cardiovascular disease. Because epicardial adipose tissue (EAT) is an inflammatory source in coronary artery disease (CAD), our aim was to evaluate the S100A9 levels in plasma and EAT and its association with CAD. Blood, EAT and/or subcutaneous adipose tissue (SAT) biopsies were obtained from 89 patients undergoing elective cardiac surgery. Plasma S100A9 and adiponectin were analyzed by enzyme-linked immunosorbent assay (ELISA) and mRNA expression in both fat pads and were measured by real-time polymerase chain reaction (PCR). Our results have shown higher levels of plasma S100A9 in patients with CAD than those without (29 [10-50] vs. 17 [3-28] ng/mL; p=0.007). They were dependent on the number of injured-coronaries (p=0.002) with tendency toward negative association with plasma adiponectin (p=0.139). Although EAT expressed higher levels than SAT and their levels were higher in CAD patients, this last difference did not reach statistical significance. However, there was a positive correlation between neutrophils and EAT S100A9 expression (p=0.007) that may reveal an increase of neutrophil filtration on this fat pad. Plasma S100A9 levels are increased in chronic CAD. The absence of differences regarding EAT S100A9 expression levels indicates a differential inflammatory process between fat tissues and blood in CAD process. Copyright © 2014 Elsevier Inc. All rights reserved.

Role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes via TLR4/ROS/NF-κB pathway.

PubMed

Yu, Jiangkun; Lu, Yanyu; Li, Yapeng; Xiao, Lili; Xing, Yu; Li, Yanshen; Wu, Leiming

2015-09-01

S100A1 plays a crucial role in hypoxia-induced inflammatory response in cardiomyocytes. However, the role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes is still unknown. enzyme-linked immunosorbent assay (ELISA) was performed for the determination of inflammatory cytokines. Immunocytochemistry and immunofluorescence, Western blot analysis and Real-time polymerase chain reaction (RT-PCR) were conducted to assess protein or mRNA expressions. Fluorogenic probe dihydroethidium (DHE) was used to evaluate the generation of reactive oxygen species (ROS) while Hoechst 33342 staining for apoptosis. Small interfering RNA (siRNA) for S100A1 was used to evaluate the role of S100A1. The levels of ROS and inflammatory cytokine including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-8 in H9c2 cells were increased remarkably by hypoxia. However, IL-37 protein or mRNA levels were decreased significantly. Both Toll-like receptor 4 (TLR4) inhibitor Ethyl (6R)-6-[N-(2-Chloro-4fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242) treatment or siRNA S100A1 downregulated TLR4 expression and inflammatory cytokine level and mRNA in H9c2 cells, as well as weakening ROS and phospho-p65 Nuclear factor (NF)-κB levels. Further, S100A1 treatment significantly reduced TNF-α protein or mRNA level whereas enhanced IL-37 protein or mRNA level, and could attenuate ROS and phospho-p65 NF-κB levels. Our results demonstrate that S100A1 can regulate the inflammatory response and oxidative stress in H9C2 cells via TLR4/ROS/NF-κB pathway. These findings provide an interesting strategy for protecting cardiomyocytes from hypoxia-induced inflammatory response. © 2015 Royal Pharmaceutical Society.

Accuracy of Mobile Phone and Handheld Light Microscopy for the Diagnosis of Schistosomiasis and Intestinal Protozoa Infections in Côte d’Ivoire

PubMed Central

Coulibaly, Jean T.; Ouattara, Mamadou; D’Ambrosio, Michael V.; Fletcher, Daniel A.; Keiser, Jennifer; Utzinger, Jürg; N’Goran, Eliézer K.

2016-01-01

Background Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis. Methodology Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope). The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d’Ivoire. One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy. Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa. Principal Findings The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively. The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8–99.6%) and 81.1% (95% CI 71.2–88.3%), respectively, and specificities of 99.5% (95% CI 97.0–100%) and 97.1% (95% CI 92.2–99.1%), respectively. The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4–74.6%) and 35.6% (95% CI 25.9–46.4%), respectively, and specificities of 99.5% (95% CI 97.0–100%) and 100% (95% CI 86.7–100%), respectively. For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1–94.7%) and 83.3% (95% CI 36.5–99.1%), respectively, and 100% specificity. Conclusions/Significance Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites. PMID:27348755

Scavenger receptor class A type I/II determines matrix metalloproteinase-mediated cartilage destruction and chondrocyte death in antigen-induced arthritis.

PubMed

van Lent, P L E M; Hofkens, W; Blom, A B; Grevers, L; Sloetjes, A; Takahashi, N; van Tits, L J; Vogl, T; Roth, J; de Winther, M P; van den Berg, W B

2009-10-01

Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA). AIA was induced in the knee joints of SR-AI/II(-/-) mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)-mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. In synovial washouts, cytokines (interleukin-1beta [IL-1beta], IL-10, and tumor necrosis factor alpha) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay. Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40-75% of the cartilage surfaces. In striking contrast, in SR-AI/II(-/-) mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1beta and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable. Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA.

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment.

PubMed

Zha, He; Sun, Hui; Li, Xueru; Duan, Liang; Li, Aifang; Gu, Yue; Zeng, Zongyue; Zhao, Jiali; Xie, Jiaqing; Yuan, Shimei; Li, Huan; Zhou, Lan

2016-07-01

Previous studies have shown that S100 calcium-binding protein A8 (S100A8) contributes to the survival and migration of colorectal cancer (CRC) cells. However, whether S100A8 participates in the progression and metastasis of CRC via the regulation of macrophages in the tumor inflammatory microenvironment remains unknown. In this study, phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. MTT assay, western blot analysis, immunofluorescence staining, semi-quantitative RT-PCR (semi-PCR), quantitative real-time PCR (qPCR), Gaussia luciferase activity assay and ELISA were performed to analyze the roles and molecular mechanisms of S100A8 in the modulation of macrophages. MTT assay, flow cytometric analysis, Hoechst staining, wound healing and Transwell migration assay were used to test the effect of S100A8 on the viability and migration of CRC cells co-cultured with macrophages in the inflammatory microenvironment. We found that THP-1 monocytes were induced by PMA and differentiated to macrophages. S100A8 activated the NF-κB pathway in the macrophages and promoted the expression of miR-155 and inflammatory cytokines IL-1β and TNF-α in the inflammatory microenvironment mimicked by lipopolysaccharides (LPS). Furthermore, S100A8 contributed to augment the migration but not the viability of the CRC cells co-cultured with the macrophages in the inflammatory microenvironment. Altogether, our study demonstrated that S100A8 facilitated the migration of CRC cells in the inflammatory microenvironment, and the underlying molecular mechanisms may be partially attributed to the overexpression of miR-155, IL-1β and TNF-α through activation of the NF-κB pathway in macrophages.

Evaluation of tumor blood flow in musculoskeletal lesions: dynamic contrast-enhanced MR imaging and its possibility when monitoring the response to preoperative chemotherapy-work in progress.

PubMed

Kajihara, Makoto; Sugawara, Yoshifumi; Sakayama, Kenshi; Kikuchi, Keiichi; Mochizuki, Teruhito; Murase, Kenya

2007-04-01

The objective of this study was to calculate tumor blood flow (TBF) in musculoskeletal lesions and to evaluate the usefulness of this parameter in differentiating malignant from benign lesions and monitoring the treatment response to preoperative chemotherapy. Altogether, 33 patients with musculoskeletal lesions underwent a total of 50 dynamic magnetic resonance imaging (MRI) examinations, including 28 on 9 patients undergoing preoperative chemotherapy. TBF was calculated using deconvolution analysis. Steepest slope (SS) was determined from the time-intensity curve during the first pass of contrast medium. TBF ranged from 2.7 to 178.6 mL/100 mL/min in benign lesions and from 15.4 to 296.3 mL/100 mL/min in malignant lesions. SS ranged from 0.5%/s to 31.8%/s for benign lesions and from 3.1%/s to 64.8%/sec for malignant lesions. TBF and SS did not differ significantly between benign and malignant lesions. Among the nine patients who underwent preoperative chemotherapy, TBF after chemotherapy was lower in good responders (11.7, 11.0, 7.9 mL/100 mL/min) (n = 3, tumor necrosis > or =90%) than in poor responders (23.4-141.5 mL/100 mL/min) (n = 6, tumor necrosis <90%). TBF and SS cannot reliably differentiate malignant from benign lesions. However, they have potential utility in evaluating the preoperative treatment response in patients with malignant musculoskeletal tumors.

The burden of road traffic crashes, injuries and deaths in Africa: a systematic review and meta-analysis

PubMed Central

Thompson, Jacqueline Y; Akanbi, Moses A; Azuh, Dominic; Samuel, Victoria; Omoregbe, Nicholas; Ayo, Charles K

2016-01-01

Abstract Objective To estimate the burden of road traffic injuries and deaths for all road users and among different road user groups in Africa. Methods We searched MEDLINE, EMBASE, Global Health, Google Scholar, websites of African road safety agencies and organizations for registry- and population-based studies and reports on road traffic injury and death estimates in Africa, published between 1980 and 2015. Available data for all road users and by road user group were extracted and analysed. We conducted a random-effects meta-analysis and estimated pooled rates of road traffic injuries and deaths. Findings We identified 39 studies from 15 African countries. The estimated pooled rate for road traffic injury was 65.2 per 100 000 population (95% confidence interval, CI: 60.8–69.5) and the death rate was 16.6 per 100 000 population (95% CI: 15.2–18.0). Road traffic injury rates increased from 40.7 per 100 000 population in the 1990s to 92.9 per 100 000 population between 2010 and 2015, while death rates decreased from 19.9 per 100 000 population in the 1990s to 9.3 per 100 000 population between 2010 and 2015. The highest road traffic death rate was among motorized four-wheeler occupants at 5.9 per 100 000 population (95% CI: 4.4–7.4), closely followed by pedestrians at 3.4 per 100 000 population (95% CI: 2.5–4.2). Conclusion The burden of road traffic injury and death is high in Africa. Since registry-based reports underestimate the burden, a systematic collation of road traffic injury and death data is needed to determine the true burden. PMID:27429490

Cross-Validation of AFOQT Form S for Cyberspace Operations - Cyberspace Control

DTIC Science & Technology

2016-04-20

50.8 61.5 66.0 69.1 82.5 VERB 60.3 26.1 .36*** 45.6 56.7 61.1 65.8 76.4 QUANT 65.7 24.9 .29*** 55.2 63.3 65.5 67.7 81.0 Notes. *** p < .001...Grade Quintile Note. Percentile scoring on y-axis. 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 PILOT NAVTECH ACAD VERB QUANT AVE

Gene Expression Differences in Infected and Noninfected Middle Ear Complementary DNA Libraries

PubMed Central

Kerschner, Joseph E.; Horsey, Edward; Ahmed, Azad; Erbe, Christy; Khampang, Pawjai; Cioffi, Joseph; Hu, Fen Ze; Post, James Christopher; Ehrlich, Garth D.

2010-01-01

Objectives To investigate genetic differences in middle ear mucosa (MEM) with nontypeable Haemophilus influenzae (NTHi) infection. Genetic upregulation and downregulation occurs in MEM during otitis media (OM) pathogenesis. A comprehensive assessment of these genetic differences using the techniques of complementary DNA (cDNA) library creation has not been performed. Design The cDNA libraries were constructed from NTHi-infected and noninfected chinchilla MEM. Random clones were picked, sequenced bidirectionally, and submitted to the National Center for Biotechnology Information (NCBI) Expressed Sequence Tags database, where they were assigned accession numbers. These numbers were used with the basic local alignment search tool (BLAST) to align clones against the nonredundant nucleotide database at NCBI. Results Analysis with the Web-based statistical program FatiGO identified several biological processes with significant differences in numbers of represented genes. Processes involved in immune, stress, and wound responses were more prevalent in the NTHi-infected library. S100 calcium-binding protein A9 (S100A9); secretory leukoprotease inhibitor (SLPI); β2-microglobulin (B2M); ferritin, heavy-chain polypeptide 1 (FTH1); and S100 calcium-binding protein A8 (S100A8) were expressed at significantly higher levels in the NTHi-infected library. Calcium-binding proteins S100A9 and S100A8 serve as markers for inflammation and have antibacterial effects. Secretory leukoprotease inhibitor is an antibacterial protein that inhibits stimuli-induced MUC1, MUC2, and MUC5AC production. Conclusions A number of genes demonstrate changes during the pathogenesis of OM, including SLPI, which has an impact on mucin gene expression; this expression is known to be an important regulator in OM. The techniques described herein provide a framework for future investigations to more thoroughly understand molecular changes in the middle ear, which will likely be important in developing new therapeutic and intervention strategies. PMID:19153305

Sequence characterization of S100A8 gene reveals structural differences of protein and transcriptional factor binding sites in water buffalo and yak.

PubMed

Kathiravan, P; Goyal, S; Kataria, R S; Mishra, B P; Jayakumar, S; Joshi, B K

2011-01-01

The present study was undertaken to characterize the structure of S100A8 gene and its promoter in water buffalo and yak. Sequence data of 2.067 kb, 2.071 kb, and 2.052 kb with respect to complete S100A8 gene including 5' flanking region was generated in river buffalo, swamp buffalo, and yak, respectively. BLAST analysis of coding DNA sequences (CDS) of S100A8 gene revealed 95% homology of buffalo sequence with cattle, 85% with pig and horse, 83% with dog, 72-73% with murines, and around 79% with primates and humans. Phylogenetic analysis of predicted CDS revealed distinct clustering of murines, primates, and domestic animals with bovines and bubalines forming a subcluster among farm animals. In silico translation of predicted CDS revealed a sequence of 89 amino acids with 7 amino acid changes between cattle and buffalo and 2 changes between cattle and yak. The search for Pfam family revealed the N-terminal calcium binding domain and the noncanonical EF hand domain in the carboxy terminus, with more variations being observed in the N-terminal domain among different species. Two amino acid changes observed in carboxy terminal EF hand domain resulted in altered secondary structure of yak S100A8 protein. Analysis of S100A8 gene promoter revealed 14 putative motifs for transcriptional factor binding sites. Two putative motifs viz. C/EBP and v-Myb were found to be absent in swamp buffalo as compared to river buffalo and cattle. Differences in the structure of S100A8 protein and the transcriptional factor binding sites identified in the present study need to be analyzed further for their functional significance in yak and swamp buffalo respectively. Copyright © Taylor & Francis Group, LLC

Blood flow variation in human muscle during electrically stimulated exercise bouts.

PubMed

Vanderthommen, Marc; Depresseux, Jean-Claude; Dauchat, Luc; Degueldre, Christian; Croisier, Jean-Louis; Crielaard, Jean-Michel

2002-07-01

To evaluate, with a high spatial resolution, the blood flow variations in human skeletal muscle during neuromuscular electric stimulation (NMES) and hence to gain better understanding of the mechanisms of muscle spatial recruitment during NMES. One thigh was submitted to 3 stimulation bouts of different durations (S1=4min, S2=8min, S3=12min) with a workload corresponding to 10% of quadriceps maximal isometric voluntary torque. A cyclotron research center at a Belgian university. Ten healthy male volunteers. Not applicable. Participants were studied with positron emission tomography and H(2)(15)O. Tissue blood flow was evaluated during the last 4 minutes of each stimulation bout in multiple regions of interest (ROIs) selected in the transverse section of the stimulated thigh. Mean tissue blood flow was significantly lower during S1 (5.9+/-1.3mL. min(-1). 100g(-1)) than during S2 (10.6+/-3.4mL. min(-1). 100g(-1)) and S3 (11.6+/-3.7mL. min(-1). 100g(-1)) (P<.05). For each ROI, an arbitrary tissue blood flow activation level of 5mLmin(-1)100g(-1) was fixed. The mean percentage of activated ROIs reached 42.4%, 62.7%, and 63.6% during S1, S2, and S3, respectively. Between S1 and S3, the newly recruited ROIs were preferentially located far from the electrode. During NMES, new muscular regions situated far from the stimulation site are recruited. These recruitment mechanisms are particular and contrast with the recruitment of motor units seen during voluntary contraction. Copyright 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

S100A8, An Oocyte-Specific Chemokine, Directs the Migration of Ovarian Somatic Cells During Mouse Primordial Follicle Assembly.

PubMed

Teng, Zhen; Wang, Chao; Wang, Yijing; Huang, Kun; Xiang, Xi; Niu, Wanbao; Feng, Lizhao; Zhao, Lihua; Yan, Hao; Zhang, Hua; Xia, Guoliang

2015-12-01

In the mammalian ovaries, the primordial follicle pool determines the reproductive capability over the lifetime of a female. The primordial follicle is composed of two cell members, namely the oocyte and the pre-granulosa cells that encircle the oocyte. However, it is unclear what factors are involved in the reorganization of the two distinct cells into one functional unit. This study was performed to address this issue. Firstly, in an in vitro reconstruction system, dispersed ovarian cells from murine fetal ovaries at 19.0 days post coitum (dpc) reassembled into follicle-like structures, independent of the physical distance between the cells, implying that either oocytes or ovarian somatic cells (OSCs) were motile. We then carried out a series of transwell assay experiments, and determined that it was in fact 19.0 dpc OSCs (as opposed to oocytes), which exhibited a significant chemotactic response to both fetal bovine serum and oocytes themselves. We observed that S100A8, a multi-functional chemokine, may participate in the process as it is mainly expressed in oocytes within the cysts/plasmodia. S100A8 significantly promoted the number of migrating OSCs by 2.5 times in vitro, of which 66.9% were FOXL2 protein-positive cells, implying that the majority of motile OSCs were pre-granulosa cells. In addition, an S100A8-specific antibody inhibited the formation of follicle-like reconstruction cell mass in vitro. And, the primordial follicle formation was reduced when S100a8-specific siRNA was applied onto in vitro cultured 17.5 dpc ovary. Therefore, S100A8 could be a chemokine of oocyte origin, which attracts OSCs to form the primordial follicles. © 2015 Wiley Periodicals, Inc.

Interaction of an S100A9 gene variant with saturated fat and carbohydrates to modulate insulin resistance in 3 populations of different ancestries

USDA-ARS?s Scientific Manuscript database

BACKGROUND: S100 calcium binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in depth analyses in other populations and ancestries. OBJECTIVES: We aimed to replicate the associations between an S10...

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

PubMed

Feng, Po-Hao; Yu, Chih-Teng; Chen, Kuan-Yuan; Luo, Ching-Shan; Wu, Shen Ming; Liu, Chien-Ying; Kuo, Lu Wei; Chan, Yao-Fei; Chen, Tzu-Tao; Chang, Chih-Cheng; Lee, Chun-Nin; Chuang, Hsiao-Chi; Lin, Chiou-Feng; Han, Chia-Li; Lee, Wei-Hwa; Lee, Kang-Yun

2018-01-26

Monocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated. Blood monocytic S100A9 + MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9 + MDSCs in PBMC were well correlated to tumor infiltrating CD68 + and S100A9 + cells, suggesting an origin of TAMs. Patient's MDMs, mostly from S100A9 + MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown. In conclusion, blood S100A9 + MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway. Patients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Surgery plus anesthesia induces loss of attention in mice

PubMed Central

Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R.; Xie, Zhongcong

2015-01-01

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium. PMID:26441522

Surgery plus anesthesia induces loss of attention in mice.

PubMed

Ren, Quan; Peng, Mian; Dong, Yuanlin; Zhang, Yiying; Chen, Ming; Yin, Ning; Marcantonio, Edward R; Xie, Zhongcong

2015-01-01

There is a need to develop animal models to study postoperative delirium. Inattention is one of the symptoms of delirium. Increases in the levels of α-synuclein and S100β have been reported to be associated with delirium. Therefore, we set out to determine the effects of surgery plus general anesthesia on the behavioral changes (including loss of attention) in mice and on the levels of α-synuclein and S100β in the brain tissues of these mice. C57BL/6J mice (2- to 8-months-old) had a simple laparotomy plus isoflurane anesthesia. The behavioral changes, including attention level and the speed of movements, were determined 12, 24, and 48 h after the surgery plus anesthesia in the mice. The levels of α-synuclein and S100β in the cortex of these mice following the surgery plus anesthesia were determined by Western blot analysis. We found that there was a loss of attention at 24, but not 12 or 48 h following the surgery plus anesthesia (49% ± 5 vs. 33% ± 2.9, P = 0.011, N = 12) in the mice without significantly affecting the speed of their movements. There were increases in the levels of total α-synuclein (139% ± 33.5 vs. 100% ± 13.7, P = 0.037, N = 6) and S100β (142% ± 7.7 vs. 100% ± 6, P = 0.002, N = 6) in the cortex of the mice 12 h following the surgery plus anesthesia. These findings suggested that the surgery plus isoflurane anesthesia might induce behavioral and biochemical/cellular changes associated with delirium. We could use the surgery plus anesthesia in mice to develop an animal model to study postoperative delirium.

Efficacy of a Novel Topical Combination of Fipronil 9.8% and (S)-Methoprene 8.8% against Ticks and Fleas in Naturally Infested Dogs.

PubMed

Nambi, Ayyanampakkam Pandurangan; Rathi, Badal; S, Kavitha; Dudhatra, Ghanshyam; Yamini, Hamsa S; Ali Bhat, Abid

2016-01-01

The efficacy of a novel topical combination of fipronil 9.8% (w/v) and (S)-methoprene 8.8% (w/v) (Fiprofort® Plus) was tested against ticks and fleas in naturally infested dogs. A total of fifty dogs were allocated in the study with ticks infestation (n = 35) and fleas infestation (n = 15). On day 0, thirty-five tick and fifteen flea infested dogs received the test formulation, a combination of fipronil 9.8% (w/v) and (S)-methoprene 8.8% (w/v) spot-on solution. Ticks and flea counts were taken on days 0 (pretreatment) and 3, 7, 14, 21, 28, and 35 after treatment. Blood samples were collected for evaluation of haematological parameters on days 0 (pretreatment) and 7, 21, and 35 after treatment. All the adult ticks and fleas collected were identified as Rhipicephalus sanguineus and Ctenocephalides felis, respectively. The efficacy of spot-on formulation against ticks was 34.00% (day 3), 53.14% (day 7), 62.71% (day 14), 65.48% (day 21), 59.80% (day 28), and 58.82% (day 35), whereas against fleas it was 38.00% (day 3), 64.34% (day 7), 89.67% (day 14), 95.40% (day 21), 100.00% (day 28), and 100.00% (day 35). Haematological parameters for ticks and fleas infested dogs were statistically nonsignificant as compared to control. The combination of fipronil and (S)-methoprene eliminated the existing ticks and fleas infestation and prevented the dogs from flea and tick infestation for four weeks.

Gene expression profiles of putative biomarker candidates in Mycobacterium avium subsp. paratuberculosis-infected cattle.

PubMed

Park, Hyun-Eui; Shin, Min-Kyoung; Park, Hong-Tae; Jung, Myunghwan; Cho, Yong Il; Yoo, Han Sang

2016-06-01

This study was conducted to analyze the gene expression of prognostic potential biomarker candidates using the whole blood of cattle naturally infected with ITALIC! Mycobacterium aviumsubsp. ITALIC! paratuberculosis(MAP). We conducted real-time PCR to evaluate 23 potential biomarker candidates. Experimental animals were divided into four groups based on fecal MAP PCR and serum ELISA. Seven ( ITALIC! KLRB1, ITALIC! HGF, ITALIC! MPO, ITALIC! LTF, ITALIC! SERPINE1, ITALIC! S100A8and ITALIC! S100A9) genes were up-regulated in fecal MAP-positive cattle and three ( ITALIC! KLRB1, ITALIC! MPOand ITALIC! S100A9) were up-regulated in MAP-seropositive cattle relative to uninfected cattle. In subclinically infected animals, 17 genes ( ITALIC! TFRC, ITALIC! S100A8, ITALIC! S100A9, ITALIC! MPO, ITALIC! GBP6, ITALIC! LTF, ITALIC! KLRB1, ITALIC! SERPINE1, ITALIC! PIGR, ITALIC! IL-10, ITALIC! CXCR3, ITALIC! CD14, ITALIC! MMP9, ITALIC! ELANE, ITALIC! CHI3L1, ITALIC! HPand ITALIC! HGF) were up-regulated compared with the control group. Moreover, six genes ( ITALIC! CXCR3, ITALIC! HP, ITALIC! HGF, ITALIC! LTF, ITALIC! TFRCand ITALIC! GBP6) showed significant differences between experimental groups. Taken together, our data suggest that six genes ( ITALIC! LTF, ITALIC! HGF, ITALIC! HP, ITALIC! CXCR3, ITALIC! GBP6and ITALIC! TFRC) played essential roles in the immune response to MAP during the subclinical stage and therefore might be useful as prognostic biomarkers. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Expected Cardiovascular Benefit of Plasma Cholesterol Lowering with or Without LDL-C Targets in Healthy Individuals at Higher Cardiovascular Risk.

PubMed

Cesena, Fernando Henpin Yue; Laurinavicius, Antonio Gabriele; Valente, Viviane A; Conceição, Raquel D; Santos, Raul D; Bittencourt, Marcio S

2017-06-01

There is controversy whether management of blood cholesterol should be based or not on LDL-cholesterol (LDL-c) target concentrations. To compare the estimated impact of different lipid-lowering strategies, based or not on LDL-c targets, on the risk of major cardiovascular events in a population with higher cardiovascular risk. We included consecutive individuals undergoing a routine health screening in a single center who had a 10-year risk for atherosclerotic cardiovascular disease (ASCVD) ≥ 7.5% (pooled cohort equations, ACC/AHA, 2013). For each individual, we simulated two strategies based on LDL-c target (≤ 100 mg/dL [Starget-100] or ≤ 70 mg/dL [Starget-70]) and two strategies based on percent LDL-c reduction (30% [S30%] or 50% [S50%]). In 1,897 subjects (57 ± 7 years, 96% men, 10-year ASCVD risk 13.7 ± 7.1%), LDL-c would be lowered from 141 ± 33 mg/dL to 99 ± 23 mg/dL in S30%, 71 ± 16 mg/dL in S50%, 98 ± 9 mg/dL in Starget-100, and 70 ± 2 mg/dL in Starget-70. Ten-year ASCVD risk would be reduced to 8.8 ± 4.8% in S50% and 8.9 ± 5.2 in Starget-70. The number of major cardiovascular events prevented in 10 years per 1,000 individuals would be 32 in S30%, 31 in Starget-100, 49 in S50%, and 48 in Starget-70. Compared with Starget-70, S50% would prevent more events in the lower LDL-c tertile and fewer events in the higher LDL-c tertile. The more aggressive lipid-lowering approaches simulated in this study, based on LDL-c target or percent reduction, may potentially prevent approximately 50% more hard cardiovascular events in the population compared with the less intensive treatments. Baseline LDL-c determines which strategy (based or not on LDL-c target) is more appropriate at the individual level. Há controvérsias sobre se o controle do colesterol plasmático deve ou não se basear em metas de concentração de colesterol LDL (LDL-c). Comparar o impacto estimado de diferentes estratégias hipolipemiantes, baseadas ou não em metas de LDL-c, sobre o risco de eventos cardiovasculares maiores em uma população de risco cardiovascular mais elevado. Foram incluídos indivíduos consecutivamente submetidos a uma avaliação rotineira de saúde em um único centro e que apresentavam um risco em 10 anos de doença cardiovascular aterosclerótica (DCVAS) ≥ 7,5% ("pooled cohort equations", ACC/AHA, 2013). Para cada indivíduo, foram simuladas duas estratégias baseadas em meta de LDL-c (≤ 100 mg/dL [Emeta-100] ou ≤ 70 mg/dL [Emeta-70]) e duas estratégias baseadas em redução percentual do LDL-c (30% [E30%] ou 50% [E50%]). Em 1.897 indivíduos (57 ± 7 anos, 96% homens, risco em 10 anos de DCVAS 13,7 ± 7,1%), o LDL-c seria reduzido de 141 ± 33 mg/dL para 99 ± 23 mg/dL na E30%, 71 ± 16 mg/dL na E50%, 98 ± 9 mg/dL na Emeta-100 e 70 ± 2 mg/dL na Emeta-70. O risco em 10 anos de DCVAS seria reduzido para 8,8 ± 4,8% na E50% e para 8,9 ± 5,2 na Emeta-70. O número de eventos cardiovasculares maiores prevenidos em 10 anos por 1.000 indivíduos seria de 32 na E30%, 31 na Emeta-100, 49 na E50% e 48 na Emeta-70. Em comparação com a Emeta-70, a E50% evitaria mais eventos no tercil inferior de LDL-c e menos eventos no tercil superior de LDL-c. As abordagens hipolipemiantes mais agressivas simuladas neste estudo, com base em meta de LDL-c ou redução percentual, podem potencialmente prevenir cerca de 50% mais eventos cardiovasculares graves na população em comparação com os tratamentos menos intensivos. Os níveis basais de LDL-c determinam qual estratégia (baseada ou não em meta de LDL-c) é mais apropriada para cada indivíduo.

Molecular evolution of a novel marsupial S100 protein (S100A19) which is expressed at specific stages of mammary gland and gut development.

PubMed

Kwek, Joly H L; Wynne, Alicia; Lefèvre, Christophe; Familari, Mary; Nicholas, Kevin R; Sharp, Julie A

2013-10-01

S100 proteins are calcium-binding proteins involved in controlling diverse intracellular and extracellular processes such as cell growth, differentiation, and antimicrobial function. We recently identified a S100-like cDNA from the tammar wallaby (Macropus eugenii) stomach. Phylogentic analysis shows wallaby S100A19 forms a new clade with other marsupial and monotreme S100A19, while this group shows similarity to eutherian S100A7 and S100A15 genes. This is also supported by amino acid and domain comparisons. We show S100A19 is developmentally-regulated in the tammar wallaby gut by demonstrating the gene is expressed in the forestomach of young animals at a time when the diet consists of only milk, but is absent in older animals when the diet is supplemented with herbage. During this transition the forestomach phenotype changes from a gastric stomach into a fermentation sac and intestinal flora changes with diet. We also show that S100A19 is expressed in the mammary gland of the tammar wallaby only during specific stages of lactation; the gene is up-regulated during pregnancy and involution and not expressed during the milk production phase of lactation. Comparison of the tammar wallaby S100A19 protein sequence with S100 protein sequences from eutherian, monotreme and other marsupial species suggest the marsupial S100A19 has two functional EF hand domains, and an extended His tail. An evolutionary analysis of S100 family proteins was carried out to gain a better understanding of the relationship between the S100 family member functions. We propose that S100A19 gene/protein is the ancestor of the eutherian S100A7 gene/protein, which has subsequently modified its original function in eutherians. This modified function may have arisen due to differentiation of evolutionary pressures placed on gut and mammary gland developmental during mammal evolution. The highly regulated differential expression patterns of S100A19 in the tammar wallaby suggests that S100A19 may play a role in gut development, which differs between metatherians and eutherians, and/or include a potential antibacterial role in order to establish the correct flora and protect against spiral bacteria in the immature forestomach. In the mammary gland it may protect the tissue from infection at times of vulnerability during the lactation cycle. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent fibrinolysis and matrix invasion in acute promyelocytic leukemia.

PubMed

Huang, Dan; Yang, Yan; Sun, Jian; Dong, Xiaorong; Wang, Jiao; Liu, Hongchen; Lu, Chengquan; Chen, Xueyu; Shao, Jing; Yan, Jinsong

2017-09-01

Aberrant expression of annexin A2-S100A10 heterotetramer (AIIt) associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia (APL), but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor a (PML/RARα) fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5'-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29 ± 0.13 fold higher than that by control pSG5 vector or wild-type RARα. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation (IRPG) in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid (ATRA) significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.

S100B Serum Levels Predict Treatment Response in Patients with Melancholic Depression

PubMed Central

Bergink, Veerle; Grosse, Laura; Alferink, Judith; Drexhage, Hemmo A.; Rothermundt, Matthias; Arolt, Volker; Birkenhäger, Tom K.

2016-01-01

Background: There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients. Methods: After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months. Results: Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement. Conclusions: Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients’ burden of nonresponding to frequently used antidepressants. PMID:26364276

Syphilis in the United States: on the rise?

PubMed

Peterman, Thomas A; Su, John; Bernstein, Kyle T; Weinstock, Hillard

2015-02-01

Syphilis rates and trends vary by population subgroup. Among men who have sex with men (MSM), rates of primary and secondary (P&S) syphilis are high throughout the USA (228.8 per 100,000 in 2013). P&S syphilis among women is much less common (0.9 per 100,000 in 2013) and occurs in isolated outbreaks plus in a few counties with persistent low levels of infection. Congenital syphilis trends closely follow P&S trends among women. These trends have implications for prevention. Routine screening among MSM can prevent tertiary syphilis, but despite interventions, rates of infection continue to rise among MSM and will soon approach those last seen in 1982 (estimate: 340.7 per 100,000). Control of syphilis among women is possible and important because it often leads to congenital syphilis. Outbreaks among heterosexuals can be halted by intensive screening, treatment and partner notification.

Trends in cancer mortality in Mexico, 1981-2007.

PubMed

Bosetti, Cristina; Rodríguez, Teresa; Chatenoud, Liliane; Bertuccio, Paola; Levi, Fabio; Negri, Eva; La Vecchia, Carlo

2011-09-01

The objective of this study was to provide information on recent trends in cancer mortality in Mexico. We analyzed data provided by the World Health Organization, using joinpoint analysis to detect changes in trends between 1981 and 2007. For most cancers, mortality was upward but started to decline in the late 1980's/early 1990's for both sexes. Overall cancer mortality was 75.53/100 000 men, world standard, and 69.2/100 000 women in 2005-2007. Mortality from uterine cancer declined by approximately 2.5% per year in the 1990s, and by approximately 5% per year in the last decade, but its rates remained exceedingly high (9.7/100 000 in 2005-2007). Other major declines over recent years were those of stomach cancer (approximately 2.5% per year, with rates of 6.6/100 000 in men and 4.9/100 000 in women in 2005-2007) and lung cancer (2-2.5% per year, 11.0/100 000 in men and 4.5/100 000 in women in 2005-2007). Mortality leveled off only since the early 1990s for breast and prostate, and since the late 1990s for colorectal cancer. Death rates from cancer in Mexico remained low on a worldwide scale and showed favorable trends over more recent calendar years. Mortality from (cervix) uterine cancer still represents a major public health priority in this country.

Chronic endurance exercise affects paracrine action of CD31+ and CD34+ cells on endothelial tube formation

PubMed Central

Landers-Ramos, Rian Q.; Sapp, Ryan M.; Jenkins, Nathan T.; Murphy, Anna E.; Cancre, Lucile; Chin, Eva R.; Spangenburg, Espen E.

2015-01-01

We aimed to determine if chronic endurance-exercise habits affected redox status and paracrine function of CD34+ and CD34−/CD31+ circulating angiogenic cells (CACs). Subjects were healthy, nonsmoking men and women aged 18–35 yr and categorized by chronic physical activity habits. Blood was drawn from each subject for isolation and culture of CD34+ and CD34−/CD31+ CACs. No differences in redox status were found in any group across either cell type. Conditioned media (CM) was generated from the cultured CACs and used in an in vitro human umbilical vein endothelial cell-based tube assay. CM from CD34+ cells from inactive individuals resulted in tube structures that were 29% shorter in length (P < 0.05) and 45% less complex (P < 0.05) than the endurance-trained group. CD34−/CD31+ CM from inactive subjects resulted in tube structures that were 26% shorter in length (P < 0.05) and 42% less complex (P < 0.05) than endurance-trained individuals. Proteomics analyses identified S100A8 and S100A9 in the CM. S100A9 levels were 103% higher (P < 0.05) and S100A8 was 97% higher in the CD34−/CD31+ CM of inactive subjects compared with their endurance-trained counterparts with no significant differences in either protein in the CM of CD34+ CACs as a function of training status. Recombinant S100A8/A9 treatment at concentrations detected in inactive subjects' CD34−/CD31+ CAC CM also reduced tube formation (P < 0.05). These findings are the first, to our knowledge, to demonstrate a differential paracrine role in CD34+ and CD34−/CD31+ CACs on tube formation as a function of chronic physical activity habits and identifies a differential secretion of S100A9 by CD34−/CD31+ CACs due to habitual exercise. PMID:26055789

Department of the Army Supply Bulletin, Army Medical Department Supply Information, SB8-75-S3

DTIC Science & Technology

2002-03-20

CITRATE INJ R 6505011282441 METHADONE HCL TABS100 R 6505011403199 ALPRAZOLAM TABS 100S Q 6505011403200 ALPRAZOLAM 1MG 100S Q 6505011403201... ALPRAZOLAM TABS 100S Q 6505011403202 ALPRAZOLAM TABS IS100 Q 6505011439269 ALPRAZOLAM TAB 100S Q 6505011461137 OXAZEPAM CAPS10MG100S Q 6505011468044...6505011932690 SUFENTANIL CITRATE IN R 6505011938484 MORPHINE SUL SOL120ML R 6505011947256 SUFENTANIL CITRATE IN R 6505011969501 ALPRAZOLAM TABS 500S Q

Fuel Character Effects on Current, High Pressure Ratio, Can-Type Turbine Combustion Systems

DTIC Science & Technology

1980-04-01

1135 17000 71 4 1130 22000 92 5 1122 32000 133 6 1126 27000 113II 7 (JP-8) 1127 25000 104 8 1132 20000 83 9 1139 14000 58 10 1123 30000 125 11 1124...0.100 0.100 - -- 143l- 7ll /( Iso -kbP[) Fool fl-s,, kg/hr 20.00 -- 29.85 20.17 21.14 24.63 --Srl (t/L 6 /kll 5.116 1 0.081 0.002 6.577 14.284 - - b

First-principles calculations on electronic properties of single-walled carbon nanotubes for H{sub 2}S gas sensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muliyati, Dewi, E-mail: dmuliyati@unj.ac.id; Dept. of Physics, Faculty of Mathematics and Natural Sciences, Universitas Negeri Jakarta; Wella, Sasfan A.

2015-09-30

In this research, we performed first-principles calculations by means of density functional theory (DFT) to investigate the interaction of H{sub 2}S gas on the surface of single-walled carbon nanotubes (SWNTs). In order to understand the effect of chirality to the electronic structure of SWNTs/H{sub 2}S, the pristine SWNTs was varied to become SWNTs (5,0), (6,0), (7,0), (8,0), (9,0), and (10,0). From the calculation we found that after H{sub 2}S adsorbed on surface of SWNTs, the electronic properties of system changes from semiconductor to metal but not vice versa. It was only SWNTs (5,0), (7,0), (8,0), and (10,0) occuring the changingmore » on its electronic properties behavior, others were remain similar with its initial behavior. In the degassing process, metal return to semiconductor behavior, which is an indication that SWNTs is a good gas sensors, responsive and reversible.« less

Establishment a real-time reverse transcription PCR based on host biomarkers for the detection of the subclinical cases of Mycobacterium avium subsp. paratuberculosis.

PubMed

Park, Hyun-Eui; Park, Hong-Tae; Jung, Young Hoon; Yoo, Han Sang

2017-01-01

Bovine paratuberculosis (PTB) is a chronic enteric inflammatory disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) that causes large economic losses in the dairy industry. Spread of PTB is mainly provoked by a long subclinical stage during which MAP is shed into the environment with feces; accordingly, detection of subclinical animals is very important to its control. However, current diagnostic methods are not suitable for detection of subclinical animals. Therefore, the current study was conducted to develop a diagnostic method for analysis of the expression of genes of prognostic potential biomarker candidates in the whole blood of cattle naturally infected with MAP. Real-time PCR with nine potential biomarker candidates was developed for the diagnosis of MAP subclinical infection. Animals were divided into four groups based on fecal MAP PCR and serum ELISA. Eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) were up-regulated in MAP-infected cattle (p <0.05). Moreover, ROC analysis revealed that eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) showed fair diagnostic performance (AUC≥0.8). Four biomarkers (Timp1, S100a8, Defb1, and Defb10) showed the highest diagnostic accuracy in the PCR positive and ELISA negative group (PN group) and three biomarkers (Tfrc, Hp, and Serpine1) showed the highest diagnostic accuracy in the PCR negative and ELISA positive group (NP group). Moreover, three biomarkers (S100a8, Hp, and Defb10) were considered the most reliable for the PCR positive and ELISA positive group (PP group). Taken together, our data suggest that real-time PCR based on eight biomarkers (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) might be useful for diagnosis of JD, including subclinical stage cases.

Establishment a real-time reverse transcription PCR based on host biomarkers for the detection of the subclinical cases of Mycobacterium avium subsp. paratuberculosis

PubMed Central

Park, Hyun-Eui; Park, Hong-Tae; Jung, Young Hoon

2017-01-01

Bovine paratuberculosis (PTB) is a chronic enteric inflammatory disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) that causes large economic losses in the dairy industry. Spread of PTB is mainly provoked by a long subclinical stage during which MAP is shed into the environment with feces; accordingly, detection of subclinical animals is very important to its control. However, current diagnostic methods are not suitable for detection of subclinical animals. Therefore, the current study was conducted to develop a diagnostic method for analysis of the expression of genes of prognostic potential biomarker candidates in the whole blood of cattle naturally infected with MAP. Real-time PCR with nine potential biomarker candidates was developed for the diagnosis of MAP subclinical infection. Animals were divided into four groups based on fecal MAP PCR and serum ELISA. Eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) were up-regulated in MAP-infected cattle (p <0.05). Moreover, ROC analysis revealed that eight genes (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) showed fair diagnostic performance (AUC≥0.8). Four biomarkers (Timp1, S100a8, Defb1, and Defb10) showed the highest diagnostic accuracy in the PCR positive and ELISA negative group (PN group) and three biomarkers (Tfrc, Hp, and Serpine1) showed the highest diagnostic accuracy in the PCR negative and ELISA positive group (NP group). Moreover, three biomarkers (S100a8, Hp, and Defb10) were considered the most reliable for the PCR positive and ELISA positive group (PP group). Taken together, our data suggest that real-time PCR based on eight biomarkers (Timp1, Hp, Serpine1, Tfrc, Mmp9, Defb1, Defb10, and S100a8) might be useful for diagnosis of JD, including subclinical stage cases. PMID:28542507

Demonstration of Mycoplasma bovis by immunohistochemistry and in situ hybridization in an aborted bovine fetus and neonatal calf.

PubMed

Hermeyer, Kathrin; Peters, Martin; Brügmann, Michael; Jacobsen, Björn; Hewicker-Trautwein, Marion

2012-03-01

Mycoplasmas are host-specific commensals on mucous membranes of the genital tract, but infection and clinical disease by Mycoplasma bovis in the genital tract of cattle is not well described. In the current study, 1 aborted bovine fetus and 1 neonatal calf were examined macroscopically and histologically. For the detection of M. bovis, bacterial isolation, immunohistochemistry (IHC), and in situ hybridization (ISH) were performed. For further characterization of the inflammatory infiltrates, IHC was performed using antibodies to cluster of differentiation (CD)3, CD79a, lysozyme, L1, S-100A8, S-100A9, and von Willebrand factor VIII. Gross examination revealed a lobular consolidation of the lung. Histologically, the lungs of both animals showed an interstitial pneumonia associated with suppurative bronchopneumonia, intraalveolar multinucleated giant cells, and lymphocytic aggregates. The expression of L1, S-100A8, and S-100A9 in multinucleated giant cells supports a histiocytic origin. Mycoplasma bovis antigen was detected by IHC in brain, lung, liver, and placenta of the fetus, and M. bovis DNA was detected by ISH in various organs of the fetus, including lung and placenta and within the lung of the calf.

Site Investigation Report. Volume 1. 120th Fighter Interceptor Group, Montana Air National Guard, International Airport, Great Falls, Montana

DTIC Science & Technology

1992-02-01

poisoning. Chromium . Cr is a transition element, occurring in nature principally as the trivalent ion Cr(III), although valence states ranging from -2...mg/kg 100 - 3,000 mg/kg Chromium 12.9 - 20.7 mg/kg 1 - 1,000 mg/kg Copper 6.9 - 18.6 mg/kg 2 - 1,000 mg/kg Lead 5.5 - 12.2 mg/kg 10 - 200 mg/kg Nickel...6.5 S 10.3 S 5.8 80 Barium ND-1,231 241 246 150 5,600 Cadmium ND ND 24.2 0.76 B 40 Chromium 8.7-22.7 13.8 64.9 14.5 8E04 Copper 3.3-19.7 16.1 66.9

HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation

PubMed Central

Liang, XiuBin; Li, Min; Shi, Ming; Li, Yan; Jenkins, Gareth; Lin, XiaWen; Wei, XueFei; Jia, ZhiJun; Feng, XueFeng; Su, DongMing; Guo, WanHua

2017-01-01

Estrogen receptor alpha positive (ER+) of breast cancer could develop resistance to antiestrogens including Tamoxifen. Our previous study showed that the E3 ubiquitin ligase HRD1 played an important role in anti-breast cancer. However, its role in chemotherapy resistance hasn't been reported. In this study, we found that HRD1 expression was downregulated in Tamoxifen-resistant breast cancer cell line MCF7/Tam compared to the Tamoxifen sensitive cell line MCF7. Moreover, S100A8 is the direct target of HRD1 by proteome analysis. Our data showed that HRD1 decreased the protein level of S100A8 through ubiquitination while HRD1 was regulated by acetylation of histone. More importantly, HRD1 knockdown significantly increased the cell survival of MCF7 cells to the Tamoxifen treatment. HRD1 overexpression sensitized MCF7/Tam cells to the Tamoxifen treatment in vitro and in vivo. In conclusion, the decrease of HRD1 expression contributed to Tamoxifen resistance in breast cancer. PMID:28423597

Incidence of type 1 and type 2 diabetes in youth in the U.S. Virgin Islands, 2001-2010.

PubMed

Washington, Raynard E; Orchard, Trevor J; Arena, Vincent C; Laporte, Ronald E; Tull, Eugene S

2013-06-01

To report the annual incidence of type 1 and type 2 diabetes among youth and to describe characteristics of youth diagnosed with diabetes in the U.S. Virgin Islands (USVI). All residents ≤19 years of age diagnosed with diabetes between January 2001 and December 2010 were identified from review of medical records of all hospitals and confirmed by physician query. A total of 82 eligible patients were identified and the registry ascertainment was estimated to be 98.7% complete. The overall age-adjusted annual incidence rates (per 100, 000) of type 1 and type 2 diabetes for the study period were 15.3 (95% CI: 11.3-20.1) and 9.6 (95% CI: 6.8-13.5), respectively. The incidence of type 1 diabetes increased significantly over the study period, with an epidemic-like threefold increase occurring from 2005 (8.7/100, 000) to 2006 (26.4/100, 000; p = 0.05). The incidence of type 1 diabetes was highest in the 10-19 age group in girls (25.6/100, 000), but no age difference was seen in boys, resulting from the lack of a pubertal peak in non-Hispanic Black boys. The incidence of type 2 diabetes rose significantly between 2001 (5.3/100, 000) and 2010 (12.5/100, 000; p = 0.03). The incidence of type 1 and type 2 diabetes in youth is increasing in the USVI, similar to global patterns. Further studies are needed to explore the missing pubertal rise in type 1 diabetes incidence in non-Hispanic Black boys and factors associated with the epidemic-like increases observed over the decade. © 2012 John Wiley & Sons A/S.

47 CFR 87.133 - Frequency stability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... operating in U.S. controlled airspace with 8.33 kHz channel spacing (except equipment being tested by... Tolerance 2 (1) Band-9 to 535 kHz: Aeronautical stations 100 100 Aircraft stations 200 100 Survival craft stations on 500 kHz 5,000 20 Hz 3 Radionavigation stations 100 100 (2) Band-1605 to 4000 kHz: Aeronautical...

47 CFR 87.133 - Frequency stability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... operating in U.S. controlled airspace with 8.33 kHz channel spacing (except equipment being tested by... Tolerance 2 (1) Band-9 to 535 kHz: Aeronautical stations 100 100 Aircraft stations 200 100 Survival craft stations on 500 kHz 5,000 20 Hz 3 Radionavigation stations 100 100 (2) Band-1605 to 4000 kHz: Aeronautical...

47 CFR 87.133 - Frequency stability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... operating in U.S. controlled airspace with 8.33 kHz channel spacing (except equipment being tested by... Tolerance 2 (1) Band-9 to 535 kHz: Aeronautical stations 100 100 Aircraft stations 200 100 Survival craft stations on 500 kHz 5,000 20 Hz 3 Radionavigation stations 100 100 (2) Band-1605 to 4000 kHz: Aeronautical...

Asynchronous recruitment of low-threshold motor units during repetitive, low-current stimulation of the human tibial nerve

PubMed Central

Dean, Jesse C.; Clair-Auger, Joanna M.; Lagerquist, Olle; Collins, David F.

2014-01-01

Motoneurons receive a barrage of inputs from descending and reflex pathways. Much of our understanding about how these inputs are transformed into motor output in humans has come from recordings of single motor units during voluntary contractions. This approach, however, is limited because the input is ill-defined. Herein, we quantify the discharge of soleus motor units in response to well-defined trains of afferent input delivered at physiologically-relevant frequencies. Constant frequency stimulation of the tibial nerve (10–100 Hz for 30 s), below threshold for eliciting M-waves or H-reflexes with a single pulse, recruited motor units in 7/9 subjects. All 25 motor units recruited during stimulation were also recruited during weak (<10% MVC) voluntary contractions. Higher frequencies recruited more units (n = 3/25 at 10 Hz; n = 25/25 at 100 Hz) at shorter latencies (19.4 ± 9.4 s at 10 Hz; 4.1 ± 4.0 s at 100 Hz) than lower frequencies. When a second unit was recruited, the discharge of the already active unit did not change, suggesting that recruitment was not due to increased synaptic drive. After recruitment, mean discharge rate during stimulation at 20 Hz (7.8 Hz) was lower than during 30 Hz (8.6 Hz) and 40 Hz (8.4 Hz) stimulation. Discharge was largely asynchronous from the stimulus pulses with “time-locked” discharge occurring at an H-reflex latency with only a 24% probability. Motor units continued to discharge after cessation of the stimulation in 89% of trials, although at a lower rate (5.8 Hz) than during the stimulation (7.9 Hz). This work supports the idea that the afferent volley evoked by repetitive stimulation recruits motor units through the integration of synaptic drive and intrinsic properties of motoneurons, resulting in “physiological” recruitment which adheres to Henneman’s size principle and results in relatively low discharge rates and asynchronous firing. PMID:25566025

Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia.

PubMed

Aguirre, Alina; Blázquez-Prieto, Jorge; Amado-Rodriguez, Laura; López-Alonso, Inés; Batalla-Solís, Estefanía; González-López, Adrián; Sánchez-Pérez, Moisés; Mayoral-Garcia, Carlos; Gutiérrez-Fernández, Ana; Albaiceta, Guillermo M

2017-05-01

ᅟ: Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 -/- mice were challenged with lipopolysaccharide. MMP-14 levels decreased after endotoxemia. Mutant animals showed 100% mortality, compared to 50% in wildtype mice. The increased mortality was related to a more severe lung injury, an impaired lung MMP-2 activation, and increased levels of the alarmin S100A9. There were no differences in the expression of other mediators including Il6, Cxcl2, Tgfb, Il10, or S100a8. A similar result was observed in lung explants of both genotypes cultured in presence of lipopolysaccharide. In this ex vivo model, exogenous activated MMP-2 ameliorated the observed increase in alarmins. Samples from septic patients showed a decrease in serum MMP-14 and activated MMP-2 compared to non-septic critically ill patients. These results demonstrate that the MMP-14-MMP-2 axis is downregulated during sepsis, leading to a proinflammatory response involving S100A9 and a more severe lung injury. This anti-inflammatory role of MMP-14 could have a therapeutic value in sepsis. • MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 -/- mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.

In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

PubMed Central

Gorbunov, Evgeniy A; Ertuzun, Irina A; Kachaeva, Evgeniya V; Tarasov, Sergey A; Epstein, Oleg I

2015-01-01

Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID:26604768

Evaluation of an On-Farm Culture System (Accumast) for Fast Identification of Milk Pathogens Associated with Clinical Mastitis in Dairy Cows.

PubMed

Ganda, Erika Korzune; Bisinotto, Rafael Sisconeto; Decter, Dean Harrison; Bicalho, Rodrigo Carvalho

2016-01-01

The present study aimed evaluate an on-farm culture system for identification of milk pathogens associated with clinical mastitis in dairy cows using two different gold standard approaches: standard laboratory culture in study 1 and 16S rRNA sequencing in study 2. In study 1, milk from mastitic quarters (i.e. presence of flakes, clots, or serous milk; n = 538) was cultured on-farm using a single plate containing three selective chromogenic media (Accumast-FERA Animal Health LCC, Ithaca, NY) and in a reference laboratory using standard culture methods, which was considered the gold standard. In study 2, mastitic milk was cultured on-farm and analyzed through 16S rRNA sequencing (n = 214). In both studies, plates were cultured aerobically at 37°C for 24 h and read by a single technician masked to gold standard results. Accuracy, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated based on standard laboratory culture in study 1, and PPV was calculated based on sequencing results in study 2. Overall accuracy of Accumast was 84.9%. Likewise, accuracy for identification of Gram-negative bacteria, Staphylococcus sp., and Streptococcus sp. was 96.4%, 93.8%, and 91.5%, respectively. Sensitivity, specificity, PPV, and NPV were 75.0%, 97.9%, 79.6%, and 97.3% for identification of E. coli, 100.0%, 99.8%, 87.5%, and 100.0% for S. aureus, 70.0%, 95.0%, 45.7%, and 98.1% for other Staphylococcus sp., and 90.0%, 92.9%, 91.8%, and 91.2% for Streptococcus sp. In study 2, Accumast PPV was 96.7% for E. coli, 100.0% for Enterococcus sp., 100.0% for Other Gram-negatives, 88.2% for Staphylococcus sp., and 95.0% for Streptococcus sp., respectively. In conclusion, Accumast is a unique approach for on-farm identification pathogens associated with mastitis, presenting overall sensitivity and specificity of 82.3% and 89.9% respectively.

Evaluation of an On-Farm Culture System (Accumast) for Fast Identification of Milk Pathogens Associated with Clinical Mastitis in Dairy Cows

PubMed Central

Ganda, Erika Korzune; Bisinotto, Rafael Sisconeto; Decter, Dean Harrison; Bicalho, Rodrigo Carvalho

2016-01-01

The present study aimed evaluate an on-farm culture system for identification of milk pathogens associated with clinical mastitis in dairy cows using two different gold standard approaches: standard laboratory culture in study 1 and 16S rRNA sequencing in study 2. In study 1, milk from mastitic quarters (i.e. presence of flakes, clots, or serous milk; n = 538) was cultured on-farm using a single plate containing three selective chromogenic media (Accumast—FERA Animal Health LCC, Ithaca, NY) and in a reference laboratory using standard culture methods, which was considered the gold standard. In study 2, mastitic milk was cultured on-farm and analyzed through 16S rRNA sequencing (n = 214). In both studies, plates were cultured aerobically at 37°C for 24 h and read by a single technician masked to gold standard results. Accuracy, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated based on standard laboratory culture in study 1, and PPV was calculated based on sequencing results in study 2. Overall accuracy of Accumast was 84.9%. Likewise, accuracy for identification of Gram-negative bacteria, Staphylococcus sp., and Streptococcus sp. was 96.4%, 93.8%, and 91.5%, respectively. Sensitivity, specificity, PPV, and NPV were 75.0%, 97.9%, 79.6%, and 97.3% for identification of E. coli, 100.0%, 99.8%, 87.5%, and 100.0% for S. aureus, 70.0%, 95.0%, 45.7%, and 98.1% for other Staphylococcus sp., and 90.0%, 92.9%, 91.8%, and 91.2% for Streptococcus sp. In study 2, Accumast PPV was 96.7% for E. coli, 100.0% for Enterococcus sp., 100.0% for Other Gram-negatives, 88.2% for Staphylococcus sp., and 95.0% for Streptococcus sp., respectively. In conclusion, Accumast is a unique approach for on-farm identification pathogens associated with mastitis, presenting overall sensitivity and specificity of 82.3% and 89.9% respectively. PMID:27176216

Stroke echoscan protocol: a fast and accurate pathway to diagnose embolic strokes.

PubMed

Pagola, Jorge; González-Alujas, Teresa; Muchada, Marian; Teixidó, Gisela; Flores, Alan; De Blauwe, Sophie; Seró, Laia; Luna, David Rodríguez; Rubiera, Marta; Ribó, Marc; Boned, Sandra; Álvarez-Sabin, José; Evangelista, Arturo; Molina, Carlos A

2015-01-01

Cardiac Echoscan is the simplified transthoracic echocardiogram focused on the main source of emboli detection in the acute stroke diagnosis (Stroke Echoscan). We describe the clinical impact related to the Stroke Echoscan protocol in our Center. Acute stroke patients who underwent the Stroke Echoscan by a trained stroke neurologist were included (Echoscan group). All examinations were reviewed by cardiologists. The main embolic stroke etiologies were: ventricular akinesia (VA), severe aortic atheroma (AA) plaque and cardiac shunt (SHUNT). The rate of the embolic stroke etiologies and the median length of stay (LOS) were compared with a cohort of patients studied by cardiologist (Echo group). Eighty acute stroke patients were included. The sensitivity (S) and specificity (E) were: VA (S 98.6%, E 66.7%, k = .7), AA (S 93.3%, E 96.9%, k = .88) and SHUNT (S 100%, E 100%, k = 1), respectively. The rate of AA diagnosis was significantly higher in Echoscan group (18.8% vs. 8.9%; P = .05). Echoscan protocol significantly reduced the LOS: 6 days (IQR 3-10) versus Echo group 9 days (IQR 6-13; P < .001). The Echoscan protocol was an accurate quick test, which reduced the length of stay and increased the percentage of severe AA plaque diagnosis. Copyright © 2014 by the American Society of Neuroimaging.

Antidepressant effects of the water extract from Taraxacum officinale leaves and roots in mice.

PubMed

Li, Yu-Cheng; Shen, Ji-Duo; Li, Yang-Yang; Huang, Qi

2014-08-01

The leaves and roots of the Taraxacum officinale F. (Asteraceae) is widely used as traditional medicinal herb in Eastern Asian countries. In the present study, the antidepressant-like effects of the water extract of T. officinale (WETO) leaves and roots were investigated in mice using forced swimming test (FST), tail suspension test (TST) and open field test (OFT). Effects of acute (1-day) and chronic treatments (14-days) with WETO (50, 100 and 200 mg/kg) on the behavioral changes in FST, TST and OFT, and the serum corticotrophin releasing factor (CRF), adrenocorticotropic hormone (ACTH) and corticosterone concentration were assessed in mice. Chronic treatment (14-days) with WETO at the doses of 50, 100 and 200 mg/kg significantly decreased the immobility time in both FST (92.6, 85.1 and 77.4 s) and TST (84.8, 72.1 and 56.9 s). Acute treatment (1-day) with WETO at a dose of 200 mg/kg also markedly decreased the immobility time in both FST (81.7 s) and TST (73.2 s). However, all treatments did not affect the locomotor activity in the OFT. Moreover, FST induced a significant increase in serum CRF (5.8 ng/ml), ACTH (104.7 pg/ml) and corticosterone levels (37.3 ng/ml). Chronic treatment (14-days) with WETO decreased the serum CRF (200 mg/kg: 3.9 ng/ml) and corticosterone (50 mg/kg: 29.9 ng/ml; 100 mg/kg: 22.5 ng/ml; 200 mg/kg: 19.8 ng/ml) levels. These results clearly demonstrated the antidepressant effects of WETO in animal models of behavioral despair and suggested the mechanism involved in the neuroendocrine system.

S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet.

PubMed

Mukai, Kaori; Miyagi, Takuya; Nishio, Kumiko; Yokoyama, Yoshinobu; Yoshioka, Teppei; Saito, Yoshinobu; Tanaka, Satoshi; Shigekawa, Minoru; Nawa, Takatoshi; Hikita, Hayato; Sakamori, Ryotaro; Yoshihara, Harumasa; Imai, Yasuharu; Hiramatsu, Naoki; Tatsumi, Tomohide; Takehara, Tetsuo

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-α production in CD11b(+)F4/80(+) cells through cellular cross-talk, which is an important mechanism in the development of NAFLD. Copyright © 2015 by The American Association of Immunologists, Inc.

The acute neutrophil response mediated by S100 alarmins during vaginal Candida infections is independent of the Th17-pathway.

PubMed

Yano, Junko; Kolls, Jay K; Happel, Kyle I; Wormley, Floyd; Wozniak, Karen L; Fidel, Paul L

2012-01-01

Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19(-/-), IL-17RA(-/-) and IL-22(-/-) mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.

The Acute Neutrophil Response Mediated by S100 Alarmins during Vaginal Candida Infections Is Independent of the Th17-Pathway

PubMed Central

Yano, Junko; Kolls, Jay K.; Happel, Kyle I.; Wormley, Floyd; Wozniak, Karen L.; Fidel, Paul L.

2012-01-01

Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19−/−, IL-17RA−/− and IL-22−/− mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway. PMID:23050010

Prevalence of and outcomes from Staphylococcus aureus pneumonia among hospitalized patients in the United States, 2009-2012.

PubMed

Jacobs, David M; Shaver, Amy

2017-04-01

The burden of Staphylococcus aureus pneumonia is unknown despite being a major cause of mortality. We investigated national estimates of methicillin-resistant S aureus (MRSA) and methicillin-susceptible S aureus (MSSA) pneumonias and predictors of in-hospital mortality and hospital length of stay (LOS). This was a retrospective analysis of the National Inpatient Sample from 2009-2012. Adult patients with an ICD-9-CM primary diagnosis code for MRSA or MSSA pneumonia were included. Data weights were used to derive national estimates. Prevalence rates were reported per 100,000 hospital discharges, with trends presented descriptively. There were 104,562 patients who had a primary diagnosis of S aureus pneumonia, with 81,275 from MRSA. MRSA pneumonia prevalence decreased steadily from 2009 (75.6 cases per 100,000 discharges) to 2012 (56.6 cases per 100,000 discharges), with MSSA pneumonia experiencing a slight decrease. Mortality rates decreased between 2009 and 2012 for MRSA pneumonia (7.9% to 6.4%) and MSSA pneumonia (6.9% to 4.7%; P = .008). LOS was higher for MRSA (6.9-7.8 days) compared with MSSA (6.1-6.4 days). The prevalence of MRSA pneumonia has decreased among hospitalized adults in the United States in recent years accompanied by improvements in mortality and LOS. Although the prevalence of MRSA pneumonia is declining, national vigilance is still warranted. Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Cortisol, Interleukins and S100B in Delirium in the Elderly

ERIC Educational Resources Information Center

van Munster, Barbara C.; Bisschop, Peter H.; Zwinderman, Aeilko H.; Korevaar, Johanna C.; Endert, Erik; Wiersinga, W. Joost; van Oosten, Hannah E.; Goslings, J. Carel; de Rooij, Sophia E. J. A.

2010-01-01

In independent studies delirium was associated with higher levels of cortisol, interleukin(IL)s, and S100B. The aim of this study was to simultaneously compare cortisol, IL-6, IL-8, and S100B levels in patients aged 65 years and older admitted for hip fracture surgery with and without delirium. Cortisol, IL-6, IL-8, and S100B were assayed in…

Potential role of S100A8 in skin rejuvenation with the 1064-nm Q-switched Nd:YAG laser.

PubMed

Qin, Yan; Qin, Xiaofeng; Xu, Peng; Zhi, Yuanting; Xia, Weili; Dang, Yongyan; Gu, Jun; Ye, Xiyun

2018-04-01

The 1064-nm Q-switched Nd:YAG laser is demonstrated to be effective for non-ablative skin rejuvenation, but the molecular mechanism by which dermis responses to laser-induced damage and initiates skin remodeling is still unclear. HaCaT cells and 3T3 skin fibroblasts were irradiated with the 1064-nm Q-switched Nd:YAG laser at the different doses. Then, cells were collected and lysed for PCR and Western blot analysis. Cell viability was detected by Cell Counting Kit-8 (CCK-8) before and after laser irradiation. The expressions of S100A8, advanced glycosylation end product-specific receptor (RAGE) and inflammatory cytokines in two cell lines were markedly upregulated after laser treatments. The PCR, Western blot, and ELISA analysis showed the significant increase of type I and III procollagen in the 3T3 cells treated with the 1064-nm laser. Interestingly, si S100A8 effectively inhibited the expression of cytokines and collagen, while S100A8 treatments significantly increased them. P-p38 and p-p65 levels were also elevated after the 1064-nm laser irradiation, which is positively related with S100A8. Cell viability and reactive oxygen species (ROS) levels were not changed, while the content of superoxidase dismutase (SOD) in two cells was increased after laser irradiation. Our results demonstrated that the overexpression of S100A8 induced by the 1064-nm laser irradiation triggered inflammatory reactions in skin cells. The inflammatory microenvironment and improvement of skin antioxidant capacity contribute to new collagen synthesis in the skin cells. Thus, S100A8 was required for laser-induced new collagen synthesis in skin cells. p38/MAPK and NF-κB signal pathways were involved in S100A8-mediated inflammatory reactions in response to laser irradiation.

Kinetic and Mechanistic Aspects of the Reactions of Iodide and Hypoiodous Acid with Permanganate: Oxidation and Disproportionation.

PubMed

Zhao, Xiaodan; Salhi, Elisabeth; Liu, Huiling; Ma, Jun; von Gunten, Urs

2016-04-19

Oxidation kinetics of iodide and HOI/OI(-) by permanganate were studied in the pH range of 5.0-10.0. Iodide oxidation and iodate formation were faster at lower pH. The apparent second-order rate constants (k(obs)) for iodide oxidation by permanganate decrease with increasing pH from 29 M(-1) s(-1) at pH 5.0 and 6.9 M(-1) s(-1) at pH 7.0 to 2.7 M(-1) s(-1) at pH 10.0. k(obs) for HOI abatement are 56 M(-1) s(-1) at pH 5.0, 2.5 M(-1) s(-1) at pH 7.0, and 173 M(-1) s(-1) at pH 10.0. Iodate yields over HOI abatement decrease from 98% at pH 6.0 to 33% for pH ≥ 9.5, demonstrating that HOI disproportionation dominates HOI transformation by permanganate at pH ≥ 8.0. MnO2 formed as a product from permanganate reduction, oxidizes HOI to iodate for pH < 8.0, and promotes HOI disproportionation for pH ≥ 8.0. The rate of HOI oxidation or disproportionation induced by MnO2 is much lower than for permanganate. During treatment of iodide-containing waters, the potential for iodinated disinfection byproducts (I-DBPs) formation is highest at pH 7.0-8.0 due to the long lifetime of HOI. For pH < 6.0, HOI/I2 is quickly oxidized by permanganate to iodate, whereas for pH ≥ 8.0, HOI/OI(-) undergoes a fast permanganate-mediated disproportionation.

Influence of Roads on the Surrounding Natural Environment - Vegetation, Soil, and Ground Water

DTIC Science & Technology

1980-02-01

0 __________ _______ ___ _ ii _ _ _ _ en 12bm ~11 I.IO .Figuz 9. Observationsomr~ de Gundlatorp (nr 15). 1W 15, - 1~Karlsharnn - Ronrioby, (Study site...0s . . number of’ srscie s - -- ANTAL ATf 1EJPER RUTA 9 10 13 3 Per souare TOTALI AITAL LATER 13 total n- -her of srnecies Table 2. Analyses of...50. It .5 POA ANNUA 2 1 3 5 100. 3. 2.7 POA NERORALIS 2 0 0 1 50. . 8 No.of species per square ANJTAL ARTER PE.R RUTA 7 6 S 6 Total no. Of S ~eciesE

S100A8/MYD88/NF-қB: a novel pathway involved in cardiomyocyte hypertrophy driven by thyroid hormone.

PubMed

Takano, Ana Paula Cremasco; Munhoz, Carolina Demarchi; Moriscot, Anselmo Sigari; Gupta, Sudhiranjan; Barreto-Chaves, Maria Luiza Morais

2017-06-01

Recent studies have evidenced the involvement of inflammation-related pathways to the development of cardiac hypertrophy and other consequences on the cardiovascular system, including the calcium-binding protein S100A8. However, this has never been investigated in the thyroid hormone (TH)-prompted cardiac hypertrophy. Thus, we aimed to test whether S100A8 and related signaling molecules, myeloid differentiation factor-88 (MyD88) and nuclear factor kappa B (NF-қB), could be associated with the cardiomyocyte hypertrophy induced by TH. Our results demonstrate that the S100A8/MyD88/NF-қB signaling pathway is activated in cardiomyocytes following TH stimulation. The knockdown of S100A8 and MyD88 indicates the contribution of those molecules to cardiomyocyte hypertrophy in response to TH, as evaluated by cell surface area, leucine incorporation assay, and gene expression. Furthermore, S100A8 and MyD88 are crucial mediators of NF-қB activation, which is also involved in the hypertrophic growth of TH-treated cardiomyocytes. Supporting the in vitro data, the contribution of NF-қB for TH-induced cardiac hypertrophy is confirmed in vivo, by using transgenic mice with cardiomyocyte-specific suppression of NF-қB. These data identify a novel pathway regulated by TH that mediates cardiomyocyte hypertrophy. However, the potential role of this new pathway in short and long-term cardiac effects of TH remains to be further investigated. Inflammation-related signaling is activated by T3 in cardiomyocytes. S100A8 and MyD88 have a crucial role in cardiomyocyte hypertrophy by T3. S100A8 and MyD88 mediate NF-қB activation by T3. NF-қB contributes to T3-induced cardiac hypertrophy in vitro and in vivo.

H-FABP: A new biomarker to differentiate between CT-positive and CT-negative patients with mild traumatic brain injury

PubMed Central

Lagerstedt, Linnéa; Egea-Guerrero, Juan José; Bustamante, Alejandro; Montaner, Joan; Rodríguez-Rodríguez, Ana; El Rahal, Amir; Turck, Natacha; Quintana, Manuel; García-Armengol, Roser; Prica, Carmen Melinda; Andereggen, Elisabeth; Rinaldi, Lara; Sarrafzadeh, Asita; Schaller, Karl; Sanchez, Jean-Charles

2017-01-01

The majority of patients with mild traumatic brain injury (mTBI) will have normal Glasgow coma scale (GCS) of 15. Furthermore, only 5%–8% of them will be CT-positive for an mTBI. Having a useful biomarker would help clinicians evaluate a patient’s risk of developing intracranial lesions. The S100B protein is currently the most studied and promising biomarker for this purpose. Heart fatty-acid binding protein (H-FABP) has been highlighted in brain injury models and investigated as a biomarker for stroke and severe TBI, for example. Here, we evaluate the performances of S100B and H-FABP for differentiating between CT-positive and CT-negative patients. A total of 261 patients with a GCS score of 15 and at least one clinical symptom of mTBI were recruited at three different European sites. Blood samples from 172 of them were collected ≤ 6 h after trauma. Patients underwent a CT scan and were dichotomised into CT-positive and CT-negative groups for statistical analyses. H-FABP and S100B levels were measured using commercial kits, and their capacities to detect all CT-positive scans were evaluated, with sensitivity set to 100%. For patients recruited ≤ 6 h after trauma, the CT-positive group demonstrated significantly higher levels of both H-FABP (p = 0.004) and S100B (p = 0.003) than the CT-negative group. At 100% sensitivity, specificity reached 6% (95% CI 2.8–10.7) for S100B and 29% (95% CI 21.4–37.1) for H-FABP. Similar results were obtained when including all the patients recruited, i.e. hospital arrival within 24 h of trauma onset. H-FABP out-performed S100B and thus seems to be an interesting protein for detecting all CT-positive mTBI patients with a GCS score of 15 and at least one clinical symptom. PMID:28419114

Expression of calcium binding protein S100 A7 (psoriasin) in laryngeal carcinoma.

PubMed

Tiveron, Rogério Costa; de Freitas, Luiz Carlos Conti; Figueiredo, David L; Serafini, Luciano N; Mamede, Rui Celso Martins; Zago, Marco A

2012-01-01

Many studies have reported increased expression of S100 A7 (psoriasin) in neoplastic lesions. Among them are studies on breast carcinoma, bladder squamous cell carcinoma, skin tumors and oral cavity squamous cell carcinoma. The expression of S100 A7 has not been described for laryngeal cancer. This study aims to identify the expression of the calcium-binding protein S100 A7 and its correlation with squamous cell carcinomas of the larynx. Specimens from 63 patients were submitted to immunohistochemistry testing with antibody S100 A7. Results were classified and compared. The group with highly differentiated tumors had the highest treatment failure scores. Moderately differentiated tumors had higher treatment failure scores than poorly differentiated tumors. Higher scores were predominantly seen on stages I and II in moderately differentiated tumors, whereas score distribution was more homogeneous in advanced stage disease (III and IV). Regarding failure in treatment, the group scoring zero (3/4 complications: 75%) differed significantly from the remaining groups (13/59: 22%). S100 A7 marker was expressed in 93.7% of laryngeal cancer cases, with higher positive correlation rates in more differentiated tumors and significantly lower rates of treatment failure. Scores had no impact on survival rates.

Impact of creatine kinase correction on the predictive value of S-100B after mild traumatic brain injury.

PubMed

Bazarian, Jeffrey J; Beck, Christopher; Blyth, Brian; von Ahsen, Nicolas; Hasselblatt, Martin

2006-01-01

To validate a correction factor for the extracranial release of the astroglial protein, S-100B, based on concomitant creatine kinase (CK) levels. The CK- S-100B relationship in non-head injured marathon runners was used to derive a correction factor for the extracranial release of S-100B. This factor was then applied to a separate cohort of 96 mild traumatic brain injury (TBI) patients in whom both CK and S-100B levels were measured. Corrected S-100B was compared to uncorrected S-100B for the prediction of initial head CT, three-month headache and three-month post concussive syndrome (PCS). Corrected S-100B resulted in a statistically significant improvement in the prediction of 3-month headache (area under curve [AUC] 0.46 vs 0.52, p=0.02), but not PCS or initial head CT. Using a cutoff that maximizes sensitivity (> or = 90%), corrected S-100B improved the prediction of initial head CT scan (negative predictive value from 75% [95% CI, 2.6%, 67.0%] to 96% [95% CI: 83.5%, 99.8%]). Although S-100B is overall poorly predictive of outcome, a correction factor using CK is a valid means of accounting for extracranial release. By increasing the proportion of mild TBI patients correctly categorized as low risk for abnormal head CT, CK-corrected S100-B can further reduce the number of unnecessary brain CT scans performed after this injury.

A Full-Scale Fatigue Test of 9-m CX-100 Wind Turbine Blades

DTIC Science & Technology

2011-09-01

A Full-Scale Fatigue Test of 9-m CX-100 Wind Turbine Blades G. PARK, K. M. FARINHOLT, S. G. TAYLOR and C. R. FARRAR ABSTRACT This paper...presents the SHM result of a 9m CX-100 wind turbine blade under full- scale fatigue loads. The test was performed at the National Renewable Energy...surface of the blade. The blade underwent fatigue excitation at 1.8 Hz for defined intervals, and data from the sensors were collected between and

Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis

PubMed Central

Wang, Yunmei; Fang, Chao; Gao, Huiyun; Bilodeau, Matthew L.; Zhang, Zijie; Croce, Kevin; Liu, Shijian; Morooka, Toshifumi; Sakuma, Masashi; Nakajima, Kohsuke; Yoneda, Shuichi; Shi, Can; Zidar, David; Andre, Patrick; Stephens, Gillian; Silverstein, Roy L.; Hogg, Nancy; Schmaier, Alvin H.; Simon, Daniel I.

2014-01-01

Expression of the gene encoding the S100 calcium–modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14–/– mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14–/– mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14–/– mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14–dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke. PMID:24691441

Effectiveness of bio-slurry on the growth and production of soybean (Glycine max (L.) Merrill)

NASA Astrophysics Data System (ADS)

Rafiuddin; Mollah, A.; Iswoyo, H.

2018-05-01

This research was aimed to determine the effectiveness of bio-slurry fertilizer on the growth and production of soybean plants which was conducted in the Pucak village, Tompobulu District, Maros Regency, South Sulawesi from July to October 2016. The research was set in randomized block design (RBD) with 8 treatments replicated three times. Treatment used were the application of bio-slurry consisted of 8 level of concentrations, namely: control (0 mL.liter-1 of water), 3, 5, 7, 9, 11, 13 and 15 mL.liter-1 of water. The variables measured were plant’s height, number of pods, weight of 100-seed, and soybean seeds’ yield per hectare. The results of research shows that the application of bio-slurry effectively improved growth and yield of soybean (pod’s number, 100-seed’s weight and seed yield per hectare). Optimal concentration of liquid bio-slurry to obtain maximum results were 9.27 mL.liter-1 of water for the highest number of pods (68.49 pods); concentration of 8.75 mL.liter-1 of water for heaviest weight of 100 grains (14.22 grams); and the concentration 8,12 mL.liter-1 of water for the highest production of seed per hectare (23.20 quintal).

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

PubMed

Daan, Nadine M P; Koster, Maria P H; de Wilde, Marlieke A; Dalmeijer, Gerdien W; Evelein, Annemieke M V; Fauser, Bart C J M; de Jager, Wilco

2016-01-01

To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. Cross-sectional comparison of serum biomarkers. University Medical Center Utrecht. Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30). Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.

Label-free as-grown double wall carbon nanotubes bundles for Salmonella typhimurium immunoassay.

PubMed

Punbusayakul, Niramol; Talapatra, Saikat; Ajayan, Pulickel M; Surareungchai, Werasak

2013-01-01

A label-free immunosensor from as-grown double wall carbon nanotubes (DW) bundles was developed for detecting Salmonella typhimurium. The immunosensor was fabricated by using the as-grown DW bundles as an electrode material with an anti-Salmonella impregnated on the surface. The immunosensor was electrochemically characterized by cyclic voltammetry. The working potential (100, 200, 300 and 400 mV vs. Ag/AgCl) and the anti-Salmonella concentration (10, 25, 50, 75, and 100 μg/mL) at the electrode were subsequently optimized. Then, chronoamperometry was used with the optimum potential of 100 mV vs. Ag/AgCl) and the optimum impregnated anti-Salmonella of 10 μg/mL to detect S. typhimurium cells (0-10(9) CFU/mL). The DW immunosensor exhibited a detection range of 10(2) to 10(7) CFU/mL for the bacteria with a limit of detection of 8.9 CFU/mL according to the IUPAC recommendation. The electrode also showed specificity to S. typhimurium but no current response to Escherichia coli. These findings suggest that the use of a label-free DW immunosensor is promising for detecting S. typhimurium.

Proteomics detection of S100A6 in tumor tissue interstitial fluid and evaluation of its potential as a biomarker of cholangiocarcinoma.

PubMed

Onsurathum, Sudarat; Haonon, Ornuma; Pinlaor, Porntip; Pairojkul, Chawalit; Khuntikeo, Narong; Thanan, Raynoo; Roytrakul, Sittiruk; Pinlaor, Somchai

2018-04-01

Tumor interstitial fluid contains tumor-specific proteins that may be useful biomarkers for cancers. In this study, we identified proteins present in cholangiocarcinoma interstitial fluid. Proteins derived from three samples of tumor interstitial fluid and paired samples of adjacent normal interstitial fluid from cholangiocarcinoma patients were subjected to two-dimensional liquid chromatography with tandem mass spectrometry. Candidate proteins were selected based on a greater than twofold change in expression levels between tumor interstitial fluid and normal interstitial fluid. Upregulation of six proteins in tumor interstitial fluid, including S100 calcium binding protein A6 (S100A6), S100 calcium binding protein A9, aldo-keto reductase family 1 member C4, neuropilin-1, 14-3-3 zeta/delta, and triosephosphate isomerase was assessed by western blot and immunohistochemistry. Their potential as markers was evaluated in human cholangiocarcinoma tissue arrays, and in serum using enzyme-linked immunosorbent assay. Expression of S100A6 was higher in tumor interstitial fluid than in normal interstitial fluid and showed the highest positive rate (98.96%) in cholangiocarcinoma tissues. Serum levels of S100A6 did not differ between cholangitis and cholangiocarcinoma patients, but were significantly higher than in healthy individuals ( p < 0.0001). In cholangiocarcinoma cases, S100A6 level was associated with vascular invasion ( p = 0.007) and could distinguish cholangiocarcinoma patients from healthy individuals as effectively as the carbohydrate antigen 19-9. In addition, potential for drug treatment targeting S100A6 and other candidate proteins was also demonstrated using STITCH analysis. In conclusion, proteomics analysis of tumor interstitial fluid could be a new approach for biomarker discovery, and S100A6 is a potential risk marker for screening of cholangiocarcinoma.

Molecular dynamics simulation of S100B protein to explore ligand blockage of the interaction with p53 protein

NASA Astrophysics Data System (ADS)

Zhou, Zhigang; Li, Yumin

2009-10-01

As a tumor suppressor, p53 plays an important role in cancer suppression. The biological function of p53 as a tumor suppressor is disabled when it binds to S100B. Developing the ligands to block the S100B-p53 interaction has been proposed as one of the most important approaches to the development of anti-cancer agents. We screened a small compound library against the binding interface of S100B and p53 to identify potential compounds to interfere with the interaction. The ligand-binding effect on the S100B-p53 interaction was explored by molecular dynamics at the atomic level. The results show that the ligand bound between S100B and p53 propels the two proteins apart by about 2 Å compared to the unligated S100B-p53 complex. The binding affinity of S100B and p53 decreases by 8.5-14.6 kcal/mol after a ligand binds to the interface from the original unligated state of the S100B-p53 complex. Ligand-binding interferes with the interaction of S100B and p53. Such interference could impact the association of S100B and p53, which would free more p53 protein from the pairing with S100B and restore the biological function of p53 as a tumor suppressor. The analysis of the binding mode and ligand structural features would facilitate our effort to identify and design ligands to block S100B-p53 interaction effectively. The results from the work suggest that developing ligands targeting the interface of S100B and p53 could be a promising approach to recover the normal function of p53 as a tumor suppressor.

MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding.

PubMed

Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Murata, Hitoshi; Watanabe, Masami; Huang, Peng; Kinoshita, Rie; Futami, Junichiro; Inoue, Yusuke; Yamauchi, Akira; Sumardika, I Wayan; Youyi, Chen; Yamamoto, Ken-Ichi; Nasu, Yasutomo; Nishibori, Masahiro; Hibino, Toshihiko; Sakaguchi, Masakiyo

2016-08-01

The dynamic interaction between tumor cells and their microenvironment induces a proinflammatory milieu that drives cancer development and progression. The S100A8/A9 complex has been implicated in chronic inflammation, tumor development, and progression. The cancer microenvironment contributes to the up-regulation of this protein complex in many invasive tumors, which is associated with the formation of pre-metastatic niches and poor prognosis. Changing adhesive preference of cancer cells is at the core of the metastatic process that governs the reciprocal interactions of cancer cells with the extracellular matrices and neighboring stromal cells. Cell adhesion molecules (CAMs) have been confirmed to have high-level expression in various highly invasive tumors. The expression and function of CAMs are profoundly influenced by the extracellular milieu. S100A8/A9 mediates its effects by binding to cell surface receptors, such as heparan sulfate, TLR4 and RAGE on immune and tumor cells. RAGE has recently been identified as an adhesion molecule and has considerably high identity and similarity to ALCAM and MCAM, which are frequently over-expressed on metastatic malignant melanoma cells. In this study, we demonstrated that ALCAM and MCAM also function as S100A8/A9 receptors as does RAGE and induce malignant melanoma progression by NF-κB activation and ROS formation. Notably, MCAM not only activated NF-κB more prominently than ALCAM and RAGE did but also mediated intracellular signaling for the formation of lung metastasis. MCAM is known to be involved in malignant melanoma development and progression through several mechanisms. Therefore, MCAM is a potential effective target in malignant melanoma treatment.

S100B Attenuates Microglia Activation in Gliomas: Possible Role of STAT3 Pathway

PubMed Central

Zhang, Leying; Liu, Wei; Alizadeh, Darya; Zhao, Dongchang; Farrukh, Omar; Lin, Jeffrey; Badie, Sam A.; Badie, Behnam

2010-01-01

Despite significant infiltration into tumors, the effector function of macrophages (MPs) and microglia (MG) appears to be suppressed in gliomas. Although STAT3 pathway is thought to play a role in this process, the exact mechanism by which gliomas induce STAT3 activation in MPs and MG is not known. Because activation of receptor for advanced glycation end products (RAGE) can induce STAT3, and because gliomas express high levels of S100B, a RAGE ligand, we hypothesized that MP/MG STAT3 activity may be modulated through S100B-RAGE interaction. Exposure of N9 MG and bone marrow-derived monocytes (BMM) to GL261 glioma condition medium (GCM) and low (nM) levels of S100B increased RAGE expression, induced STAT3 and suppressed MG function in vitro. Furthermore, neutralization of S100B in GCM, partially reversed IL-1β suppression in BMM, suggesting that the inhibitory effect of GCM to be in part due to S100B. Finally, blockage of S100B-RAGE interaction inhibited STAT3 activation in N9 MG and in glioma MG/MP in vivo. These findings suggest that the RAGE pathway may play an important role in STAT3 induction in glioma-associated MG/MPs, and that this process may be mediated through S100B. PMID:21264954

S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway.

PubMed

Zhang, Leying; Liu, Wei; Alizadeh, Darya; Zhao, Dongchang; Farrukh, Omar; Lin, Jeffrey; Badie, Sam A; Badie, Behnam

2011-03-01

Despite significant infiltration into tumors, the effector function of macrophages (MPs) and microglia (MG) appears to be suppressed in gliomas. Although STAT3 pathway is thought to play a role in this process, the exact mechanism by which gliomas induce STAT3 activation in MPs and MG is not known. Because activation of receptor for advanced glycation end products (RAGE) can induce STAT3, and because gliomas express high levels of S100B, a RAGE ligand, we hypothesized that MP/MG STAT3 activity may be modulated through S100B-RAGE interaction. Exposure of N9 MG and bone marrow-derived monocytes (BMM) to GL261 glioma condition medium (GCM) and low (nM) levels of S100B increased RAGE expression, induced STAT3 and suppressed MG function in vitro. Furthermore, neutralization of S100B in GCM, partially reversed IL-1β suppression in BMM, suggesting that the inhibitory effect of GCM to be in part due to S100B. Finally, blockage of S100B-RAGE interaction inhibited STAT3 activation in N9 MG and in glioma MG/MP in vivo. These findings suggest that the RAGE pathway may play an important role in STAT3 induction in glioma-associated MG/MPs, and that this process may be mediated through S100B. Copyright © 2010 Wiley-Liss, Inc.

Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function

PubMed Central

Gielen, Paul R.; Schulte, Barbara M.; Kers-Rebel, Esther D.; Verrijp, Kiek; Bossman, Sandra A.J.F.H.; ter Laan, Mark; Wesseling, Pieter

2016-01-01

Background Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC). Methods We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity. Results We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro. Conclusions These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade. PMID:27006175

Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis.

PubMed

Yan, Xin-Long; Jia, Ya-Li; Chen, Lin; Zeng, Quan; Zhou, Jun-Nian; Fu, Chun-Jiang; Chen, Hai-Xu; Yuan, Hong-Feng; Li, Zhi-Wei; Shi, Lei; Xu, Ying-Chen; Wang, Jing-Xue; Zhang, Xiao-Mei; He, Li-Juan; Zhai, Chao; Yue, Wen; Pei, Xue-Tao

2013-06-01

Cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic microRNA (miR)-155 in HCC cells was significantly up-regulated by coculture with LC-MSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the down-regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. S100A4 secreted from LC-MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013). Copyright © 2013 American Association for the Study of Liver Diseases.

Transmission of 2 × 56 Gb/s PAM-4 signal over 100 km SSMF using 18 GHz DMLs.

PubMed

Zhou, Shiwei; Li, Xiang; Yi, Lilin; Yang, Qi; Fu, Songnian

2016-04-15

We experimentally demonstrate C-band 2 × 56 Gb/s pulse-amplitude modulation (PAM)-4 signal transmission over 100 km standard single-mode fiber (SSMF) using 18 GHz direct-modulated lasers (DMLs) and direct detection, without inline optical amplifier. A delay interferometer (DI) at the transmitter side is used to extend the transmission reach from 40 to 100 km. A digital Volterra filter at the receiver side is used to mitigate the nonlinear distortions. We obtain an average bit error ratio (BER) of 1.5 × 10(-3) for 2 × 56 Gb/s PAM-4 signal after 100 km SSMF transmission at the optimal input power, which is below the 7% forward error correction (FEC) threshold (3.8 × 10(-3)).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rajagopalan, B.; Raine, A.E.; Cooper, R.

The intravenous /sup 133/xenon injection method was used to estimate global cerebral blood flow before and after treatment with captopril in nine patients with severe heart failure. The pretreatment mean blood pressure was 94.9 mm Hg (S.D. 13.9) and fell to 85.1 mm Hg (S.D. 18.1) after treatment with captopril for between four and 15 days. The cerebral blood flow before captopril was 61.1 ml/100 g per minute (S.D. 6.9), which was less than the value of 75.8 ml/100 g per minute found in control subjects. After treatment with captopril the cerebral blood flow increased to 73.8 ml/100 g permore » minute (S.D. 11.8, p less than 0.01). The fraction of carbon dioxide in the expired air was not significantly different in the two studies (4.1 +/- 0.88 versus 3.97 +/- 0.65). It is concluded that cerebral blood flow is reduced in severe heart failure and can be restored by treatment with captopril, but the reasons for the reduced flow and its improvement after converting enzyme inhibition are not known.« less

Contamination by Salmonella spp., Campylobacter spp. and Listeria spp. of most popular chicken- and pork-sausages sold in Reunion Island.

PubMed

Trimoulinard, A; Beral, M; Henry, I; Atiana, L; Porphyre, V; Tessier, C; Leclercq, A; Cardinale, E

2017-06-05

One of the most popular meat products of the local "cuisine" is sausage composed with 100% chicken or 100% pork. In this study, we aimed to determine the presence of Salmonella spp., Campylobacter spp. and Listeria spp. in chicken- and pork-sausages, quantify Salmonella spp. population and identify the factors that could be associated with contamination in the outlets. Two hundred and three batches of pork and chicken sausages were randomly collected from 67 local outlets (supermarkets, groceries and butcher shops). Salmonella spp. was detected in 11.8% (95% confidence interval (CI): [10.0; 13.5]) of samples, Campylobacter spp. in 1.5% [0.7; 4.2] and Listeria monocytogenes in 5.9% [4.4; 7.3]. Most probable number of Salmonella spp. varied between 6cfu per gram to 320cfu per gram. Salmonella serotypes isolated from pork and chicken sausages were S. Typhimurium (45.8%), S. London (20.8%), S. Derby (16.7%), S. Newport (8.33%), S. Blockley (4.2%) and S. Weltevreden (4.17%). Using a logistic (mixed-effect) regression model, we found that Salmonella spp. contamination was positively associated with sausages sold in papers or plastic bags and no control of rodents. Chicken sausages were associated with a decreasing risk of Salmonella contamination. Listeria monocytogenes contamination was positively associated with the presence of fresh rodent droppings in the outlet and negatively when the staff was cleaning regularly their hands with soap and water or water only. All the sampled outlets of Reunion Island were not equivalent in terms of food safety measures. Increasing awareness of these traders remains a cornerstone to limit the presence of Salmonella spp. and Listeria spp. in sausages, particularly in a tropical context (high temperature and humidity). Copyright © 2017 Elsevier B.V. All rights reserved.

Engineering Design Guidelines for Electromagnetic Pulse Hardening of Naval Equipment.

DTIC Science & Technology

1981-07-15

Implementation 396 3- 8.10 Alternate Winding Configurations 397 8.11 Winding Arrangements 398 . 8.12 Effect of Driving with Different Source Impedances 400 . 8.13...kHz 1 MHz 3 MHz lO MHz 15 MHz 00 MHz 1l000 MHz 1 500 MHz 10,000 !-IH: * .,. -r | 1000 700 600 508 400 / 100 50 I 10 Copper and aluminum, on the other...and Absorption Loss of Metal s at 151" 0-7 £3.7] g I"Al Mtal Reiative Rejative .A~s.r’?itr *~a; I (a,, 150 kHz) - =Siiver .0 Copper. annealed 1.00

Validity and reliability of the session-RPE method for quantifying training in Australian football: a comparison of the CR10 and CR100 scales.

PubMed

Scott, Tannath J; Black, Cameron R; Quinn, John; Coutts, Aaron J

2013-01-01

The purpose of this study was to examine and compare the criterion validity and test-retest reliability of the CR10 and CR100 rating of perceived exertion (RPE) scales for team sport athletes that undertake high-intensity, intermittent exercise. Twenty-one male Australian football (AF) players (age: 19.0 ± 1.8 years, body mass: 83.92 ± 7.88 kg) participated the first part (part A) of this study, which examined the construct validity of the session-RPE (sRPE) method for quantifying training load in AF. Ten male athletes (age: 16.1 ± 0.5 years) participated in the second part of the study (part B), which compared the test-retest reliability of the CR10 and CR100 RPE scales. In part A, the validity of the sRPE method was assessed by examining the relationships between sRPE, and objective measures of internal (i.e., heart rate) and external training load (i.e., distance traveled), collected from AF training sessions. Part B of the study assessed the reliability of sRPE through examining the test-retest reliability of sRPE during 3 different intensities of controlled intermittent running (10, 11.5, and 13 km·h(-1)). Results from part A demonstrated strong correlations for CR10- and CR100-derived sRPE with measures of internal training load (Banisters TRIMP and Edwards TRIMP) (CR10: r = 0.83 and 0.83, and CR100: r = 0.80 and 0.81, p < 0.05). Correlations between sRPE and external training load (distance, higher speed running and player load) for both the CR10 (r = 0.81, 0.71, and 0.83) and CR100 (r = 0.78, 0.69, and 0.80) were significant (p < 0.05). Results from part B demonstrated poor reliability for both the CR10 (31.9% CV) and CR100 (38.6% CV) RPE scales after short bouts of intermittent running. Collectively, these results suggest both CR10- and CR100-derived sRPE methods have good construct validity for assessing training load in AF. The poor levels of reliability revealed under field testing indicate that the sRPE method may not be sensible to detecting small changes in exercise intensity during brief intermittent running bouts. Despite this limitation, the sRPE remains a valid method to quantify training loads in high-intensity, intermittent team sport.

Testing New Survey Questions of Sexual Harassment and Sexual Assault

DTIC Science & Technology

2011-01-01

Technical Report No. 100-11 REPORT DOCUMENTATION PAGE Standard Form 298 (Rev. 8 /98) Prescribed by ANSI Std. Z39.18 Form Approved OMB No. 0704...S) AND ADDRESS(ES) 8 . PERFORMING ORGANIZATION REPORT NUMBER 10. SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 9... 8 Conclusion

Trends in hospital admission rates for whooping cough in England across five decades: database studies.

PubMed

Haslam, Nick; Hoang, Uy; Goldacre, Michael J

2014-04-01

Our aim was to report on trends in hospitalisation rates for pertussis in England from the 1960s to 2011; and to provide context for the recent unexpected activity of Bordetella pertussis in the UK. A retrospective analysis of English national Hospital Episode Statistics (HES, 1968-2011) and the Oxford Record Linkage Study (ORLS, 1963-2011) for people admitted to hospital with whooping cough. England and the Oxford Record Linkage Study area. Age- and gender-specific hospital admission rates, and summary age- and sex-standardised rates, for people aged under 25 years per 100,000 population in each age group. Admission rates declined from the 1960s to the early 1970s. For example, the standardised rates were 12.8 (95% confidence interval 11.2-14.5) per 100,000 in England in 1968 and 4.0 (3.0-4.9) per 100,000 in 1973. They then increased to reach 45.0 (41.4-48.6) per 100,000 in 1978 and 47.4 (43.7-51.1) in 1982. From the late 1980s, admission rates continued to decline, falling to between 1 and 4 per 100,000 in each of the years between 2003 and 2011. While the trend in hospital admissions closely followed that in notifications, the annual ratio between these two measures was not consistent ranging from 1.07 (95% confidence interval 1.00-1.14) to 4.03 (3.79-4.27) notifications per admission over the last 10 years. Epidemics of whooping cough in the late 1970s and early 1980s were associated with a significant rise in hospital admission rates. Current admission rates are low, by historical comparison. Vaccine programmes must continue to be fully implemented in order to improve control of pertussis activity.

49 CFR Appendix A to Part 593 - List of Vehicles Determined To Be Eligible for Importation

Code of Federal Regulations, 2012 CFR

2012-10-01

... Vantage 2006-2007 530 Audi 80 1988-1989 223 Audi 100 1989 93 Audi 100 1993 244 Audi 100 1990-1992 317 Audi A4 1996-2000 352 Audi A4, RS4, S4 8D 2000-2001 400 Audi A6 1998-1999 332 Audi A8 2000 424 Audi A8 1997-2000 337 Audi A8 Avant Quattro 1996 238 Audi RS6 & RS Avant 2003 443 Audi S6 1996 428 Audi S8 2000...

H-FABP: A new biomarker to differentiate between CT-positive and CT-negative patients with mild traumatic brain injury.

PubMed

Lagerstedt, Linnéa; Egea-Guerrero, Juan José; Bustamante, Alejandro; Montaner, Joan; Rodríguez-Rodríguez, Ana; El Rahal, Amir; Turck, Natacha; Quintana, Manuel; García-Armengol, Roser; Prica, Carmen Melinda; Andereggen, Elisabeth; Rinaldi, Lara; Sarrafzadeh, Asita; Schaller, Karl; Sanchez, Jean-Charles

2017-01-01

The majority of patients with mild traumatic brain injury (mTBI) will have normal Glasgow coma scale (GCS) of 15. Furthermore, only 5%-8% of them will be CT-positive for an mTBI. Having a useful biomarker would help clinicians evaluate a patient's risk of developing intracranial lesions. The S100B protein is currently the most studied and promising biomarker for this purpose. Heart fatty-acid binding protein (H-FABP) has been highlighted in brain injury models and investigated as a biomarker for stroke and severe TBI, for example. Here, we evaluate the performances of S100B and H-FABP for differentiating between CT-positive and CT-negative patients. A total of 261 patients with a GCS score of 15 and at least one clinical symptom of mTBI were recruited at three different European sites. Blood samples from 172 of them were collected ≤ 6 h after trauma. Patients underwent a CT scan and were dichotomised into CT-positive and CT-negative groups for statistical analyses. H-FABP and S100B levels were measured using commercial kits, and their capacities to detect all CT-positive scans were evaluated, with sensitivity set to 100%. For patients recruited ≤ 6 h after trauma, the CT-positive group demonstrated significantly higher levels of both H-FABP (p = 0.004) and S100B (p = 0.003) than the CT-negative group. At 100% sensitivity, specificity reached 6% (95% CI 2.8-10.7) for S100B and 29% (95% CI 21.4-37.1) for H-FABP. Similar results were obtained when including all the patients recruited, i.e. hospital arrival within 24 h of trauma onset. H-FABP out-performed S100B and thus seems to be an interesting protein for detecting all CT-positive mTBI patients with a GCS score of 15 and at least one clinical symptom.

Metabolite changes during natural and lactic acid bacteria fermentations in pastes of soybeans and soybean–maize blends

PubMed Central

Ng'ong'ola-Manani, Tinna Austen; Østlie, Hilde Marit; Mwangwela, Agnes Mbachi; Wicklund, Trude

2014-01-01

The effect of natural and lactic acid bacteria (LAB) fermentation processes on metabolite changes in pastes of soybeans and soybean–maize blends was studied. Pastes composed of 100% soybeans, 90% soybeans and 10% maize, and 75% soybeans and 25% maize were naturally fermented (NFP), and were fermented by lactic acid bacteria (LFP). LAB fermentation processes were facilitated through back-slopping using a traditional fermented gruel, thobwa as an inoculum. Naturally fermented pastes were designated 100S, 90S, and 75S, while LFP were designated 100SBS, 90SBS, and 75SBS. All samples, except 75SBS, showed highest increase in soluble protein content at 48 h and this was highest in 100S (49%) followed by 90SBS (15%), while increases in 100SBS, 90S, and 75S were about 12%. Significant (P < 0.05) increases in total amino acids throughout fermentation were attributed to cysteine in 100S and 90S; and methionine in 100S and 90SBS. A 3.2% increase in sum of total amino acids was observed in 75SBS at 72 h, while decreases up to 7.4% in 100SBS at 48 and 72 h, 6.8% in 100S at 48 h and 4.7% in 75S at 72 h were observed. Increases in free amino acids throughout fermentation were observed in glutamate (NFP and 75SBS), GABA and alanine (LFP). Lactic acid was 2.5- to 3.5-fold higher in LFP than in NFP, and other organic acids detected were acetate and succinate. Maltose levels were the highest among the reducing sugars and were two to four times higher in LFP than in NFP at the beginning of the fermentation, but at 72 h, only fructose levels were significantly (P < 0.05) higher in LFP than in NFP. Enzyme activities were higher in LFP at 0 h, but at 72 h, the enzyme activities were higher in NFP. Both fermentation processes improved nutritional quality through increased protein and amino acid solubility and degradation of phytic acid (85% in NFP and 49% in LFP by 72 h). PMID:25493196

[Serum calgranulin C is a highly sensitive autoinflammation activity indicator in patients with familial periodic fevers].

PubMed

Bogdanova, M V; Rameev, V V; Kozlovskaya, L V; Fedorov, E S; Salugina, S O

2016-01-01

To determine the possibility of using the serum proinflammatory calcium-binding protein, or calgranulin C (S100A12), to assess activity and therapeutic efficiency in patients with periodic disease (PD) and other familial periodic fevers (FPFs). Thirty-five patients with PD and other FPDs, which were verified by molecular genetic study, were examined. In accordance with the disease activity, the patients were divided into 2 groups. The investigators determined the concentration of S100A12 by solid-phase enzyme immunoassay and that of other acute-phase inflammatory markers (erythrocyte sedimentation rate (ERT), neutrophil counts, and fibrinogen and C-reactive protein (CRP) concentrations). The serum concentration of S100A12 in the stage of disease activity was 466.7 (265.22--851.7) ng/ml, which was significantly higher than in remission (244.29 (118.93--409.85) ng/ml (p=0.000002). The highest S100A12 concentrations were noted in the patients with PD; these were 758.95 (434.80--1035.95) ng/ml; the S100A12 level in the majority of PD patients even during remission remained moderately higher. An investigation of the relationship of A100A12 to genetic variants found no differences between the patients homozygous for M694V and those with other genotypes (p=0.37). Estimation of the time course of therapy-induced changes in the serum S100A12 concentration revealed its considerable reduction (р=0.0018). However, normalization of S100A12 levels was not achieved in PD. The remaining increased S100A12 concentration in these patients may be suggestive of the activity of PD despite the absence of its clinical manifestations. S100A12 as a highly sensitive marker allows more exact evaluation of the anti-inflammatory effect of therapy. The S100A12 identification of the subclinical activity of autoinflammatory diseases made all the more important since traditional inflammatory markers, such as ERT, CRP, fibrinogen, and leukocyte counts, are less sensitive for these purposes. In our study, these markers were within the reference range in remission. No differences were found in the S100A12 levels between the groups with and without amyloidosis (p=0.62). S100A12 is a highly sensitive marker for the activity of autoinflammatory diseases and the efficiency of their therapy. The serum level of S100A12 in PD may be used to diagnose the subclinical activity of inflammation, which is of importance in monitoring the risk of amyloidosis.

S100A11 promotes human pancreatic cancer PANC-1 cell proliferation and is involved in the PI3K/AKT signaling pathway.

PubMed

Xiao, Mingbing; Li, Tao; Ji, Yifei; Jiang, Feng; Ni, Wenkai; Zhu, Jing; Bao, Baijun; Lu, Cuihua; Ni, Runzhou

2018-01-01

S100A11, a member of S100 calcium-binding protein family, is associated with the numerous processes of tumorigenesis and metastasis. In the present study, the role of S100A11, and its possible underlying mechanisms in cell proliferation, apoptosis and cell cycle distribution in human pancreatic cancer were explored. Immunohistochemical analyses of S100A11 and phosphorylated (p)-AKT serine/threonine kinase (AKT) were performed in 30 resected specimens from patients with pancreatic cancer. PANC-1 cells were transfected with pcDNA3.1-S100A11 or treated with 50 µmol/l LY294002 for 48 h. Cell proliferation was determined using a cell counting kit-8 assay, whereas apoptosis and cell cycle distribution were determined by flow cytometry analysis. The mRNA and protein levels of S100A11, and AKT were determined using semi quantitative reverse transcription-polymerase chain reaction and western blot analyses, respectively. Pearson correlation analysis revealed that the expression levels of S100A11 and p-AKT were positively correlated (r, 0.802; P<0.05). Compared with the control group, S100A11 overexpression significantly promoted PANC-1 cell proliferation and reduced the percentage of early apoptotic cells. Flow cytometric analysis indicated that the proportion of PANC-1 cells in the S phase was significantly elevated and cell percentage in the G0/G1 phase declined in response to S100A11 overexpression (all P<0.05). S100A11 overexpression also significantly increased AKT mRNA and p-AKT protein expression levels (both P<0.05). The phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, significantly inhibited PANC-1 cell proliferation, promoted apoptosis and caused G1/S phase arrest in PANC-1 cells (all P<0.05). These findings together suggest that S100A11 promotes the viability and proliferation of human pancreatic cancer PANC-1 cells through the upregulation of the PI3K/AKT signaling pathway. Thus, S100A11 may be considered as a novel drug target for targeted therapy of pancreatic cancer.

Differential association of S100A9, an inflammatory marker, and p53, a cell cycle marker, expression with epicardial adipocyte size in patients with cardiovascular disease.

PubMed

Agra, Rosa María; Fernández-Trasancos, Ángel; Sierra, Juan; González-Juanatey, José Ramón; Eiras, Sonia

2014-10-01

S100A9 (calgranulin B) has inflammatory and oxidative stress properties and was found to be associated with atherosclerosis and obesity. One of the proteins that can regulate S100A9 transcription is p53, which is involved in cell cycle, apoptosis and adipogenesis. Thus, it triggers adipocyte enlargement and finally obesity. Because epicardial adipose tissue (EAT) volume and thickness is related to coronary artery disease (CAD), we studied the gene expression of this pathway in patients with cardiovascular disease and its association with obesity. Adipocytes and stromal cells from EAT and subcutaneous adipose tissue (SAT) from 48 patients who underwent coronary artery bypass graft and/or valve replacement were obtained after collagenase digestion and differential centrifugation. The expression levels of the involved genes on adipogenesis and cell cycle like fatty acid-binding protein (FABP) 4, retinol-binding protein (RBP)4, p53 and S100A9 were determined by real-time polymerase chain reaction (PCR). Adipocyte diameter was measured by optical microscopy. We found that epicardial adipocytes expressed significantly lower levels of adipogenic genes (FABP4 and RBP4) and cell cycle-related genes (S100A9 and p53) than subcutaneous adipocytes. However, in obese patients, upregulation of adipogenic and cell cycle-related genes in subcutaneous and epicardial adipocytes, respectively, was observed. The enlargement of adipocyte size was related to FABP4, S100A9 and p53 expression levels in stromal cells. But only the p53 association was maintained in epicardial stromal cells from obese patients (p=0.003). The expression of p53, but not S100A9, in epicardial stromal cells is related to adipocyte enlargement in obese patients with cardiovascular disease. These findings suggest new mechanisms for understanding the relationship between epicardial fat thickness, obesity and cardiovascular disease.

Mutagenic and clastogenic properties of 3-chloro-4-(dichloromethyl)-5-hydroxy-2 (5H)-furanone: a potent bacterial mutagen in drinking water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meier, J.R.; Blazak, W.F.; Knohl, R.B.

1987-01-01

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was found to be a direct-acting mutagen in the Ames test for strains TA1535, TA1538, TA92, TA97, TA98, TA100 and TA102. The highest mutagenic response (approximately 13,000 revertants/nmol) was seen in strain TA100. The TA100 response was six- to tenfold higher than in TA98, TA97, and TA102, and 100- to 500-fold higher than in TA1535, TA92, and TA1538. The addition of a 9,000 x g supernatant fraction (S-9) from livers of polychlorinated biphenyl-treated rats, along with cofactors for NADPH generation, resulted in a 90% reduction in the TA100 mutagenicity. MX induced chromosomal aberrations in Chinese hamster ovary cellsmore » after 6-8 hr exposure without S-9 at a dose as low as 4 micrograms/ml, and after 2 hr exposure with S-9 at a dose of 75 micrograms/ml. The oral dose of MX lethal to 50% (LD50) in Swiss-Webster mice was determined to be 128 mg/kg. MX did not induce micronuclei in mouse bone marrow when administered by oral gavage at doses up to 70% of the LD50.« less

Fecal S100A12 concentration predicts a lack of response to treatment in dogs affected with chronic enteropathy.

PubMed

Heilmann, Romy M; Volkmann, Maria; Otoni, Cristiane C; Grützner, Niels; Kohn, Barbara; Jergens, Albert E; Steiner, Jörg M

2016-09-01

S100A12 is a potential biomarker of gastrointestinal inflammation in dogs and fecal S100A12 concentrations are correlated with disease severity and outcome. The aim of the present study was to investigate whether there was any association between pre-treatment fecal S100A12 concentrations in dogs affected with chronic enteropathy (CE) and the response to treatment. Dogs affected with CE were recruited into the study and were classified as antibiotic-responsive diarrhea (ARD; n = 9), food-responsive diarrhea (FRD; n = 30) or idiopathic inflammatory bowel disease (IBD; n = 25). They were also grouped based on their response to treatment as complete remission (n = 35), partial response (n = 25) or no response (n = 4). Fecal S100A12 concentrations, measured by ELISA, were elevated in dogs affected with IBD compared with those from dogs affected with FRD (P = 0.010) or ARD (P = 0.025). Dogs with IBD that did not respond to treatment (n = 4) had significantly greater fecal S100A12 concentrations than dogs in complete remission (P = 0.009). Measurement of fecal S100A12 at the time of diagnosis discriminated between dogs with IBD that were refractory to therapy (≥2700 ng/g fecal S100A12) from those with at least a partial response (<2700 ng/g fecal S100A12), with a sensitivity of 100% and a specificity of 76%. These preliminary results suggest that testing of fecal S100A12 may be useful for predicting the lack of response to treatment in dogs affected with CE. The utility of serial fecal S100A12 measurements for monitoring dogs undergoing treatment for CE warrants further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Asynchronous recruitment of low-threshold motor units during repetitive, low-current stimulation of the human tibial nerve.

PubMed

Dean, Jesse C; Clair-Auger, Joanna M; Lagerquist, Olle; Collins, David F

2014-01-01

Motoneurons receive a barrage of inputs from descending and reflex pathways. Much of our understanding about how these inputs are transformed into motor output in humans has come from recordings of single motor units during voluntary contractions. This approach, however, is limited because the input is ill-defined. Herein, we quantify the discharge of soleus motor units in response to well-defined trains of afferent input delivered at physiologically-relevant frequencies. Constant frequency stimulation of the tibial nerve (10-100 Hz for 30 s), below threshold for eliciting M-waves or H-reflexes with a single pulse, recruited motor units in 7/9 subjects. All 25 motor units recruited during stimulation were also recruited during weak (<10% MVC) voluntary contractions. Higher frequencies recruited more units (n = 3/25 at 10 Hz; n = 25/25 at 100 Hz) at shorter latencies (19.4 ± 9.4 s at 10 Hz; 4.1 ± 4.0 s at 100 Hz) than lower frequencies. When a second unit was recruited, the discharge of the already active unit did not change, suggesting that recruitment was not due to increased synaptic drive. After recruitment, mean discharge rate during stimulation at 20 Hz (7.8 Hz) was lower than during 30 Hz (8.6 Hz) and 40 Hz (8.4 Hz) stimulation. Discharge was largely asynchronous from the stimulus pulses with "time-locked" discharge occurring at an H-reflex latency with only a 24% probability. Motor units continued to discharge after cessation of the stimulation in 89% of trials, although at a lower rate (5.8 Hz) than during the stimulation (7.9 Hz). This work supports the idea that the afferent volley evoked by repetitive stimulation recruits motor units through the integration of synaptic drive and intrinsic properties of motoneurons, resulting in "physiological" recruitment which adheres to Henneman's size principle and results in relatively low discharge rates and asynchronous firing.

Trends in hospital admission rates for whooping cough in England across five decades: database studies

PubMed Central

Hoang, Uy; Goldacre, Michael J

2014-01-01

Objectives Our aim was to report on trends in hospitalisation rates for pertussis in England from the 1960s to 2011; and to provide context for the recent unexpected activity of Bordetella pertussis in the UK. Design A retrospective analysis of English national Hospital Episode Statistics (HES, 1968–2011) and the Oxford Record Linkage Study (ORLS, 1963–2011) for people admitted to hospital with whooping cough. Setting England and the Oxford Record Linkage Study area. Main outcome measures Age- and gender-specific hospital admission rates, and summary age- and sex-standardised rates, for people aged under 25 years per 100,000 population in each age group. Results Admission rates declined from the 1960s to the early 1970s. For example, the standardised rates were 12.8 (95% confidence interval 11.2–14.5) per 100,000 in England in 1968 and 4.0 (3.0–4.9) per 100,000 in 1973. They then increased to reach 45.0 (41.4–48.6) per 100,000 in 1978 and 47.4 (43.7–51.1) in 1982. From the late 1980s, admission rates continued to decline, falling to between 1 and 4 per 100,000 in each of the years between 2003 and 2011. While the trend in hospital admissions closely followed that in notifications, the annual ratio between these two measures was not consistent ranging from 1.07 (95% confidence interval 1.00–1.14) to 4.03 (3.79–4.27) notifications per admission over the last 10 years. Conclusions Epidemics of whooping cough in the late 1970s and early 1980s were associated with a significant rise in hospital admission rates. Current admission rates are low, by historical comparison. Vaccine programmes must continue to be fully implemented in order to improve control of pertussis activity. PMID:24526463

Regulated expression of the rat recombinant P2X(3) receptor in stably transfected CHO-K1 tTA cells.

PubMed

Lachnit, W G; Oglesby, I B; Gever, J R; Gever, M; Huang, C; Li, X C; Jin, H; McGivern, J G; Ford, A P

2000-07-03

In this report, the regulatable expression by tetracycline of the rat recombinant P2X(3) receptor in stably transfected Chinese hamster ovary (CHO-K1) expressing the tetracycline-controlled transactivator (tTA) is described. cDNA encoding the rat P2X(3)-receptor was subcloned into pTRE (a tetracycline-repressible expression vector) which was used to transfect stably CHO-K1 tTA cells. Using whole cell patch clamp techniques, 100 microM ATP evoked inward currents of 2.9+/-1.6 nA in transfected cells grown in the absence of tetracycline (tet-). The P2X(3) receptor protein was detectable by immunoblot as early as 24 h and protein expression levels continued to increase as much as 192 h following activation of tTA by the removal of the antibiotic. Saturation binding isotherms using [35S]ATP gamma S yielded a pK(d) of 8.2+/-0.1 and a B(max) of 31.9+/-3.5 pmol/mg protein in tet- cell membranes and a pK(d) of 8.1+/-0.1 and a B(max) of 5.8+/-0.8 pmol/mg protein in tet+ cell membranes. The agonist ligands 2MeSATP and alpha beta MeATP displaced the binding of [35S]ATP gamma S in tet- cell membranes with very high affinity, yielding pIC(50) values of 9.4+/-0.2 and 7.5+/-0. 2, respectively. In tet+ cell membrane, displacement of [35S]ATP gamma S by 2MeSATP and alpha beta MeATP was of much lower affinity (pIC(50) values of 7.8 and 6.2, respectively). ATP, ADP and UTP showed similar displacement of [35S]ATP gamma S binding in tet- and tet+ cell membranes. In other experiments, cytosolic Ca(2+) was monitored using the fluorescent indicator, fluo-3. Increases in cytosolic Ca(2+) were elicited by 100 nM alpha beta MeATP in tet- cells while no increases in cytosolic Ca(2+) were detected below 100 microM alpha beta MeATP in either tet+ cells or untransfected cells. These calcium responses to alpha beta MeATP had a pEC(50) of 6.7 and were transient, returning to baseline within 120 s. Suramin produced concentration-dependent, parallel, dextral shifts of E/[A] curves to alpha beta MeATP yielding a pK(B) of 5.6. PPADS produced non-parallel, dextral shifts of E/[A] curves to alpha beta MeATP which were insurmountable. These results show for the first time, expression of a functional, homomeric recombinant rat P2X(3) receptor which is under regulated expression in a stably transfected mammalian cell line.

Local S100A8 Levels Correlate With Recurrence of Experimental Autoimmune Uveitis and Promote Pathogenic T Cell Activity

PubMed Central

Yun, Juan; Xiao, Tong; Zhou, Lei; Beuerman, Roger W.; Li, Juanjuan; Zhao, Yuan; Hadayer, Amir; Zhang, Xiaomin; Sun, Deming; Kaplan, Henry J.

2018-01-01

Purpose To investigate the role of damage-associated molecular patterns (DAMPs) in recurrent experimental autoimmune uveitis (EAU). Methods Recurrent EAU was induced in Lewis rats by interphotoreceptor retinoid-binding protein (IRBP) R16-peptide specific T cells (tEAU). Aqueous humor and serum samples were kinetically collected and DAMPs examined by quantitative proteomics, Western blot analysis, and ELISA. tEAU rats were treated with S100 inhibitor paquinimod followed by disease evaluation. The functions of T effector cells and T regulatory cells (Tregs) were compared between treated and nontreated groups. The expression of costimulatory molecules on antigen-presenting cells was examined by flow cytometry. Results S100A8, but not high mobility group box 1 (HMGB1), in the eye was found to be correlated with intraocular inflammatory episodes. Administration of paquinimod significantly protected tEAU rats from recurrence. Treated tEAU rats had fewer R16-specific Th1 and Th17 cells, but increased numbers of Tregs. R16-specific T cells from treated tEAU rats into naïve recipients prevented induction of tEAU by R16-specific T cells from nontreated tEAU rats. Moreover, APCs from treated tEAU rats expressed higher levels of a negative costimulatory molecule, CD200R, and lower levels of CD80, CD86, and MHC class II molecules compared to APCs from nontreated tEAU rats. An opposite pattern of expression of these molecules was observed on APCs incubated in vitro with recombinant S100A8. Conclusions Our data demonstrate a link between local expression of DAMPs and autoimmune responses, and suggest that complete S100A8/A9 blockade may be a new therapeutic target in recurrent autoimmune uveitis. PMID:29625456

Niagara Falls IAP, New York. Revised Uniform Summary of Surface Weather Observations. Parts A-F.

DTIC Science & Technology

1987-09-30

TOTLS 1 21 . 32." 3 1. q 7 1 h .2 DO . 00 9.1 ..... .. . 30181 r, UPl’ OP O:’.rvI49A10.S: 33991? - A pPPPP,P~ppl A:. A RRRRR TY TIIII1 T0DD000D0...94.6 99.1 99.3 99.6 9’.q 99.9 530.0 10.0 130.0 100 .0 TO IAL hM "E" CF UnS[VATIONS: 9uU" .L K GLrObAL CLIPAIOLUGY BpAnFC P[.C[NfArE FkFELENCY OF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warner, Thomas; Jalilehvand, Farideh

Mercury(II) ions precipitate from aqueous cysteine (H 2Cys) solutions containing H 2Cys/Hg(II) mole ratio ≥ 2.0 as Hg( S-HCys) 2. In absence of additional cysteine, the precipitate dissolves at pH ~12 with the [Hg( S, N-Cys) 2] 2- complex dominating. With excess cysteine (H 2Cys/Hg(II) mole ratio ≥ 4.0), higher complexes form and the precipitate dissolves at lower pH values. Previously, we found that tetrathiolate [Hg( S-Cys) 4] 6- complexes form at pH = 11.0; in this work we extend the investigation to pH values of physiological interest. We examined two series of Hg(II)-cysteine solutions in which C Hg(II) variedmore » between 8 – 9 mM and 80 – 100 mM, respectively, with H 2Cys/Hg(II) mole ratios from 4 to ~20. The solutions were prepared in the pH range 7.1 – 8.8, at the pH at which the initial Hg( S-HCys) 2 precipitate dissolved. The variations in the Hg(II) speciation were followed by 199Hg NMR, X-ray absorption and Raman spectroscopic techniques. Our results show that in the dilute solutions (C Hg(II) = 8 – 9 mM), mixtures of di-, tri- (major) and tetrathiolate complexes exist at moderate cysteine excess (C H2Cys ~ 0.16 M) at pH 7.1. In the more concentrated solutions (C Hg(II) = 80 – 100 mM) with high cysteine excess (C H2Cys > 0.9 M), tetrathiolate [Hg( S-cysteinate) 4] m-6 ( m = 0 – 4) complexes dominate in the pH range 7.3 – 7.8, with lower charge than for the [Hg( S-Cys) 4] 6- complex due to protonation of some ( m) of the amino groups of the coordinated cysteine ligands. In conclusion, the results of this investigation could provide a key to the mechanism of biosorption and accumulation of Hg(II) ions in biological / environmental systems.« less

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study

PubMed Central

Daan, Nadine M. P.; Koster, Maria P. H.; de Wilde, Marlieke A.; Dalmeijer, Gerdien W.; Evelein, Annemieke M. V.; Fauser, Bart C. J. M.; de Jager, Wilco

2016-01-01

Objective To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. Design Cross-sectional comparison of serum biomarkers. Setting University Medical Center Utrecht. Patients Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6–8 years), and a paedriatic reference population (n = 30). Main Outcome Measure(s) Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). Results The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. Conclusion In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation. PMID:27806063

MX Siting Investigation. Water Resources Program. Technical Summary Report. Volume IIB.

DTIC Science & Technology

1981-11-30

8801014 4:144- 5886 1s 3 576 9 9 /it8 1o 2 57?57 ERTEC 80/88560 15 441441- 6481 TONOPAH 1943 63 12 S749 611962 12 5733 THORDARSON ETAL 71 16 4N/446- lA...7030 THORDARSON IT AL 71 3 9N/I1E- So SP MOREY CANYON 3/1967 5.0 7200 TRORDARSON IT AL 71 6 9N/SIE- BA SP SO. CYN. SPRING 3/1967 7.0 7360 TNORDARSON IT...SP COLD SPRING 411967 10.0 610G THORDARSON ET AL 71 10 EN/49E-23A9 SP 8/1967 2.0 5900 TWORDARSON IT AL 71 11 8N/69E-259A SP OLD DUGAN NOT SPA. 9/1967

An enigmatic long-lasting gamma-ray burst not accompanied by a bright supernova.

PubMed

Della Valle, M; Chincarini, G; Panagia, N; Tagliaferri, G; Malesani, D; Testa, V; Fugazza, D; Campana, S; Covino, S; Mangano, V; Antonelli, L A; D'Avanzo, P; Hurley, K; Mirabel, I F; Pellizza, L J; Piranomonte, S; Stella, L

2006-12-21

Gamma-ray bursts (GRBs) are short, intense flashes of soft gamma-rays coming from the distant Universe. Long-duration GRBs (those lasting more than approximately 2 s) are believed to originate from the deaths of massive stars, mainly on the basis of a handful of solid associations between GRBs and supernovae. GRB 060614, one of the closest GRBs discovered, consisted of a 5-s hard spike followed by softer, brighter emission that lasted for approximately 100 s (refs 8, 9). Here we report deep optical observations of GRB 060614 showing no emerging supernova with absolute visual magnitude brighter than M(V) = -13.7. Any supernova associated with GRB 060614 was therefore at least 100 times fainter, at optical wavelengths, than the other supernovae associated with GRBs. This demonstrates that some long-lasting GRBs can either be associated with a very faint supernova or produced by different phenomena.

The value of detection of S100A8 and ASAH1 in predicting the chemotherapy response for breast cancer patients.

PubMed

Li, Yu-Hong; Liu, Hai-Ting; Xu, Jing; Xing, Ai-Yan; Zhang, Jie; Wang, Ya-Wen; Yin, Gang; Gao, Peng

2018-04-01

Chemotherapy plays an important role in the treatment of breast cancer. However, chemoresistance remains the main obstacle for effective treatment, leading to poor prognosis. This study aims to investigate the value of detection of S100A8 and ASAH1 in predicting the chemotherapy response. Miller and Payne grades were used to assess the chemotherapy response in breast cancers. The expression of S100A8 and ASAH1, as well as ER, PR, HER2 and Ki-67 were assessed by immunohistochemical staining in 120 cases of non-special type invasive ductal carcinoma (IDC-NOS). S100A8 expression was higher in chemosensitive breast cancers than chemoresistant ones. Moreover, S100A8 expression was significantly correlated with the molecular subtypes and histological grade, but not with patients' age, tumor size and lymph nodes status. However, there was no significant difference in ASAH1 expression between chemoresistant and chemosensitive group. We also found that higher ASAH1 expression was correlated with positive lymph nodes status, but not with age, tumor size, molecular subtypes and histological grade. S100A8 was valuable in predicting chemotherapy response in breast cancers. The expression of ASAH1 was associated significantly with lymph nodes metastasis, indicating that ASAH1 may serve as a biomarker to predict patients' lymph nodes status in breast cancers. Copyright © 2018 Elsevier Inc. All rights reserved.

Multidimensional analysis of intracellular bacteriophage T7 DNA: effects of amber mutations in genes 3 and 19.

PubMed Central

Serwer, P; Watson, R H; Hayes, S J

1987-01-01

By use of rate-zonal centrifugation, followed by either one- or two-dimensional agarose gel electrophoresis, the forms of intracellular bacteriophage T7 DNA produced by replication, recombination, and packaging have been analyzed. Previous studies had shown that at least some intracellular DNA with sedimentation coefficients between 32S (the S value of mature T7 DNA) and 100S is concatemeric, i.e., linear and longer than mature T7 DNA. The analysis presented here confirmed that most of this DNA is linear, but also revealed a significant amount of circular DNA. The data suggest that these circles are produced during DNA packaging. It is proposed that circles are produced after a capsid has bound two sequential genomes in a concatemer. The size distribution of the linear, concatemeric DNA had peaks at the positions of dimeric and trimeric concatemers. Restriction endonuclease analysis revealed that most of the mature T7 DNA subunits of concatemers were joined left end to right end. However, these data also suggest that a comparatively small amount of left-end to left-end joining occurs, possibly by blunt-end ligation. A replicating form of T7 DNA that had an S value greater than 100 (100S+ DNA) was also found to contain concatemers. However, some of the 100S+ DNA, probably the most branched component, remained associated with the origin after agarose gel electrophoresis. It has been found that T7 protein 19, known to be required for DNA packaging, was also required to prevent loss, probably by nucleolytic degradation, of the right end of all forms of intracellular T7 DNA. T7 gene 3 endonuclease, whose activity is required for both recombination of T7 DNA and degradation of host DNA, was required for the formation of the 32S to 100S molecules that behaved as concatemers during gel electrophoresis. In the absence of gene 3 endonuclease, the primary accumulation product was origin-associated 100S+ DNA with properties that suggest the accumulation of branches, primarily at the left end of mature DNA subunits within the 100S+ DNA. Images PMID:2822958

Overexpression of Human S100B Exacerbates Brain Damage and Periinfarct Gliosis After Permanent Focal Ischemia

PubMed Central

Mori, Takashi; Tan, Jun; Arendash, Gary W.; Koyama, Naoki; Nojima, Yoshiko; Town, Terrence

2009-01-01

Background and Purpose We have previously demonstrated that augmented and prolonged activation of astrocytes detrimentally influences both the subacute and chronic phases of cerebral ischemia. Furthermore, we have suggested that the astrocyte-derived protein S100B may be important in these pathogenic events. However, the causal relationship between S100B and exacerbation of brain damage in vivo remains to be elucidated. Methods Using transgenic mice overexpressing human S100B (Tg huS100B mice), we examined whether S100B plays a cardinal role in aggravation of brain damage after permanent middle cerebral artery occlusion (pMCAO). Results Tg huS100B mice had significantly larger infarct volumes and worse neurological deficits at any time point examined after pMCAO as compared with CD-1 background strain-matched control mice. Infarct volumes in Tg huS100B mice were significantly increased from 1 to 3 and 5 days after pMCAO (delayed infarct expansion), whereas those in control mice were not significantly altered. S100, glial fibrillary acidic protein, and Iba1 burdens in the periinfarct area were significantly increased through to 7 days after pMCAO in Tg huS100B mice, whereas those in control mice reached a plateau at 3 days after pMCAO. Conclusions These results provide genetic evidence that overexpression of human S100B acts to exacerbate brain damage and periinfarct reactive gliosis (astrocytosis and microgliosis) during the subacute phase of pMCAO. PMID:18451356

New Human Immunodeficiency Virus diagnoses among Men Who Have Sex with Men attending STD clinics, STD Surveillance Network, January 2010 to June 2013.

PubMed

Llata, Eloisa; Braxton, Jim; Asbel, Lenore; Kerani, Roxanne P; Murphy, Ryan; Pugsley, River; Pathela, Preeti; Schumacher, Christina; Tabidze, Irina; Weinstock, Hillard S

2018-02-07

To estimate new HIV diagnosis rates among HIV negative MSM who are repeatedly tested for HIV in sexually transmitted disease (STD) clinics, and assess the impact of demographic and disease-specific characteristics that are associated with higher HIV diagnosis rates. Retrospective analysis using 2010-2013 data from the STD Surveillance Network (SSuN), a sentinel surveillance system comprised of health departments in 12 cities conducting sentinel surveillance in 40 STD clinics. We analyzed data from all MSM repeatedly (≥2 times) tested for HIV, with an initial negative HIV test required for staggered cohort entry. Follow-up time was accrued from the date of the first negative HIV test to the most recent negative test or the first positive HIV test. STD diagnoses during the follow-up period were reviewed. We estimated HIV diagnoses rates (number of HIV diagnoses/total number of person-years at risk) by demographic and clinical characteristics with 95% confidence intervals (CI) using an inverse variance weighted random effects model, adjusting for heterogeneity between SSuN jurisdictions. Overall, 640 HIV diagnoses occurred among 14,824 individuals and 20,951.6 person-years (PY) of observation, for an adjusted incidence of HIV diagnosis of 3.0 per 100 PY (95% CI 2.6, 3.4). Rates varied across race/ethnicity groups with the highest rate among Blacks (4.7/100 PY; 95% CI 4.1-5.3) followed by Hispanics, Whites and persons of other races/ethnicities. MSM having a diagnosis of P&S syphilis on or after the first negative HIV test had a higher new HIV diagnosis rate (7.2/100 PY; 95% CI 5.8-9.0) compared to MSM who did not have a P&S syphilis diagnosis (2.8/100 PY; 95% CI 2.6-3.1). MSM who tested positive for rectal gonorrhea (6.3/100 PY; 95% CI 5.7-6.9) or rectal chlamydia (5.6/100 PY; 95% CI 4.6-6.6) had higher rates of new HIV diagnosis when compared to those with negative test results. MSM attending SSuN STD clinics have high rates of new HIV diagnoses, particularly those with a previous diagnosis of P&S syphilis, rectal chlamydia and/or gonorrhea. STD clinics continue to be important clinical setting for diagnosing HIV among MSM populations.

Racial Equity in Selection in Air Force Officer Training School and Undergraduate Flying Training

DTIC Science & Technology

1977-05-01

8217- _____________________OTS Steles W3UN Ne- I 6031L a.go& isease of -A N "SN N 32iell(E 23.5 7 5.1 35 4 -9 North Central(NM 37 272 14 10.2 51 0 100.0 othS,32...23.2 Quant. M 58.0 54.1 56.3 45.9 33.5 37.8- " SD 26.5 25.7 26.2 24.1 21.6 23.°2 Bio . Inv. Ma 39.6 - 39.6 36.8 - 36.8 SD 7.9 - 7.9 12.1 - 12.1 Off. Qual

The vascular health status of a population of adult Canadian Indigenous peoples from British Columbia.

PubMed

Foulds, H J A; Bredin, S S D; Warburton, D E R

2016-04-01

Indigenous populations currently experience greater cardiovascular disease burdens. However, subclinical vascular structure and function among these populations is not well known. This investigation evaluated vascular structure and function among Canadian Indigenous populations. Blood pressure, body composition, pulse-wave velocity (PWV), baroreceptor sensitivity (BRS), arterial compliance and intima-media thickness (IMT) were measured. Vascular measures were evaluated across sexes and age groups. Vascular assessments were conducted among 55 Indigenous adults (38±18 years, 29 Female), including both First Nations (N=36) and Métis (N=19) individuals. Some differences in vascular measures were found between males and females, respectively (spectral BRS: 9.6±6.8 ms mm Hg(-1) vs 16.9±10.0 ms mm Hg(-1), P=0.01; small arterial compliance: 8.9±3.7 ml mm Hg(-1) × 100 vs 6.4±2.3 ml mm Hg(-1) × 100, P=0.004), with similar measures of overall IMT (0.61±0.14 mm vs 0.57±0.08 mm, P=0.19) and central PWV (5.7±2.5 m s(-1) vs 5.1±2.3 m s(-1), P=0.58). Greater IMT, and lower BRS and arterial compliance were identified among older adults. This relatively healthy population demonstrated healthy vascular measures, with poorer measures among older individuals.

Presence and resistance of Streptococcus agalactiae in vaginal specimens of pregnant and adult non-pregnant women and association with other aerobic bacteria.

PubMed

Numanović, Fatima; Smajlović, Jasmina; Gegić, Merima; Delibegović, Zineta; Bektaš, Sabaheta; Halilović, Emir; Nurkić, Jasmina

2017-02-01

Aim To determine the prevalence rate and resistance profile of Streptococcus agalactiae (S. agalactiae) in vaginal swabs of pregnant and adult non-pregnant women in the Tuzla region, Bosnia and Herzegovina (B&H), as well as its association with other aerobic bacteria. Methods This prospective study included 200 women, 100 pregnant and 100 adult non-pregnant. The research was conducted at the Institute of Microbiology, University Clinical Center Tuzla from October to December 2015. Standard aerobic microbiological techniques were used for isolation and identification of S. agalactiae and other aerobic bacteria. Antimicrobial susceptibility was determined by the disk diffusion and microdilution method(VITEK 2/AES instrument). Results Among 200 vaginal swabs, 17 (8.50%) were positive for S. agalactiae, e. g., 7% (7/100) of pregnant and 10% (10/100) of adult non-pregnant women. In the pregnant group, 71.4% (5/7) of S. agalactiae isolates were susceptible to clindamycin and 85.7%(6/7) to erythromycin. In the adult non-pregnant group, only resistance to clindamycin was observed in one patient (1/10; 10%). S. agalactiae as single pathogen was isolated in 57.14% (4/7) of pregnant and 60% (6/10) of adult non-pregnant S. agalactiae positive women. In mixed microbial cultures S. agalactiae was most frequently associated with Enterococcus faecalis and Escherichia coli. Conclusion The rate of S. agalactiae positive women in the population of pregnant and adult non-pregnant women of Tuzla Canton, B&H is comparable with other European countries. Large studies are needed to develop a common national strategy for the prevention of S. agalactiae infection in B&H, especially during pregnancy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

Expression of Slug in S100β-protein-positive cells of postnatal developing rat anterior pituitary gland.

PubMed

Horiguchi, Kotaro; Fujiwara, Ken; Tsukada, Takehiro; Yako, Hideji; Tateno, Kozue; Hasegawa, Rumi; Takigami, Shu; Ohsako, Shunji; Yashiro, Takashi; Kato, Takako; Kato, Yukio

2016-02-01

Among heterogeneous S100β-protein-positive (S100β-positive) cells, star-like cells with extended cytoplasmic processes, the so-called folliculo-stellate cells, envelop hormone-producing cells or interconnect homophilically in the anterior pituitary. S100β-positive cells are known, from immunohistochemistry, to emerge from postnatal day (P) 10 and to proliferate and migrate in the parenchyma of the anterior pituitary with growth. Recent establishment of S100β-GFP transgenic rats expressing specifically green fluorescent protein (GFP) under the control of the S100β-promoter has allowed us to observe living S100β-positive cells. In the present study, we first confirmed that living S100β-positive cells in tissue cultures of S100β-GFP rat pituitary at P5 were present prior to P10 by means of confocal laser microscopy and that they proliferated and extended their cytoplasmic processes. Second, we examined the expression of the Snail-family zinc-finger transcription factors, Snail and Slug, to investigate the mechanism behind the morphological changes and the proliferation of S100β-positive cells. Interestingly, we detected Slug expression in S100β-positive cells and its increase together with development in the anterior pituitary. To analyze downstream of SLUG in S100β-positive cells, we utilized specific small interfering RNA for Slug mRNAs and observed that the expression of matrix metalloprotease (Mmp) 9, Mmp14 and chemokine Cxcl12 was down-regulated and that morphological changes and proliferation were decreased. Thus, our findings suggest that S100β-positive cells express Slug and that its expression is important for subsequent migration and proliferation.

High-Power Vehicle-Towed TEM for Small Ordnance Detection at Depth

DTIC Science & Technology

2014-02-01

Operations,100A Donner Dr,Oak Ridge,TN, 37830 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10...T. Jeffrey Gamey Battelle, 100A Donner Dr., Oak Ridge, TN 37830 (865) 599-0820 gameytj@battelle.org Geophysicist – Principle Investigator...William Doll Battelle, 100A Donner Dr., Oak Ridge, TN 37830 (865) 599-6165 dollw@battelle.org Geophysicist – modeling assessment, data collection, data

Ultraviolet-C light effect on physicochemical, bioactive, microbiological, and sensorial characteristics of carrot (Daucus carota) beverages.

PubMed

Hernández-Carranza, Paola; Ruiz-López, Irving Israel; Pacheco-Aguirre, Francisco Manuel; Guerrero-Beltrán, José Ángel; Ávila-Sosa, Raúl; Ochoa-Velasco, Carlos Enrique

2016-09-01

The aim of this research was to evaluate the effect of ultraviolet-C light on physicochemical, bioactive, microbial, and sensory characteristics of carrot beverages. Beverages were formulated with different concentrations of carrot juice (60, 80, and 100% [v/v]) and treated with ultraviolet-C light at different flow rates (0, 0.5, 3.9, and 7.9 mL s(-1)) and times (5, 10, 15, 20, and 30 min), equivalent to ultraviolet-C dosages of 13.2, 26.4, 39.6, 52.8, and 79.2 J cm(-2) Total soluble solids, pH, and titratable acidity were not affected by the ultraviolet-C light treatment. Ultraviolet-C light significantly affected (p < 0.05) color parameters of pure juice; however, at low concentration of juice, total color change was slightly affected (ΔE = 2.0 ± 0.7). Phenolic compounds (4.1 ± 0.1, 5.2 ± 0.2, and 8.6 ± 0.3 mg of GAE 100 mL(-1) of beverage with 60, 80, and 100% of juice, respectively) and antioxidant capacity (6.1 ± 0.4, 8.5 ± 0.4, and 9.4 ± 0.3 mg of Trolox 100 mL(-1) of beverage with 60, 80, and 100% of juice, respectively) of carrot beverages were not affected by ultraviolet-C light treatment. Microbial kinetics showed that mesophiles were mostly reduced at high flow rates in carrot beverages with 60% of juice. Maximum logarithmic reductions for mesophiles and total coliforms were 3.2 ± 0.1 and 2.6 ± 0.1, respectively, after 30 min of ultraviolet-C light processing. Beverages were well accepted (6-7) by judges who did not perceive the difference between untreated and Ultraviolet-C light treated beverages. © The Author(s) 2016.

Changes in Lower Extremity Biomechanics Due to a Short-Term Fatigue Protocol

PubMed Central

Cortes, Nelson; Greska, Eric; Kollock, Roger; Ambegaonkar, Jatin; Onate, James A.

2013-01-01

Context: Noncontact anterior cruciate ligament injury has been reported to occur during the later stages of a game when fatigue is most likely present. Few researchers have focused on progressive changes in lower extremity biomechanics that occur throughout fatiguing. Objective: To evaluate the effects of a sequential fatigue protocol on lower extremity biomechanics during a sidestep-cutting task (SS). Design: Controlled laboratory study. Setting: Laboratory. Patients or Other Participants: Eighteen uninjured female collegiate soccer players (age = 19.2 ± 0.9 years, height = 1.66 ± 0.5 m, mass = 61.6 ± 5.1 kg) volunteered. Intervention(s): The independent variable was fatigue level, with 3 levels (prefatigue, 50% fatigue, and 100% fatigue). Using 3-dimensional motion capture, we assessed lower extremity biomechanics during the SS. Participants alternated between a fatigue protocol that solicited different muscle groups and mimicked actual sport situations and unanticipated SS trials. The process was repeated until fatigue was attained. Main Outcome Measure(s): Dependent variables were hip- and knee-flexion and abduction angles and internal moments measured at initial contact and peak stance and defined as measures obtained between 0% and 50% of stance phase. Results: Knee-flexion angle decreased from prefatigue (−17° ± 5°) to 50% fatigue (−16° ± 6°) and to 100% fatigue (−14° ± 4°) (F2,34 = 5.112, P = .004). Knee flexion at peak stance increased from prefatigue (−52.9° ± 5.6°) to 50% fatigue (−56.1° ± 7.2°) but decreased from 50% to 100% fatigue (−50.5° ± 7.1°) (F2,34 = 8.282, P = 001). Knee-adduction moment at peak stance increased from prefatigue (0.49 ± 0.23 Nm/kgm) to 50% fatigue (0.55 ± 0.25 Nm/kgm) but decreased from 50% to 100% fatigue (0.37 ± 0.24) (F2,34 = 3.755, P = 03). Hip-flexion angle increased from prefatigue (45.4° ± 10.9°) to 50% fatigue (46.2° ± 11.2°) but decreased from 50% to 100% fatigue (40.9° ± 11.3°) (F2,34 = 6.542, P = .004). Hip flexion at peak stance increased from prefatigue (49.8° ± 9.9°) to 50% fatigue (52.9° ± 12.1°) but decreased from 50% to 100% fatigue (46.3° ± 12.9°) (F2,34 = 8.639, P = 001). Hip-abduction angle at initial contact decreased from prefatigue (−13.8° ± 6.6°) to 50% fatigue (−9.1° ± 6.5°) and to 100% fatigue (−7.8° ± 6.5°) (F2,34 = 11.228, P < .001). Hip-adduction moment decreased from prefatigue (0.14 ± 0.13 Nm/kgm) to 50% fatigue (0.08 ± 0.13 Nm/kgm) and to 100% fatigue (0.06 ± 0.05 Nm/kg) (F2,34 = 5.767, P = .007). Conclusions: The detrimental effects of fatigue on sagittal and frontal mechanics of the hip and knee were visible at 50% of the participants' maximal fatigue and became more marked at 100% fatigue. Anterior cruciate ligament injury-prevention programs should emphasize feedback on proper mechanics throughout an entire practice and not only at the beginning of practice. PMID:23675789

Morphological analysis of astrocytes in the hippocampus in mechanical asphyxiation.

PubMed

Li, Dong-Ri; Ishikawa, Takaki; Quan, Li; Zhao, Dong; Michiue, Tomomi; Zhu, Bao-Li; Wang, Hui Jun; Maeda, Hitoshi

2010-03-01

The present study investigated the morphology of astrocytes in the hippocampus and serum S100B levels in cases of mechanical asphyxia due to neck compression (n=23: atypical hanging, n=7; ligature/manual strangulation, n=16) with regard to the classical autopsy findings, compared with those of other types of asphyxiation (n=9) and acute myocardial infarction/ischemia (AMI, n=20). The decrease in intact astrocyte number, as shown by S100 and GFAP-immunostaining, was larger for asphyxiation due to neck compression compared with that for other asphyxiation and AMI, showing a correlation with the increase in the serum S100B levels. The decrease in intact astrocyte number and increase in serum S100B were closely related to the severity of conjunctival petechial hemorrhage and fracture(s) of the hyoid bone and/or thyroid cartilage in asphyxia due to neck compression. These findings suggest that hippocampal astrocyte injury is caused by cerebral hypoxia accompanied by congestion, especially in mechanical asphyxia due to neck compression. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Effect of selected gastrointestinal parasites and viral agents on fecal S100A12 concentrations in puppies as a potential comparative model.

PubMed

Heilmann, Romy M; Grellet, Aurélien; Grützner, Niels; Cranford, Shannon M; Suchodolski, Jan S; Chastant-Maillard, Sylvie; Steiner, Jörg M

2018-04-17

Previous data suggest that fecal S100A12 has clinical utility as a biomarker of chronic gastrointestinal inflammation (idiopathic inflammatory bowel disease) in both people and dogs, but the effect of gastrointestinal pathogens on fecal S100A12 concentrations is largely unknown. The role of S100A12 in parasite and viral infections is also difficult to study in traditional animal models due to the lack of S100A12 expression in rodents. Thus, the aim of this study was to evaluate fecal S100A12 concentrations in a cohort of puppies with intestinal parasites (Cystoisospora spp., Toxocara canis, Giardia sp.) and viral agents that are frequently encountered and known to cause gastrointestinal signs in dogs (coronavirus, parvovirus) as a comparative model. Spot fecal samples were collected from 307 puppies [median age (range): 7 (4-13) weeks; 29 different breeds] in French breeding kennels, and fecal scores (semiquantitative system; scores 1-13) were assigned. Fecal samples were tested for Cystoisospora spp. (C. canis and C. ohioensis), Toxocara canis, Giardia sp., as well as canine coronavirus (CCV) and parvovirus (CPV). S100A12 concentrations were measured in all fecal samples using an in-house radioimmunoassay. Statistical analyses were performed using non-parametric 2-group or multiple-group comparisons, non-parametric correlation analysis, association testing between nominal variables, and construction of a multivariate mixed model. Fecal S100A12 concentrations ranged from < 24-14,363 ng/g. Univariate analysis only showed increased fecal S100A12 concentrations in dogs shedding Cystoisospora spp. (P = 0.0384) and in dogs infected with parvovirus (P = 0.0277), whereas dogs infected with coronavirus had decreased fecal S100A12 concentrations (P = 0.0345). However, shedding of any single enteropathogen did not affect fecal S100A12 concentrations in multivariate analysis (all P > 0.05) in this study. Only fecal score and breed size had an effect on fecal S100A12 concentrations in multivariate analysis (P < 0.0001). An infection with any single enteropathogen tested in this study is unlikely to alter fecal S100A12 concentrations, and these preliminary data are important for further studies evaluating fecal S100A12 concentrations in dogs or when using fecal S100A12 concentrations as a biomarker in patients with chronic idiopathic gastrointestinal inflammation.

Emptying of Intracellular Calcium Pool and Oxidative Stress Imbalance Are Associated with the Glyphosate-Induced Proliferation in Human Skin Keratinocytes HaCaT Cells

PubMed Central

George, Jasmine; Shukla, Yogeshwer

2013-01-01

We demonstrated that glyphosate possesses tumor promoting potential in mouse skin carcinogenesis and SOD 1, calcyclin (S100A6), and calgranulin B (S100A9) have been associated with this potential, although the mechanism is unclear. We aimed to clarify whether imbalance in between [Ca2+]i levels and oxidative stress is associated with glyphosate-induced proliferation in human keratinocytes HaCaT cells. The [Ca2+]i levels, ROS generation, and expressions of G1/S cyclins, IP3R1, S100A6, S100A9, and SOD 1, and apoptosis-related proteins were investigated upon glyphosate exposure in HaCaT cells. Glyphosate (0.1 mM) significantly induced proliferation, decreases [Ca2+]i, and increases ROS generation in HaCaT cells, whereas antioxidant N-acetyl-L-cysteine (NAC) pretreatment reverts these effects which directly indicated that glyphosate induced cell proliferation by lowering [Ca2+]i levels via ROS generation. Glyphosate also enhanced the expression of G1/S cyclins associated with a sharp decrease in G0/G1 and a corresponding increase in S-phases. Additionally, glyphosate also triggers S100A6/S100A9 expression and decreases IP3R1 and SOD 1 expressions in HaCaT cells. Notably, Ca2+ suppression also prevented apoptotic related events including Bax/Bcl-2 ratio and caspases activation. This study highlights that glyphosate promotes proliferation in HaCaT cells probably by disrupting the balance in between [Ca2+]i levels and oxidative stress which in turn facilitated the downregulation of mitochondrial apoptotic signaling pathways. PMID:24073338

Validation of the ICON-S staging for HPV-associated oropharyngeal carcinoma using a pre-defined treatment policy.

PubMed

Porceddu, Sandro V; Milne, Rob; Brown, Elizabeth; Bernard, Anne; Rahbari, Reza; Cartmill, Bena; Foote, Matthew; McGrath, Margaret; Coward, Jermaine; Panizza, Benedict

2017-03-01

To determine whether the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) for HPV associated oropharyngeal carcinoma (HPV+OPC) is a better discriminator of overall survival (OS), compared with the 7th edition (7th Ed) AJCC/UICC TNM staging following curative radiotherapy (RT). The 5-year OS for all patients with non-metastatic (M0) p16-confirmed OPC treated between 2005 and 2015 was determined and grouped based on the 7th Ed AJCC/UICC TNM and ICON-S staging. A total of 279 patients met the inclusion criteria. The 5-year OS with the 7th Ed TNM classification were Stage I/II 88.9% (95% CI; 70.6-100%), Stage III 93.8% (95% CI; 85.9-100%), Stage IVa 86.4% (95% CI; 81.6-91.5%) and Stage IVb 62.3% (95% CI; 46.8-82.8%). On multivariate Cox regression analysis there was no statistically significant OS difference when comparing Stage I/II with, Stage III (p=0.98, HR=0.97, 95% CI; 0.11-8.64), IVa (p=0.67, HR=1.56, 95% CI; 0.2-11.94) and IVb (p=0.11, HR=5.54, 95% CI; 0.69-44.52), respectively. The 5-year OS with ICON-S staging were Stage I 93.6% (95% CI; 89.4-98.0%), Stage II 81.9% (95% CI; 73.7-91.1%) and Stage III 69.1% (95%; 57.9-82.6%). There was a consistent decrease of OS with increasing stage. On multivariate Cox regression analysis, when compared to Stage I, OS was significantly lower for stage II (p=0.007, HR=2.84, 95% CI; 1.33-6.05) and stage III (p<0.001, HR=3.78, 95% CI; 1.81-7.92), respectively. The ICON-S staging provides better OS stratification for HPV+OPC following RT compared with the 7th Ed TNM staging. Copyright © 2017 Elsevier Ltd. All rights reserved.

100% orange juice consumption is associated with better diet quality, improved nutrient adequacy, decreased risk for obesity, and improved biomarkers of health in adults: National Health and Nutrition Examination Survey, 2003-2006.

PubMed

O'Neil, Carol E; Nicklas, Theresa A; Rampersaud, Gail C; Fulgoni, Victor L

2012-12-12

Consumption of 100% orange juice (OJ) has been positively associated with nutrient adequacy and diet quality, with no increased risk of overweight/obesity in children; however, no one has examined these factors in adults. The purpose of this study was to examine the association of 100% OJ consumption with nutrient adequacy, diet quality, and risk factors for metabolic syndrome (MetS) in a nationally representative sample of adults. Data from adults 19+ years of age (n = 8,861) participating in the National Health and Nutrition Examination Survey 2003-2006 were used. The National Cancer Institute method was used to estimate the usual intake (UI) of 100% OJ consumption, selected nutrients, and food groups. Percentages of the population below the Estimated Average Requirement (EAR) or above the Adequate Intake (AI) were determined. Diet quality was measured by the Healthy Eating Index-2005 (HEI-2005). Covariate adjusted logistic regression was used to determine if consumers had a lower odds ratio of being overweight or obese or having risk factors of MetS or MetS. Usual per capita intake of 100% OJ was 50.3 ml/d. Among consumers (n = 2,310; 23.8%), UI was 210.0 ml/d. Compared to non-consumers, consumers had a higher (p < 0.05) percentage (% ± SE) of the population meeting the EAR for vitamin A (39.7 ± 2.5 vs 54.0 ± 1.2), vitamin C (0.0 ± 0.0 vs 59.0 ± 1.4), folate (5.8 ± 0.7 vs 15.1 ± 0.9), and magnesium (51.6 ± 1.6 vs 63.7 ± 1.2). Consumers were also more likely to be above the AI for potassium (4.1 ± 0.8 vs 1.8 ± 0.2). HEI-2005 was significantly (p < 0.05) higher in consumers (55.0 ± 0.4 vs 49.7 ± 0.3). Consumers also had higher intakes of total fruit, fruit juice, whole fruit, and whole grain. Consumers had a lower (p < 0.05) mean body mass index (27.6 ± 0.2 vs 28.5 ± 0.1), total cholesterol levels (197.6 ± 1.2 vs 200.8 ± 0.75 mg/dL), and low density lipoprotein-cholesterol levels (112.5 ± 1.4 vs 116.7 ± 0.93 mg/dL). Finally, compared to non-consumers of 100% OJ, consumers were 21% less likely to be obese and male consumers were 36% less likely to have MetS. The results suggest that moderate consumption of 100% OJ should be encouraged to help individuals meet the USDA daily recommendation for fruit intake and as a component of a healthy diet.

100% Orange juice consumption is associated with better diet quality, improved nutrient adequacy, decreased risk for obesity, and improved biomarkers of health in adults: National Health and Nutrition Examination Survey, 2003-2006

PubMed Central

2012-01-01

Background Consumption of 100% orange juice (OJ) has been positively associated with nutrient adequacy and diet quality, with no increased risk of overweight/obesity in children; however, no one has examined these factors in adults. The purpose of this study was to examine the association of 100% OJ consumption with nutrient adequacy, diet quality, and risk factors for metabolic syndrome (MetS) in a nationally representative sample of adults. Methods Data from adults 19+ years of age (n = 8,861) participating in the National Health and Nutrition Examination Survey 2003-2006 were used. The National Cancer Institute method was used to estimate the usual intake (UI) of 100% OJ consumption, selected nutrients, and food groups. Percentages of the population below the Estimated Average Requirement (EAR) or above the Adequate Intake (AI) were determined. Diet quality was measured by the Healthy Eating Index-2005 (HEI-2005). Covariate adjusted logistic regression was used to determine if consumers had a lower odds ratio of being overweight or obese or having risk factors of MetS or MetS. Results Usual per capita intake of 100% OJ was 50.3 ml/d. Among consumers (n = 2,310; 23.8%), UI was 210.0 ml/d. Compared to non-consumers, consumers had a higher (p < 0.05) percentage (% ± SE) of the population meeting the EAR for vitamin A (39.7 ± 2.5 vs 54.0 ± 1.2), vitamin C (0.0 ± 0.0 vs 59.0 ± 1.4), folate (5.8 ± 0.7 vs 15.1 ± 0.9), and magnesium (51.6 ± 1.6 vs 63.7 ± 1.2). Consumers were also more likely to be above the AI for potassium (4.1 ± 0.8 vs 1.8 ± 0.2). HEI-2005 was significantly (p < 0.05) higher in consumers (55.0 ± 0.4 vs 49.7 ± 0.3). Consumers also had higher intakes of total fruit, fruit juice, whole fruit, and whole grain. Consumers had a lower (p < 0.05) mean body mass index (27.6 ± 0.2 vs 28.5 ± 0.1), total cholesterol levels (197.6 ± 1.2 vs 200.8 ± 0.75 mg/dL), and low density lipoprotein-cholesterol levels (112.5 ± 1.4 vs 116.7 ± 0.93 mg/dL). Finally, compared to non-consumers of 100% OJ, consumers were 21% less likely to be obese and male consumers were 36% less likely to have MetS. Conclusion The results suggest that moderate consumption of 100% OJ should be encouraged to help individuals meet the USDA daily recommendation for fruit intake and as a component of a healthy diet. PMID:23234248

Summary of Meteorological Observations, Surface (SMOS), Midway Island.

DTIC Science & Technology

1984-08-01

8 1.7 415 !I _? .,8 1.3.. 35 1962 9 ’.2 32 l󈧽 9 t.o 27 1965 10 1.2 2 1062 10 1 z1 1*6?2 11 1 - 641 ’ .E 24 1971 12 ’.11 1 !97 12 100 77 19 __9 13 1... 1971 22 1. 4 72 19ev 22 2 0 < 53 1’$6 7_______ 23 *1 . 961 23 1.13 2 ; 1981 24 ". 1’ 5 46P 24 1.-4 42’ 1952 25 ’. 0 36 1i)79 26 l.’b %s 蚝 1 26 𔃻. 6...OBSERVATIONS) j2 7ŕ 74!:WAY !SLA.𔃼 73-R2 MAY SiUUlm iS&AYWI MUl Y IOUAI kALL WEATHEP IP MMW=N ( L.8.1 . SIf, UL S aiim MEAN INTS I13 4.6 7-10 1114 17.21

Influence of body condition score on live and carcass value of cull beef cows.

PubMed

Apple, J K

1999-10-01

Mature beef cows (n = 88) were slaughtered to determine the influence of body condition score (BCS) on carcass and live animal value. Cows were weighed and assigned a BCS (9-point scale), 24 h before slaughter. Hide and by-products weights were recorded during harvest. After a 48-h chill period, the right side of each carcass was fabricated into boneless subprimal cuts, minor cuts, lean trim, fat, and bone. Weights were recorded at all stages of fabrication. Carcass values (U.S.$/100 kg of hot carcass weight) were calculated for U.S. Utility and U.S. Cutter grades, as well as for the Utility/Cutter mix for each BCS. Gross value included the carcass value and the value of the hide and byproducts, whereas net value was calculated after harvest and fabrication costs and by-product value were considered. Live value (U.S.$/100 kg of live weight) was computed by dividing the net value by the animal's live weight 24 h before harvest. The value of the hide and by-products for BCS-2 cows was greater (P<.05) than for cows assigned a BCS of 3 through 8. Even though U.S. Utility carcasses from BCS-8 cows produced the least (P<.05) valuable subprimal cuts from the chuck, loin, and round, the gross and net values of BCS-8 cows were greater (P<.05) than those of BCS-3, 4, 5, and 6. Within the grade of U.S. Cutter, carcasses from BCS-6 cows had the highest (P<.05), and BCS-2 cows had the lowest (P<.05), gross and net values. Across the U.S. Utility/Cutter mix, cows designated with a BCS of 7 and 8 had greater (P<.05) gross and net values than cows assigned a BCS of 6, or lower. Live value increased linearly (P = .0002) from a low of $76.10/100 kg for BCS-2 cows to a high of $90.84/100 kg for BCS-7 cows. Carcasses from BCS-6 cows were relatively lean (8.4 mm of fat opposite of the longissimus muscle), and approximately 73% of the carcasses achieved a quality grade of U.S. Utility. Moreover, carcasses from BCS-6 cows had the highest total carcass values and live values comparable (P>.05) to BCS-7 cows. Information from this study can be used by the non-fed beef industry to establish a value-based marketing system. Data from this study would indicate that marketing cull beef cows at a BCS of 6 could optimize economic returns to both cow-calf producers and non-fed beef packers.

Discovery of high and very high-energy emission from the BL Lacertae object SHBL J001355.9-185406

NASA Astrophysics Data System (ADS)

H.E.S.S. Collaboration; Abramowski, A.; Acero, F.; Aharonian, F.; Akhperjanian, A. G.; Angüner, E.; Anton, G.; Balenderan, S.; Balzer, A.; Barnacka, A.; Becherini, Y.; Becker Tjus, J.; Bernlöhr, K.; Birsin, E.; Bissaldi, E.; Biteau, J.; Boisson, C.; Bolmont, J.; Bordas, P.; Brucker, J.; Brun, F.; Brun, P.; Bulik, T.; Carrigan, S.; Casanova, S.; Cerruti, M.; Chadwick, P. M.; Chalme-Calvet, R.; Chaves, R. C. G.; Cheesebrough, A.; Chrétien, M.; Colafrancesco, S.; Cologna, G.; Conrad, J.; Couturier, C.; Dalton, M.; Daniel, M. K.; Davids, I. D.; Degrange, B.; Deil, C.; deWilt, P.; Dickinson, H. J.; Djannati-Ataï, A.; Domainko, W.; O'C. Drury, L.; Dubus, G.; Dutson, K.; Dyks, J.; Dyrda, M.; Edwards, T.; Egberts, K.; Eger, P.; Espigat, P.; Farnier, C.; Fegan, S.; Feinstein, F.; Fernandes, M. V.; Fernandez, D.; Fiasson, A.; Fontaine, G.; Förster, A.; Füßling, M.; Gajdus, M.; Gallant, Y. A.; Garrigoux, T.; Gast, H.; Giebels, B.; Glicenstein, J. F.; Göring, D.; Grondin, M.-H.; Grudzińska, M.; Häffner, S.; Hague, J. D.; Hahn, J.; Harris, J.; Heinzelmann, G.; Henri, G.; Hermann, G.; Hervet, O.; Hillert, A.; Hinton, J. A.; Hofmann, W.; Hofverberg, P.; Holler, M.; Horns, D.; Jacholkowska, A.; Jahn, C.; Jamrozy, M.; Janiak, M.; Jankowsky, F.; Jung, I.; Kastendieck, M. A.; Katarzyński, K.; Katz, U.; Kaufmann, S.; Khélifi, B.; Kieffer, M.; Klepser, S.; Klochkov, D.; Kluźniak, W.; Kneiske, T.; Kolitzus, D.; Komin, Nu.; Kosack, K.; Krakau, S.; Krayzel, F.; Krüger, P. P.; Laffon, H.; Lamanna, G.; Lefaucheur, J.; Lemoine-Goumard, M.; Lenain, J.-P.; Lennarz, D.; Lohse, T.; Lopatin, A.; Lu, C.-C.; Marandon, V.; Marcowith, A.; Maurin, G.; Maxted, N.; Mayer, M.; McComb, T. J. L.; Medina, M. C.; Méhault, J.; Menzler, U.; Meyer, M.; Moderski, R.; Mohamed, M.; Moulin, E.; Murach, T.; Naumann, C. L.; de Naurois, M.; Nedbal, D.; Niemiec, J.; Nolan, S. J.; Oakes, L.; Ohm, S.; de Oña Wilhelmi, E.; Opitz, B.; Ostrowski, M.; Oya, I.; Panter, M.; Parsons, R. D.; Paz Arribas, M.; Pekeur, N. W.; Pelletier, G.; Perez, J.; Petrucci, P.-O.; Peyaud, B.; Pita, S.; Poon, H.; Pühlhofer, G.; Punch, M.; Quirrenbach, A.; Raab, S.; Raue, M.; Reimer, A.; Reimer, O.; Renaud, M.; de los Reyes, R.; Rieger, F.; Rob, L.; Rosier-Lees, S.; Rowell, G.; Rudak, B.; Rulten, C. B.; Sahakian, V.; Sanchez, D. A.; Santangelo, A.; Schlickeiser, R.; Schüssler, F.; Schulz, A.; Schwanke, U.; Schwarzburg, S.; Schwemmer, S.; Sol, H.; Spengler, G.; Spieß, F.; Stawarz, Ł.; Steenkamp, R.; Stegmann, C.; Stinzing, F.; Stycz, K.; Sushch, I.; Szostek, A.; Tavernet, J.-P.; Terrier, R.; Tluczykont, M.; Trichard, C.; Valerius, K.; van Eldik, C.; Vasileiadis, G.; Venter, C.; Viana, A.; Vincent, P.; Völk, H. J.; Volpe, F.; Vorster, M.; Wagner, S. J.; Wagner, P.; Ward, M.; Weidinger, M.; White, R.; Wierzcholska, A.; Willmann, P.; Wörnlein, A.; Wouters, D.; Zacharias, M.; Zajczyk, A.; Zdziarski, A. A.; Zech, A.; Zechlin, H.-S.

2013-06-01

The detection of the high-frequency peaked BL Lac object (HBL) SHBL J001355.9-185406 (z = 0.095) at high (HE; 100 MeV < E < 300 GeV) and very high-energy (VHE; E > 100 GeV) with the Fermi Large Area Telescope (LAT) and the High Energy Stereoscopic System (H.E.S.S.) is reported. Dedicated observations were performed with the H.E.S.S. telescopes, leading to a detection at the 5.5σ significance level. The measured flux above 310 GeV is (8.3 ± 1.7stat ± 1.7sys) × 10-13 photons cm-2 s-1 (about 0.6% of that of the Crab Nebula), and the power-law spectrum has a photon index of Γ = 3.4 ± 0.5stat ± 0.2sys. Using 3.5 years of publicly available Fermi-LAT data, a faint counterpart has been detected in the LAT data at the 5.5σ significance level, with an integrated flux above 300 MeV of (9.3 ± 3.4stat ± 0.8sys) × 10-10 photons cm-2 s-1 and a photon index of Γ = 1.96 ± 0.20stat ± 0.08sys. X-ray observations with Swift-XRT allow the synchrotron peak energy in νFν representation to be located at ~1.0 keV. The broadband spectral energy distribution is modelled with a one-zone synchrotronself-Compton (SSC) model and the optical data by a black-body emission describing the thermal emission of the host galaxy. The derived parameters are typical of HBLs detected at VHE, with a particle-dominated jet.

Discovery of high and very high-energy emission from the BL Lacertae object SHBL J001355.9–185406

DOE PAGES

Abramowski, A.; Acero, F.; Aharonian, F.; ...

2013-06-05

In this paper, the detection of the high-frequency peaked BL Lac object (HBL) SHBL J001355.9–185406 (z = 0.095) at high (HE; 100 MeV < E < 300 GeV) and very high-energy (VHE; E > 100 GeV) with the Fermi Large Area Telescope (LAT) and the High Energy Stereoscopic System (H.E.S.S.) is reported. Dedicated observations were performed with the H.E.S.S. telescopes, leading to a detection at the 5.5σ significance level. The measured flux above 310 GeV is (8.3 ± 1.7 stat ± 1.7 sys) × 10 -13 photons cm -2 s -1 (about 0.6% of that of the Crab Nebula), andmore » the power-law spectrum has a photon index of Γ = 3.4 ± 0.5 stat ± 0.2 sys. Using 3.5 years of publicly available Fermi-LAT data, a faint counterpart has been detected in the LAT data at the 5.5σ significance level, with an integrated flux above 300 MeV of (9.3 ± 3.4 stat ± 0.8 sys) × 10 -10 photons cm -2 s -1 and a photon index of Γ = 1.96 ± 0.20 stat ± 0.08 sys. X-ray observations with Swift-XRT allow the synchrotron peak energy in νF ν representation to be located at ~1.0 keV. The broadband spectral energy distribution is modelled with a one-zone synchrotronself-Compton (SSC) model and the optical data by a black-body emission describing the thermal emission of the host galaxy. Lastly, the derived parameters are typical of HBLs detected at VHE, with a particle-dominated jet.« less

Novel Interactions of the TRTK12 Peptide with S100 Protein Family Members: Specificity and Thermodynamic Characterization

PubMed Central

Wafer, Lucas N.; Tzul, Franco O.; Pandharipande, Pranav P.; Makhatadze, George I.

2013-01-01

The S100 protein family consists of small, dimeric proteins that exert their biological functions in response to changing calcium concentrations. S100B is the best studied member and has been shown to interact with over 20 binding partners in a calcium-dependent manner. The TRTK12 peptide, derived from the consensus binding sequence for S100B, has previously been found to interact with S100A1 and has been proposed to be a general binding partner of the S100 family. To test this hypothesis and gain a better understanding of the specificity of binding for the S100 proteins sixteen members of the human S100 family were screened against this peptide and its alanine variants. Novel interactions were only found with two family members: S100P and S100A2, indicating that TRTK12 selectively interacts with a small subset of the S100 proteins. Substantial promiscuity was observed in the binding site of S100B to accommodate variations in the peptide sequence, while S100A1, S100A2, and S100P exhibited larger differences in the binding constants for the TRTK12 alanine variants. This suggests that single-point substitutions can be used to selectively modulate the affinity of TRTK12 peptides for individual S100 proteins. This study has important implications for the rational drug design of inhibitors for the S100 proteins, which are involved in a variety of cancers and neurodegenerative diseases. PMID:23899389

Discovery of VHE γ-ray emission and multi-wavelength observations of the BL Lacertae object 1RXS J101015.9-311909

NASA Astrophysics Data System (ADS)

H.E.S.S. Collaboration; Abramowski, A.; Acero, F.; Aharonian, F.; Akhperjanian, A. G.; Anton, G.; Balzer, A.; Barnacka, A.; Becherini, Y.; Becker, J.; Bernlöhr, K.; Birsin, E.; Biteau, J.; Bochow, A.; Boisson, C.; Bolmont, J.; Bordas, P.; Brucker, J.; Brun, F.; Brun, P.; Bulik, T.; Büsching, I.; Carrigan, S.; Casanova, S.; Cerruti, M.; Chadwick, P. M.; Charbonnier, A.; Chaves, R. C. G.; Cheesebrough, A.; Cologna, G.; Conrad, J.; Dalton, M.; Daniel, M. K.; Davids, I. D.; Degrange, B.; Deil, C.; Dickinson, H. J.; Djannati-Ataï, A.; Domainko, W.; Drury, L. O'C.; Dubus, G.; Dutson, K.; Dyks, J.; Dyrda, M.; Egberts, K.; Eger, P.; Espigat, P.; Fallon, L.; Fegan, S.; Feinstein, F.; Fernandes, M. V.; Fiasson, A.; Fontaine, G.; Förster, A.; Füßling, M.; Gallant, Y. A.; Gast, H.; Gérard, L.; Gerbig, D.; Giebels, B.; Glicenstein, J. F.; Glück, B.; Göring, D.; Häffner, S.; Hague, J. D.; Hahn, J.; Hampf, D.; Harris, J.; Hauser, M.; Heinz, S.; Heinzelmann, G.; Henri, G.; Hermann, G.; Hillert, A.; Hinton, J. A.; Hofmann, W.; Hofverberg, P.; Holler, M.; Horns, D.; Jacholkowska, A.; de Jager, O. C.; Jahn, C.; Jamrozy, M.; Jung, I.; Kastendieck, M. A.; Katarzyński, K.; Katz, U.; Kaufmann, S.; Keogh, D.; Khélifi, B.; Klochkov, D.; Kluźniak, W.; Kneiske, T.; Komin, Nu.; Kosack, K.; Kossakowski, R.; Krayzel, F.; Laffon, H.; Lamanna, G.; Lenain, J.-P.; Lennarz, D.; Lohse, T.; Lopatin, A.; Lu, C.-C.; Marandon, V.; Marcowith, A.; Masbou, J.; Maxted, N.; Mayer, M.; McComb, T. J. L.; Medina, M. C.; Méhault, J.; Moderski, R.; Mohamed, M.; Moulin, E.; Naumann, C. L.; Naumann-Godo, M.; de Naurois, M.; Nedbal, D.; Nekrassov, D.; Nguyen, N.; Nicholas, B.; Niemiec, J.; Nolan, S. J.; Ohm, S.; de Oña Wilhelmi, E.; Opitz, B.; Ostrowski, M.; Oya, I.; Panter, M.; Paz Arribas, M.; Pekeur, N. W.; Pelletier, G.; Perez, J.; Petrucci, P.-O.; Peyaud, B.; Pita, S.; Pühlhofer, G.; Punch, M.; Quirrenbach, A.; Raue, M.; Rayner, S. M.; Reimer, A.; Reimer, O.; Renaud, M.; de los Reyes, R.; Rieger, F.; Ripken, J.; Rob, L.; Rosier-Lees, S.; Rowell, G.; Rudak, B.; Rulten, C. B.; Sahakian, V.; Sanchez, D. A.; Santangelo, A.; Schlickeiser, R.; Schulz, A.; Schwanke, U.; Schwarzburg, S.; Schwemmer, S.; Sheidaei, F.; Skilton, J. L.; Sol, H.; Spengler, G.; Stawarz, Ł.; Steenkamp, R.; Stegmann, C.; Stinzing, F.; Stycz, K.; Sushch, I.; Szostek, A.; Tavernet, J.-P.; Terrier, R.; Tluczykont, M.; Valerius, K.; van Eldik, C.; Vasileiadis, G.; Venter, C.; Viana, A.; Vincent, P.; Völk, H. J.; Volpe, F.; Vorobiov, S.; Vorster, M.; Wagner, S. J.; Ward, M.; White, R.; Wierzcholska, A.; Zacharias, M.; Zajczyk, A.; Zdziarski, A. A.; Zech, A.; Zechlin, H.-S.

2012-06-01

1RXS J101015.9-311909 is a galaxy located at a redshift of z=0.14 hosting an active nucleus (called AGN) belonging to the class of bright BL Lac objects. Observations at high (HE, E > 100 MeV) and very high (VHE, E > 100 GeV) energies provide insights into the origin of very energetic particles present in such sources and the radiation processes at work. We report on results from VHE observations performed between 2006 and 2010 with the H.E.S.S. instrument, an array of four imaging atmospheric Cherenkov telescopes. H.E.S.S. data have been analysed with enhanced analysis methods, making the detection of faint sources more significant. VHE emission at a position coincident with 1RXS J101015.9-311909 is detected with H.E.S.S. for the first time. In a total good-quality livetime of about 49 h, we measure 263 excess counts, corresponding to a significance of 7.1 standard deviations. The photon spectrum above 0.2 TeV can be described by a power-law with a photon index of Γ = 3.08 ± 0.42stat ± 0.20sys. The integral flux above 0.2 TeV is about 0.8% of the flux of the Crab nebula and shows no significant variability over the time reported. In addition, public Fermi/LAT data are analysed to search for high energy emission from the source. The Fermi/LAT HE emission in the 100 MeV to 200 GeV energy range is significant at 8.3 standard deviations in the chosen 25-month dataset. UV and X-ray contemporaneous observations with the Swift satellite in May 2007 are also reported, together with optical observations performed with the atom telescope located at the H.E.S.S. site. Swift observations reveal an absorbed X-ray flux of F(0.3-7) keV = 1.04+0.04-0.05 × 10-11 erg cm-2 s-1 in the 0.3-7 keV range. Finally, all the available data are used to study the multi-wavelength properties of the source. The spectral energy distribution (SED) can be reproduced using a simple one-zone Synchrotron Self Compton (SSC) model with emission from a region with a Doppler factor of 30 and a magnetic field between 0.025 and 0.16 G. These parameters are similar to those obtained for other sources of this type.

Protein S100-A8: A potential metastasis-associated protein for breast cancer determined via iTRAQ quantitative proteomic and clinicopathological analysis.

PubMed

Zhong, Jing-Min; Li, Jing; Kang, An-Ding; Huang, San-Qian; Liu, Wen-Bin; Zhang, Yun; Liu, Zhi-Hong; Zeng, Liang

2018-04-01

Breast cancer is the most common malignancy in females, with metastasis of this type of cancer frequently proving lethal. However, there are still no effective biomarkers to predict breast cancer metastasis. The aim of the present study was, therefore, to analyze breast cancer metastasis-associated proteins and evaluate the association between protein S100-A8 and the prognosis of breast cancer. The isobaric tags for relative and absolute quantitation (iTRAQ) proteomic technique was used to analyze the differential expression of proteins between fresh primary breast tumor (PBT) tissue and fresh paired metastatic lymph nodes (PMLN) tissue. Subsequently, immunohistochemical staining was used to locate and assess the expression of protein S100-A8 in benign breast disease (n=15), primary breast cancer with (n=109) or without (n=83) metastasis, and in paired metastatic lymph nodes (n=109) formalin fixed paraffin embedded (FFPE) tissue. Staining scores were evaluated and the association between protein S100-A8 expression levels and the clinicopathological characteristics of 192 patients with breast cancer were evaluated using the χ 2 test. Kaplan-Meier and Cox hazards regression analyses were utilized to investigate the association between the expression of protein S100-A8 and the prognosis of patients with breast cancer. A total of 4,837 proteins were identified using the iTRAQ proteomic technique. Among these proteins, 643 differentially expressed proteins were revealed. Protein S100-A8 expression levels were identified to differ between PBT and PMLN tissues. Immunohistochemical staining suggested a significant difference between NMBT and PMLN (P=0.002), and also between PBT and PMLN (P<0.001). Cox hazards regression model analyses suggested that histological grade (P=0.031) and nodal status (P=0.001) were risk factors for lymph nodes metastasis of breast cancer. Kaplan-Meier analyses revealed no significant relationship between protein S100-A8 expression level and overall survival rate of patients with breast cancer. In conclusion, by using the iTRAQ proteomic technique and immunohistochemistry staining, it was identified that protein S100-A8 may be associated with lymph nodes metastasis of breast cancer and be a marker for progression of breast cancer.

Manganese Binding Properties of Human Calprotectin Under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced EPR Spectroscopic Analysis

PubMed Central

Gagnon, Derek M.; Brophy, Megan Brunjes; Bowman, Sarah E. J.; Stich, Troy A.; Drennan, Catherine L.; Britt, R. David; Nolan, Elizabeth M.

2015-01-01

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin-echo envelope modulation and electron nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed 15N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by ca. two orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His6 site of human calprotectin. PMID:25597447

Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis.

PubMed

Gagnon, Derek M; Brophy, Megan Brunjes; Bowman, Sarah E J; Stich, Troy A; Drennan, Catherine L; Britt, R David; Nolan, Elizabeth M

2015-03-04

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Herein, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimer is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin-echo envelope modulation and electron-nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed (15)N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His6 site of human calprotectin.

Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis

DOE PAGES

Gagnon, Derek M.; Brophy, Megan Brunjes; Bowman, Sarah E. J.; ...

2015-01-18

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Here in this paper, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimermore » is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin–echo envelope modulation and electron–nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed 15N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His 6 site of human calprotectin.« less

Manganese Binding Properties of Human Calprotectin under Conditions of High and Low Calcium: X-ray Crystallographic and Advanced Electron Paramagnetic Resonance Spectroscopic Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gagnon, Derek M.; Brophy, Megan Brunjes; Bowman, Sarah E. J.

The antimicrobial protein calprotectin (CP), a hetero-oligomer of the S100 family members S100A8 and S100A9, is the only identified mammalian Mn(II)-sequestering protein. Human CP uses Ca(II) ions to tune its Mn(II) affinity at a biologically unprecedented hexahistidine site that forms at the S100A8/S100A9 interface, and the molecular basis for this phenomenon requires elucidation. Here in this paper, we investigate the remarkable Mn(II) coordination chemistry of human CP using X-ray crystallography as well as continuous-wave (CW) and pulse electron paramagnetic resonance (EPR) spectroscopies. An X-ray crystallographic structure of Mn(II)-CP containing one Mn(II), two Ca(II), and two Na(I) ions per CP heterodimermore » is reported. The CW EPR spectrum of Ca(II)- and Mn(II)-bound CP prepared with a 10:0.9:1 Ca(II):Mn(II):CP ratio is characterized by an unusually low zero-field splitting of 485 MHz (E/D = 0.30) for the S = 5/2 Mn(II) ion, consistent with the high symmetry of the His6 binding site observed crystallographically. Results from electron spin–echo envelope modulation and electron–nuclear double resonance experiments reveal that the six Mn(II)-coordinating histidine residues of Ca(II)- and Mn(II)-bound CP are spectroscopically equivalent. The observed 15N (I = 1/2) hyperfine couplings (A) arise from two distinct classes of nitrogen atoms: the coordinating ε-nitrogen of the imidazole ring of each histidine ligand (A = [3.45, 3.71, 5.91] MHz) and the distal δ-nitrogen (A = [0.11, 0.18, 0.42] MHz). In the absence of Ca(II), the binding affinity of CP for Mn(II) drops by two to three orders of magnitude and coincides with Mn(II) binding at the His6 site as well as other sites. This study demonstrates the role of Ca(II) in enabling high-affinity and specific binding of Mn(II) to the His 6 site of human calprotectin.« less

New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 2).

PubMed

Terauchi, Y; Koyama, M; Cheng, X; Takahashi, Y; Riddle, M C; Bolli, G B; Hirose, T

2016-04-01

To compare the efficacy and safety of insulin glargine 300 U/ml (Gla-300) with glargine 100 U/ml (Gla-100) in Japanese people with type 2 diabetes using basal insulin plus oral antihyperglycaemic drug(s) [OAD(s)]. The EDITION JP 2 study (NCT01689142) was a 6-month, multicentre, open-label, phase III study. Participants (n = 241, male 61%, mean diabetes duration 14 years, mean weight 67 kg, mean body mass index 25 kg/m(2), mean glycated haemoglobin (HbA1c) 8.02 %, mean basal insulin dose 0.24 U/kg/day) were randomized to Gla-300 or Gla-100, while continuing OAD(s). Basal insulin was titrated to target fasting self-monitored plasma glucose 4.4-5.6 mmol/l. The primary efficacy endpoint was HbA1c change over 6 months. Safety endpoints included hypoglycaemia and weight change. Gla-300 was non-inferior to Gla-100 for HbA1c reduction [least squares (LS) mean difference 0.10 (95% confidence interval [CI] -0.08, 0.27) %]. The mean HbA1c at month 6 was 7.56 and 7.52 % with Gla-300 and Gla-100, respectively. Nocturnal confirmed (≤3.9 mmol/l) or severe hypoglycaemia risk was 38% lower with Gla-300 versus Gla-100 [relative risk 0.62 (95% CI 0.44, 0.88)]; annualized rates were 55% lower at night [rate ratio 0.45 (95% CI 0.21, 0.96)] and 36% lower at any time [24 h; rate ratio 0.64 (95% CI 0.43, 0.96)]. Severe hypoglycaemia was infrequent. A significant between-treatment difference in weight change favoured Gla-300 [LS mean difference -1.0 (95% CI -1.5, -0.5) kg; p = 0.0003]. Adverse event rates were comparable between groups. Japanese people with type 2 diabetes using basal insulin plus OAD(s) experienced less hypoglycaemia with Gla-300 than with Gla-100, while glycaemic control did not differ. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Na; Sato, Daisuke; Saiki, Yuriko

2014-05-09

Highlights: • We observed frequent overexpression of S100A4 in lung cancer cell lines. • Knockdown of S100A4 suppressed proliferation in lung cancer cells. • Forced expression of S100A4 accelerated cell motility in lung cancer cells. • PRDM2 was found to be one of the downstream suppressed genes of S100A4. - Abstract: S100A4, a small calcium-binding protein belonging to the S100 protein family, is commonly overexpressed in a variety of tumor types and is widely accepted to associate with metastasis by regulating the motility and invasiveness of cancer cells. However, its biological role in lung carcinogenesis is largely unknown. In thismore » study, we found that S100A4 was frequently overexpressed in lung cancer cells, irrespective of histological subtype. Then we performed knockdown and forced expression of S100A4 in lung cancer cell lines and found that specific knockdown of S100A4 effectively suppressed cell proliferation only in lung cancer cells with S100A4-overexpression; forced expression of S100A4 accelerated cell motility only in S100A4 low-expressing lung cancer cells. PRDM2 and VASH1, identified as novel upregulated genes by microarray after specific knockdown of S100A4 in pancreatic cancer, were also analyzed, and we found that PRDM2 was significantly upregulated after S100A4-knockdown in one of two analyzed S100A4-overexpressing lung cancer cells. Our present results suggest that S100A4 plays an important role in lung carcinogenesis by means of cell proliferation and motility by a pathway similar to that in pancreatic cancer.« less

Optical LDPC decoders for beyond 100 Gbits/s optical transmission.

PubMed

Djordjevic, Ivan B; Xu, Lei; Wang, Ting

2009-05-01

We present an optical low-density parity-check (LDPC) decoder suitable for implementation above 100 Gbits/s, which provides large coding gains when based on large-girth LDPC codes. We show that a basic building block, the probabilities multiplier circuit, can be implemented using a Mach-Zehnder interferometer, and we propose corresponding probabilistic-domain sum-product algorithm (SPA). We perform simulations of a fully parallel implementation employing girth-10 LDPC codes and proposed SPA. The girth-10 LDPC(24015,19212) code of the rate of 0.8 outperforms the BCH(128,113)xBCH(256,239) turbo-product code of the rate of 0.82 by 0.91 dB (for binary phase-shift keying at 100 Gbits/s and a bit error rate of 10(-9)), and provides a net effective coding gain of 10.09 dB.

Effect of pre-drilling on intraosseous temperature during self-drilling mini-implant placement in a porcine mandible model.

PubMed

Gurdán, Zsuzsanna; Vajta, László; Tóth, Ákos; Lempel, Edina; Joób-Fancsaly, Árpád; Szalma, József

2017-03-31

This in vitro study investigated intraos seous heat production during insertion, with and without pre-drilling, of a self-drilling orthodontic mini-implant. To measure temperature changes and drilling times in pig ribs, a special testing apparatus was used to examine new and worn pre-drills at different speeds. Temperatures were measured during mini-implant placement with and without pre-drilling. The average intraosseous temperature increase during manual mini-implant insertion was similar with and without pre-drilling (11.8 ± 2.1°C vs. 11.3 ± 2.4°C, respectively; P = 0.707). During pre-drilling the mean temperature increase for new drills was 2.1°C at 100 rpm, 2.3°C at 200 rpm, and 7.6°C at 1,200 rpm. Temperature increases were significantly higher for worn drills at the same speeds (2.98°C, 3.0°C, and 12.3°C, respectively), while bone temperatures at 100 and 200 rpm were similar for new and worn drills (P = 0.345 and 0.736, respectively). Baseline bone temperature was approximated within 30 s after drilling in most specimens. Drilling time at 100 rpm was 2.1 ± 0.9 s, but was significantly shorter at 200 rpm (1.1 ± 0.2 s) and 1,200 rpm (0.1 ± 0.03 s). Pre-drilling did not decrease intraosseous temperatures. In patients for whom pre-drilling is indicated, speeds of 100 or 200 rpm are recommended, at least 30 s after pilot drilling.

Shared features of S100B immunohistochemistry and cytochrome oxidase histochemistry in the ventroposterior thalamus and lateral habenula in neonatal rats.

PubMed

Muneoka, Katsumasa; Funahashi, Hisayuki; Ogawa, Tetsuo; Whitaker-Azmitia, Patricia M; Shioda, Seiji

2012-10-01

The ventroposterior thalamus and the habenular nuclei of the epithalamus are relevant to the monoaminergic system functionally and anatomically. The glia-derived S100B protein plays a critical role in the development of the nervous system including the monoaminergic systems. In this study, we performed an immunohistochemical study of glia-related proteins including S100B, serotonin transporter, and microtubule-associated protein 2, as well as cytochrome oxidase histochemistry in neonatal rats. Results showed the same findings for S100B immunohistochemistry between the ventroposterior thalamus and the lateral habenula at postnatal day 7: intense staining in cell bodies of astrocytes, diffusely spread immunoproduct in the intercellular space, and S100B-free areas as well as a strong reaction to cytochrome oxidase histochemistry. Further common features were the scarcity of glial fibrillary acidic protein-positive astrocytes and the few apoptotic cells observed. The results of the cytochrome oxidase reaction suggested that S100B is released actively into intercellular areas in restricted brain regions showing high neuronal activity at postnatal day 7. Pathology of the ventroposterior thalamus and the habenula is suggested in mental disorders, and S100B might be a key factor for investigations in these areas. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Interplay between Trx-1 and S100P promotes colorectal cancer cell epithelial-mesenchymal transition by up-regulating S100A4 through AKT activation.

PubMed

Zuo, Zhigui; Zhang, Peili; Lin, Feiyan; Shang, Wenjing; Bi, Ruichun; Lu, Fengying; Wu, Jianbo; Jiang, Lei

2018-04-01

We previously reported a novel positive feedback loop between thioredoxin-1 (Trx-1) and S100P, which promotes the invasion and metastasis of colorectal cancer (CRC). However, the underlying molecular mechanisms remain poorly understood. In this study, we examined the roles of Trx-1 and S100P in CRC epithelial-to-mesenchymal transition (EMT) and their underlying mechanisms. We observed that knockdown of Trx-1 or S100P in SW620 cells inhibited EMT, whereas overexpression of Trx-1 or S100P in SW480 cells promoted EMT. Importantly, S100A4 and the phosphorylation of AKT were identified as potential downstream targets of Trx-1 and S100P in CRC cells. Silencing S100A4 or inhibition of AKT phosphorylation eliminated S100P- or Trx-1-mediated CRC cell EMT, migration and invasion. Moreover, inhibition of AKT activity reversed S100P- or Trx-1-induced S100A4 expression. The expression of S100A4 was higher in human CRC tissues compared with their normal counterpart tissues and was significantly correlated with lymph node metastasis and poor survival. The overexpression of S100A4 protein was also positively correlated with S100P or Trx-1 protein overexpression in our cohort of CRC tissues. In addition, overexpression of S100P reversed the Trx-1 knockdown-induced inhibition of S100A4 expression, EMT and migration and invasion in SW620 cells. The data suggest that interplay between Trx-1 and S100P promoted CRC EMT as well as migration and invasion by up-regulating S100A4 through AKT activation, thus providing further potential therapeutic targets for suppressing the EMT in metastatic CRC. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Base (100-year) flood elevations for selected sites in Livingston County, Missouri

USGS Publications Warehouse

Southard, Rodney E.; Richards, Joseph M.

2002-01-01

The primary criteria for community participation in the National Flood Insurance Program is the adoption and enforcement of floodplain management requirements that minimize the potential for flood damages to existing and proposed development in flood-hazard areas. This report provides base flood elevations (BFE) for a 100-year recurrence-interval flood for use in the management and regulation of 18 flood-hazard areas designated by the Federal Emergency Management Agency as approximate Zone A areas in Livingston County, Missouri. The one-dimensional surface-water flow models HEC-RAS and Water-Surface PROfile (WSPRO) were used to compute base (100-year) flood elevations for 18 Zone A sites. The HEC-RAS model was used at BFE sites 1 to 6, 9, 10, and 15 to 18. The WSPRO model was used at BFE sites 7, 8, and 11 to 14. The 18 sites are all located in Livingston County, Missouri, at U.S., State, or County road crossings, and the base flood elevation was determined at the upstream side of each crossing. The base (100-year) flood elevations for BFE 1, 2, and 3 on Shoal Creek at Dawn and Shoal Creek Drainage Ditch near Dawn are 701.0, 701.0, and 696.5 feet, respectively. The base (100-year) flood elevations for BFE 4 and 5 on Indian Branch near Sampsel and a tributary to Indian Branch near Sampsel are 711.7 and 755.4 feet, respectively. Site BFE 6 is located on Honey Creek near Farmersville and the base (100-year) flood elevation for this site is 730.8 feet. One site (BFE 7) is located on No Creek near Farmersville. The base (100-year) flood elevation for this site is 731.3 feet. Site BFE 8 is located on Crooked Creek near Chillicothe and the base (100-year) elevation is 716.4 feet. One site (BFE 9) is located on a tributary to Coon Creek at Chillicothe. The base (100-year) flood elevation for this site is 734.9 feet. Two sites (BFE 10 and 11) are located on Blackwell Branch at Chillicothe. The base (100-year) flood elevation for BFE 10 is 738.9 feet and for BFE 11 is 701.7 feet. The base (100-year) flood elevation for BFE 12 on Medicine Creek near Chula is 721.7 feet. Sites BFE 13 and 15 are on Muddy Creek and for BFE 14 is on Little Muddy Creek near Chula. The base (100-year) flood elevations for BFE 13 and 15 are 733.0 and 717.9 feet, respectively and for BFE 14 is 734.6 feet. Downstream from BFE 12 is site BFE 16 on Medicine Creek near Wheeling. The base (100-year) flood elevation for site BFE 16 is 686.1 feet. One site (BFE 17) is located on Campbell Creek near Bedford. The base (100-year) flood elevation at this site is 691.8 feet. Site BFE 18 is located on Towstring Creek near Hale. The base (100-year) flood elevation for site BFE 18 is 667.4 feet.

Alarmins as biomarkers of gastrointestinal surgical injury - a pilot study.

PubMed

Maca, Jan; Holub, Michal; Bursa, Filip; Ihnat, Peter; Reimer, Petr; Svagera, Zdenek; Burda, Michal; Sevcik, Pavel

2018-02-01

The dysregulation of inflammatory response to surgical injury affects outcomes. Alarmins, the earliest bioactive substances from damaged cells, play a crucial role in initiating the inflammation. We analyzed serum levels of alarmins (S100A8, S100A12, high mobility group box, and heat shock protein 70) after major abdominal surgery (MAS) in surgical (S) (n = 82) and nonsurgical (NS) groups (n = 35). The main objective was determining a role of selected alarmins in host response to MAS. The secondary objectives were (i) evaluation of the relationship among alarmins and selected biomarkers (C-reactive protein, interleukin-6), (ii) influence of the place of gastrointestinal resection, and (iii) role of alarmins in MAS for cancer. Except for HMGB1, the levels of all alarmins were higher in the S group compared with the NS group. In the S group, positive correlations were found between S100A8 and both IL-6 and CRP. Additionally, the S100A8 level was higher (p < 0.01) in patients who underwent upper gastrointestinal tract (GIT) surgery compared to middle and lower GIT resections. Alarmins levels did not differ between cancer and noncancer patients. MAS is able to elicit increase in alarmin levels. S100A8 can be considered a potential biomarker of surgical injury, especially in the upper part of the GIT. © 2018 APMIS. Published by John Wiley & Sons Ltd.

Comparison of diagnostic methods to detect Histoplasma capsulatum in serum and blood samples from AIDS patients

PubMed Central

da Silva, Marcos Vinicius; Criado, Paulo Ricardo; Luiz, Olinda do Carmo; Vicentini, Adriana Pardini

2018-01-01

Background Although early and rapid detection of histoplasmosis is essential to prevent morbidity and mortality, few diagnostic tools are available in resource-limited areas, especially where it is endemic and HIV/AIDS is also epidemic. Thus, we compared conventional and molecular methods to detect Histoplasma capsulatum in sera and blood from HIV/AIDS patients. Methodology We collected a total of 40 samples from control volunteers and patients suspected of histoplasmosis, some of whom were also infected with other pathogens. Samples were then analyzed by mycological, serological, and molecular methods, and stratified as histoplasmostic with (group I) or without AIDS (group II), uninfected (group III), and infected with HIV and other pathogens only (group IV). All patients were receiving treatment for histoplasmosis and other infections at the time of sample collection. Results Comparison of conventional methods with nested PCR using primers against H. capsulatum 18S rRNA (HC18S), 5.8S rRNA ITS (HC5.8S-ITS), and a 100 kDa protein (HC100) revealed that sensitivity against sera was highest for PCR with HC5.8S-ITS, followed by immunoblotting, double immunodiffusion, PCR with HC18S, and PCR with HC100. Specificity was equally high for double immunodiffusion, immunoblotting and PCR with HC100, followed for PCR with HC18S and HC5.8-ITS. Against blood, sensitivity was highest for PCR with HC5.8S-ITS, followed by PCR with HC18S, Giemsa staining, and PCR with HC100. Specificity was highest for Giemsa staining and PCR with HC100, followed by PCR with HC18S and HC5.8S-ITS. PCR was less efficient in patients with immunodeficiency due to HIV/AIDS and/or related diseases. Conclusion Molecular techniques may detect histoplasmosis even in cases with negative serology and mycology, potentially enabling early diagnosis. PMID:29342162

[Serum level of S100B as a marker of progression of vascular mild cognitive impairment into subcortical vascular dementia and therapy effectiveness].

PubMed

Levada, O A; Traïlin, A V

2012-01-01

We evaluated serum level of S100B in 11 patients with subcortical vascular dementia (SVD) and 19 patients with subcortical vascular mild cognitive impairment (SVMCI). Comparable groups were age-matched (79.18 +/- 7.76 in SVD group, 77.84 +/- 3.83 in SVMCI; P = 0.53). 22 patients were assessed after 1 month therapy. It was shown that the serum S100B level significantly increased--(0.065 +/- 0.020) micro/l (P = 0.0005) in SVD patients comparing to SVMCI ones - (0.043 +/- 0.010) microg/l. S100B level was significantly correlated with the clinical parameters: MMSE performance (r(s) = -0.61), CDR (r(s) = 0.58), attention task (r(s) = -0.46), pseudobulbar syndrome severity (r(s) = 0.37) and walking alteration (r(s)= 0.37). In patients with reduction of S100B level due to therapy (positive dynamics, n = 12) we registered significant improvement of some clinical parameters: MMSE, attention level, walking. In patients with increasing of S100B level (negative dynamics, n = 10) we didn't registered improvement of any clinical parameters. We made the conclusion that the serum level of S100B could be used as marker of progression SVMCI into SVD and therapy effectiveness.

Prevalence and characterization of methicillin-resistant Staphylococcus aureus isolates from retail meat and humans in Georgia.

PubMed

Jackson, Charlene R; Davis, Johnnie A; Barrett, John B

2013-04-01

There is increasing interest in the presence of Staphylococcus aureus, specifically methicillin-resistant S. aureus (MRSA), on retail meat products. In this study, staphylococci were isolated from retail pork and retail beef in Georgia, and MRSA from the products was compared to human MRSA from the same geographic area using broth microdilution antimicrobial susceptibility testing, multilocus sequence typing (MLST), spa typing, SCCmec typing, and pulsed-field gel electrophoresis (PFGE). S. aureus was isolated from 45% (45/100) of pork products and 63% (63/100) of beef products; mecA was detected in S. aureus from both pork (3/100; 3%) and beef (4/100; 4%). Fifty percent (50/100) of human S. aureus also contained mecA. Multidrug resistance was detected among MRSA from all sources. All MRSA (n = 57) was SCCmec type IV, and nine different spa types were present among the isolates (t002, t008, t012, t024, t179, t337, t548, t681, and t1062). Four sequence types (ST5, ST8, ST9, and ST30) were detected using MLST; the majority of MRSA isolates belonged to ST8, followed by ST5. One retail beef MRSA isolate belonged to ST8, while the remaining three were ST5. In retail pork MRSA, ST5, ST9, and ST30 were observed. The majority of human MRSA isolates belonged to ST8. Thirty-seven MRSA isolates, one of which was a retail beef MRSA isolate, were pvl(+). Using PFGE, MLST, and spa typing, three retail beef MRSA isolates were found to be identical in PFGE pattern, ST, and spa type to two human clonal MRSA isolates (USA100 and USA300). One additional retail beef MRSA isolate had a PFGE pattern similar to that of a human MRSA isolate, whereas none of the retail pork MRSA isolates had PFGE patterns similar to those of human MRSA isolates. These data suggest that the retail beef samples were contaminated by a human source, possibly during processing of the meat, and may present a source of MRSA for consumers and others who handle raw meat.

Prevalence and Characterization of Methicillin-Resistant Staphylococcus aureus Isolates from Retail Meat and Humans in Georgia

PubMed Central

Davis, Johnnie A.; Barrett, John B.

2013-01-01

There is increasing interest in the presence of Staphylococcus aureus, specifically methicillin-resistant S. aureus (MRSA), on retail meat products. In this study, staphylococci were isolated from retail pork and retail beef in Georgia, and MRSA from the products was compared to human MRSA from the same geographic area using broth microdilution antimicrobial susceptibility testing, multilocus sequence typing (MLST), spa typing, SCCmec typing, and pulsed-field gel electrophoresis (PFGE). S. aureus was isolated from 45% (45/100) of pork products and 63% (63/100) of beef products; mecA was detected in S. aureus from both pork (3/100; 3%) and beef (4/100; 4%). Fifty percent (50/100) of human S. aureus also contained mecA. Multidrug resistance was detected among MRSA from all sources. All MRSA (n = 57) was SCCmec type IV, and nine different spa types were present among the isolates (t002, t008, t012, t024, t179, t337, t548, t681, and t1062). Four sequence types (ST5, ST8, ST9, and ST30) were detected using MLST; the majority of MRSA isolates belonged to ST8, followed by ST5. One retail beef MRSA isolate belonged to ST8, while the remaining three were ST5. In retail pork MRSA, ST5, ST9, and ST30 were observed. The majority of human MRSA isolates belonged to ST8. Thirty-seven MRSA isolates, one of which was a retail beef MRSA isolate, were pvl+. Using PFGE, MLST, and spa typing, three retail beef MRSA isolates were found to be identical in PFGE pattern, ST, and spa type to two human clonal MRSA isolates (USA100 and USA300). One additional retail beef MRSA isolate had a PFGE pattern similar to that of a human MRSA isolate, whereas none of the retail pork MRSA isolates had PFGE patterns similar to those of human MRSA isolates. These data suggest that the retail beef samples were contaminated by a human source, possibly during processing of the meat, and may present a source of MRSA for consumers and others who handle raw meat. PMID:23363837

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in Rheumatoid Arthritis.

PubMed

Nguyen, Minh Vu Chuong; Baillet, Athan; Romand, Xavier; Trocmé, Candice; Courtier, Anaïs; Marotte, Hubert; Thomas, Thierry; Soubrier, Martin; Miossec, Pierre; Tébib, Jacques; Grange, Laurent; Toussaint, Bertrand; Lequerré, Thierry; Vittecoq, Olivier; Gaudin, Philippe

2018-06-06

Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients. Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi. A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually. A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment. Copyright © 2018. Published by Elsevier Masson SAS.

The structure directing effect of organic cations onto the crystal structures of layered thioantimonates(III): Solvothermal synthesis and crystal structures of five new compounds containing the 2∞[Sb 8S 13] 2- anion

NASA Astrophysics Data System (ADS)

Puls, Angela; Näther, Christian; Kiebach, Ragnar; Bensch, Wolfgang

2006-09-01

The five new thioantimonates(III) ( iprH) 2[Sb 8S 13] ( I), (1,2-dapH) 2[Sb 8S 13] ( II), (1,3-dapH 2)[Sb 8S 13] ( III), (dienH 2)[Sb 8S 13]ṡ1.5H 2O ( IV), and (C 6H 9N 2)[Sb 8S 13]ṡ2.5H 2O ( V) were synthesised under solvothermal conditions ( ipr = iso-propylamine; 1,2-dap = 1,2-diaminopropane; 1,3-dap = 1,3-diaminopropane; dien = diethylentriamine; C 6H 9N 2 = 3-(aminoethyl)-pyridine). The structures of compounds I and II are topological very similar and a central motif is a Sb 10S 10 ring. On both sides of this ring Sb 5S 5 rings are condensed. These rings are connected via Sb 4S 4 rings leading to the sequence Sb 10S 10-Sb 5S 5-Sb 4S 4-Sb 5S 5-Sb 10Sb 10 in the [010] direction. Further interconnection into the two-dimensional [Sb 8S 13] 2- anion produces a large central Sb 18S 18 ring with dimensions of 11ṡ11 Å in both compounds. The two atoms thick layers are linear and stacked along the a axis generating large channels running along [010]. The layered anion of compound III is constructed by interconnection of the SbS 3 and SbS 4 units yielding Sb 19S 19, Sb 14S 14, Sb 13S 13, and Sb 8S 8 rings. The linear layers are two atoms thick and are stacked perpendicular to [001] to form channels running along the same direction. The last two compounds IV and V show a similar network topology. The layered anion is constructed by SbS 3 trigonal pyramids and SbS 4 units. The layer contains a Sb 12S 12 rings as the main structural motif. The corrugated layers extending in the (100) plane are two atoms thick and are stacked in a manner that large tunnels run along [100]. The total potential solvent areas are large and range from 20.7% for III to 35% for II.

Differential proteomics reveals S100-A11 as a key factor in aldosterone-induced collagen expression in human cardiac fibroblasts.

PubMed

Martínez-Martínez, Ernesto; Ibarrola, Jaime; Lachén-Montes, Mercedes; Fernández-Celis, Amaya; Jaisser, Frederic; Santamaría, Enrique; Fernández-Irigoyen, Joaquín; López-Andrés, Natalia

2017-08-23

Aldosterone (Aldo) could induce cardiac fibrosis, a hallmark of heart disease. Aldo direct effects on collagen production in cardiac fibroblasts remain controversial. Our aim is to characterize changes in the proteome of adult human cardiac fibroblasts treated with Aldo to identify new proteins altered that might be new therapeutic targets in cardiovascular diseases. Aldo increased collagens expressions in human cardiac fibroblasts. Complementary, using a quantitative proteomic approach, 30 proteins were found differentially expressed between control and Aldo-treated cardiac fibroblasts. Among these proteins, 7 were up-regulated and 23 were down-regulated by Aldo. From the up-regulated proteins, collagen type I, collagen type III, collagen type VI and S100-A11 were verified by Western blot. Moreover, protein interaction networks revealed a functional link between a third of Aldo-modulated proteome and specific survival routes. S100-A11 was identified as a possible link between Aldo and collagen. Interestingly, CRISPR/Cas9-mediated knock-down of S100-A11 blocked Aldo-induced collagen production in human cardiac fibroblasts. In adult human cardiac fibroblasts treated with Aldo, proteomic analyses revealed an increase in collagen production. S100-A11 was identified as a new regulator of Aldo-induced collagen production in human cardiac fibroblasts. These data could identify new candidate proteins for the treatment of cardiac fibrosis in cardiovascular diseases. S100-A11 is identified by a proteomic approach as a novel regulator of Aldosterone-induced collagen production in human cardiac fibroblasts. Our data could identify new candidate proteins of interest for the treatment of cardiac fibrosis in cardiovascular diseases. Copyright © 2017. Published by Elsevier B.V.

Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis.

PubMed

Smith, Miriam J; Esparza, Sonia; Merker, Vanessa L; Muzikansky, Alona; Bredella, Miriam A; Harris, Gordon J; Kassarjian, Ara; Cai, Wenli; Walker, James A; Mautner, Victor F; Plotkin, Scott R

2013-05-01

Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are characterized by a predisposition to develop multiple neurofibromas and schwannomas. Currently, there is no blood test to estimate tumor burden in patients with these disorders. We explored whether S100β would act as a biomarker of tumor burden in NF since S100β is a classic immunohistochemical marker of astrocytes, oligodendrocytes and Schwann cells and a small study showed S100β concentrations correlate with the volume of vestibular schwannomas. We calculated whole-body tumor burden in subjects with NF1, NF2, and schwannomatosis using whole-body MRI (WBMRI) and measured the concentration of S100β in plasma using ELISA. We used chi-square tests and Spearman rank correlations to test the relationship between S100β levels and whole-body tumor burden. 127 consecutive patients were enrolled in the study (69 NF1 patients, 28 NF2 patients, and 30 schwannomatosis patients). The median age was 40years, 43% were male, and median whole-body tumor volume was 26.9mL. There was no relationship between the presence of internal tumors and the presence of detectable S100β in blood for the overall group or for individual diagnoses (p>0.05 by chi-square for all comparisons). Similarly, there was no correlation between whole-body tumor volume and S100β concentration for the overall group or for individual diagnoses (p>0.05 by Spearman for all comparisons). Plasma S100β is not a useful biomarker for tumor burden in the neurofibromatoses. Further work is needed to identify a reliable biomarker of tumor burden in NF patients. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Update of contemporary antimicrobial resistance rates across China: reference testing results for 12 medical centers (2011).

PubMed

Jones, Ronald N; Castanheira, Mariana; Hu, Bijie; Ni, Yuxing; Lin, Stephen S F; Mendes, Rodrigo E; Wang, Yao

2013-11-01

Antimicrobial resistance (R) surveillance across Asia and especially in China has documented unique patterns and mechanisms. This 2011 study reports results for 2278 isolates from 12 hospitals in China (94-216 strains/site); most from bacteremia (20.4%), pneumonias (29.1%), or skin and skin structure infections (20.9%). Samples were tested by reference broth microdilution methods, interpreted by published susceptibility (S) breakpoints. The most common species were Staphylococcus aureus (343, 45.8% MRSA), Escherichia coli (EC; 288), Pseudomonas aeruginosa (PSA; 221), Klebsiella spp. (KSP; 208), acinetobacters (ACB; 178), enterobacters (155), Streptococcus pneumoniae (SPN; 154, 46.8% penicillin-S), and enterococci (ENT; 137). Among 849 Gram-positive (GP) cocci, linezolid, tigecycline (TIG), daptomycin, and vancomycin provided best antimicrobial coverage (≥99.7% S). Resistance patterns of concern were 0.3% VISA, 15.4% teicoplanin non-S coagulase-negative staphylococci, 1.5% vancomycin-R ENT (all Enterococcus faecium), 1.9% levofloxacin-R β-haemolytic streptococci, and 35.1 and 12.7% ceftriaxone-non-S rates for SPN and viridans group streptococci, respectively. For Gram-negative bacilli, R among Enterobacteriaceae was highest against β-lactams (extended spectrum β-lactamase-phenotype strains at 73.6 and 42.8% in EC and KSP, respectively; carbapenem-R was only 2.1-4.3% with KPC and IMP type enzymes detected in KSP). The widest spectrum agents were cefoperazone/sulbactam (79.5-86.1%), piperacillin/tazobactam (88.9-92.0%), TIG (98.6-100%), amikacin (AMK; 91.8-93.7%), and meropenem (95.7-97.1% S). PSA was most inhibited by AMK (90.5% S) and colistin (COL; 99.5%), with cefepime (67.9%) best among the tested β-lactams. Only COL (100% S) and TIG (MIC90, 2 μg/mL) showed significant potencies against ACB. In conclusion, R among pathogens from 12 Chinese hospitals illustrates several agents active against GP pathogens, but more serious R problems were noted among Enterobacteriaceae, PSA, and ACB. Combination treatment for the latter multidrug-R strains appears necessary, guided by local antibiograms and national surveillance results applying reference methods. © 2013.

[Correlations of plasma concentrations of β-amyloid peptide and S-100β with postoperative cognitive dysfunction in patients undergoing oral and maxillofacial cancer surgery].

PubMed

Liang, Bing; Sun, Yuan-Qing; Jiang, Jue; Xu, Hui

2016-12-01

To evaluate the changes of perioperative plasma concentrations of Aβ 1-40 and S-100β to determine the relationship with postoperative cognitive dysfunction in elderly patients undergoing oral and maxillofacial cancer surgeries. One hundred and fifteen patients aged at least 60 years undergoing oral and maxillofacial tumor resection were investigated between May 2014 to December 2014.Neuropsychological tests for detecting postoperative cognitive dysfunction(POCD) were performed one day before surgery and 7 days postoperatively. According to the results of neuropsychological tests on day 7, patients were divided into POCD group and non-POCD group.Plasma values of Aβ 1-40 and S-100β were determined with enzyme linked immunosorbent assay (ELISA) before anesthesia induction, 24 h and 7 days after surgery. The data were analyzed using SPSS 19.0 software package. According to the definition, POCD was present in 37 of 115 (32.3%) patients 1 week after surgery. Compared with pre-anesthesia, S-100β levels in POCD group were significantly increased (P<0.05); the level of Aβ 1-40 was significantly higher 24 h after surgery (P<0.05). Compared with non-POCD group, S-100β levels were significantly increased 24 h postoperatively (P<0.05); Aβ1-40 levels were significantly higher 24 h and 7 days postoperatively (P<0.05). POCD was present in 32.2% of patients on day 7 after oral and maxillofacial surgeries with general anesthesia. The increasing levels of Aβ 1-40 , S-100β may be associated with the occurence of POCD. Patients with long-lasting operation and high concentrations of Aβ 1-40 and S-100β after surgeries were at a higher risk of POCD. The clinical values of Aβ 1-40 and S-100 as predictive measurements of POCD after oral and maxillofacial cancer surgery appear to be reasonable.

Biological and antibacterial activities of the natural herb Houttuynia cordata water extract against the intracellular bacterial pathogen salmonella within the RAW 264.7 macrophage.

PubMed

Kim, Gon Sup; Kim, Dong Hyeok; Lim, Jeong Ju; Lee, Jin Ju; Han, Dae Yong; Lee, Whi Min; Jung, Won Chul; Min, Won Gi; Won, Chung Gil; Rhee, Man Hee; Lee, Hu Jang; Kim, Suk

2008-11-01

Salmonellosis is a major bacterial zoonosis that causes a variety of disease syndromes, from self-limiting enteritis to fatal infection in animals and food-borne infection and typhoid fever in humans. Recently, the emergence of multidrug-resistant strains of Salmonella sp. has caused more serious problems in public health. The present study investigated the antibacterial effects of Houttuynia cordata water extract (HCWE) against murine salmonellosis. In RAW 264.7 cells, there was no detectable cytotoxic effect of HCWE at any concentration between 25 and 100 microg/ml after 8-h incubation. The antibacterial activity of HCWE was then examined in a Salmonella enterica serovar (Salmonella typhimurium), and was found to increase in a dose-dependent manner at concentrations from 25 to 100 microg/ml during 8-h incubation. HCWE also affected RAW 264.7 cells including morphologic change and bacterial uptake, but there was no significant difference in bacterial replication in RAW 264.7 cells. With HCWE alone, nitric oxide (NO) production by RAW 264.7 cells did not increase, but when RAW 264.7 cells were infected by S. typhimurium, with or without HCWE, NO production with HCWE was 2-fold higher than that without HCWE. Treatment with HCWE did not affect inducible NO synthase (iNOS) mRNA expression by RAW 264.7 cells, but when RAW 264.7 cells with HCWE were infected by S. typhimurium, iNOS mRNA expression was increased during 8-h incubation. Furthermore, HCWE showed virulence reduction effects in S. typhimurium-infected BALB/c mice. After a lethal dose of S. typhimurium, the mortality rate in the HCWE untreated group was 100% at 7 d, but the HCWE 25, 50, and 100 microg/ml groups survived until 11, 17, and 23 d, respectively. These data suggest that HCWE is stable and beneficial in the treatment of bacterial infection including intracellularly replicating pathogens and may solve antimicrobial misuse and overuse.

BIOMARKERS S100B AND NSE PREDICT OUTCOME IN HYPOTHERMIA-TREATED ENCEPHALOPATHIC NEWBORNS

PubMed Central

Massaro, An N.; Chang, Taeun; Baumgart, Stephen; McCarter, Robert; Nelson, Karin B.; Glass, Penny

2014-01-01

Objective To evaluate if serum S100B protein and neuron specific enolase (NSE) measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy (NE). Design Prospective longitudinal cohort study Setting A level IV neonatal intensive care unit in a free-standing children’s hospital. Patients Term newborns with moderate to severe NE referred for therapeutic hypothermia during the study period. Interventions Serum NSE and S100B were measured at 0, 12, 24 and 72 hrs of hypothermia. Measurements and Main Reseults Of the 83 infants were enrolled, fifteen (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development (BSID-II) at 15 months of age. Outcomes were assessed in 49/68 (72%) survivors at a mean age of 15.2±2.7 months. Neurodevelopmental outcome was classified by BSID-II Mental (MDI) and Psychomotor (PDI) Developmental Index scores, reflecting cognitive and motor outcomes respectively. Four-level outcome classifications were defined a priori: normal= MDI/PDI within 1SD (>85), mild= MDI/PDI <1SD (70–85), moderate/severe= MDI/PDI <2SD (<70), or died. Elevated serum S100B and NSE levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and soceioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were: S100B 2.5 (95% CI 1.3–4.8) and NSE 2.1 (1.2–3.6); for motor outcome: S100B 2.6 (1.2–5.6) and NSE 2.1 (1.2–3.6). Conclusions Serum S100B and NSE levels in babies with NE are associated with neurodevelopmental outcome at 15 months. These putative biomarkers of brain injury may help direct care during therapeutic hypothermia. PMID:24777302

Ice Forces and Ship Response to Ice. Consolidated Report

DTIC Science & Technology

1990-09-01

1922 09:54:07 877 145 19 289 781 81 36 308 0.0 10 OCT 1992 17:56:27 878 124 10 130 878 124 10 130 0.0 12 OCT 1982 16:24:33 889 ISO 18 252 889 ISO Is...26 111 0.0 26 MAR 1983 2:54:5 194 17 57 100 136 19 55 110 0.0 25 MAR 1983 22:29:22 197 IZ 57 69 197 12 57 69 0.0 26 MAR 1983 0:54:54 197 18 S9 112 ISO ...12Z1 6 (03 228 ISO S l05 0.0 30 A~PR (863 Z:i7:49 368 38 (6 68 2427 48 3 7i 8.0 30 APR I(883- 3:i8:48 36C8 88 4 63 36S 88 4 63 3.0 30 tlAR (S63 S:i:3

Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis.

PubMed

Uhel, Fabrice; Azzaoui, Imane; Grégoire, Murielle; Pangault, Céline; Dulong, Joelle; Tadié, Jean-Marc; Gacouin, Arnaud; Camus, Christophe; Cynober, Luc; Fest, Thierry; Le Tulzo, Yves; Roussel, Mikael; Tarte, Karin

2017-08-01

Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined. To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis. Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14 pos HLA-DR low/neg monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14 neg CD15 pos low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P < 0.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and arginase 1 were significantly increased. In vitro, CD14 pos - and CD15 pos -cell depletion increased T-cell proliferation in patients with sepsis. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections. M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.

Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

PubMed

Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

2017-06-01

We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p < .05). At 60MAE, ROS concentration was higher following HI (2.5 ± 1.2 mM) than after LI (1.5 ± 0.5 mM) and MI (1.4 ± 0.3 mM) conditions (p < .05). Plasma NO IAE increased significantly after MI and HI exercise (p < .05). Serum BDNF, NGF, and S-100b levels were significantly higher IAE following MI and HI exercise (p < .05). BDNF and S-100b were higher IAE following MI (29.6 ± 3.4 ng/mL and 87.1 ± 22.8 ng/L, respectively) and HI (31.4 ± 3.8 ng/mL and 100.6 ± 21.2 ng/L, respectively) than following LI (26.5 ± 3.0 ng/mL and 64.8 ± 19.2 ng/L, respectively) exercise (p < .05). 60MAE, S-100b was higher following HI (71.1 ± 14.5 ng/L) than LI (56.2 ± 14.7 ng/L) exercise (p < .05). NSE levels were not significantly different among all intensity conditions and time points (p > .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Ching Chang, E-mail: ccjwo@yahoo.com.tw; Chou, Ruey Hwang, E-mail: rhchou@mail.cmu.edu.tw; Yu, Chin, E-mail: cyu.nthu@gmail.com

The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. Wemore » elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models—the S100A5-RAGE V domain and S100A5-Pentamidine complex—and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.« less

S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages

PubMed Central

Wang, Huaqing; Zhang, Leying; Zhang, Ian Y.; Chen, Xuebo; Da Fonseca, Anna; Wu, Shihua; Ren, Hui; Badie, Sam; Sadeghi, Sam; Ouyang, Mao; Warden, Charles D.; Badie, Behnam

2013-01-01

Purpose S100B is member of a multigenic family of Ca2+-binding proteins that is overexpressed by gliomas. Recently, we demonstrated that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAMs). Experimental Design We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors. Results Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, RAGE (receptor for advanced glycation end products), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that CCL2 was upregulated in S100Bhigh tumors. Furthermore, analysis of TCGA’s glioma data bank demonstrated a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. Conclusions These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. PMID:23719262

Evaluation of the VITEK 2 System for Identification and Antimicrobial Susceptibility Testing of Medically Relevant Gram-Positive Cocci

PubMed Central

Ligozzi, Marco; Bernini, Cinzia; Bonora, Maria Grazia; de Fatima, Maria; Zuliani, Jessica; Fontana, Roberta

2002-01-01

A study was conducted to evaluate the new VITEK 2 system (bioMérieux) for identification and antibiotic susceptibility testing of gram-positive cocci. Clinical isolates of Staphylococcus aureus (n = 100), coagulase-negative staphylococci (CNS) (n = 100), Enterococcus spp. (n = 89), Streptococcus agalactiae (n = 29), and Streptococcus pneumoniae (n = 66) were examined with the ID-GPC identification card and with the AST-P515 (for staphylococci), AST-P516 (for enterococci and S. agalactiae) and AST-P506 (for pneumococci) susceptibility cards. The identification comparison methods were the API Staph for staphylococci and the API 20 Strep for streptococci and enterococci; for antimicrobial susceptibility testing, the agar dilution method according to the procedure of the National Committee for Clinical Laboratory Standards (NCCLS) was used. The VITEK 2 system correctly identified to the species level (only one choice or after simple supplementary tests) 99% of S. aureus, 96.5% of S. agalactiae, 96.9% of S. pneumoniae, 92.7% of Enterococcus faecalis, 91.3% of Staphylococcus haemolyticus, and 88% of Staphylococcus epidermidis but was least able to identify Enterococcus faecium (71.4% correct). More than 90% of gram-positive cocci were identified within 3 h. According to the NCCLS breakpoints, antimicrobial susceptibility testing with the VITEK 2 system gave 96% correct category agreement, 0.82% very major errors, 0.17% major errors, and 2.7% minor errors. Antimicrobial susceptibility testing showed category agreement from 94 to 100% for S. aureus, from 90 to 100% for CNS, from 91 to 100% for enterococci, from 96 to 100% for S. agalactiae, and from 91 to 100% for S. pneumoniae. Microorganism-antibiotic combinations that gave very major errors were CNS-erythromycin, CNS-oxacillin, enterococci-teicoplanin, and enterococci-high-concentration gentamicin. Major errors were observed for CNS-oxacillin and S. agalactiae-tetracycline combinations. In conclusion the results of this study indicate that the VITEK 2 system represents an accurate and acceptable means for performing identification and antibiotic susceptibility tests with medically relevant gram-positive cocci. PMID:11980942

Interaction of S100A1 with LATS1 promotes cell growth through regulation of the Hippo pathway in hepatocellular carcinoma.

PubMed

Guo, Qingping; Wang, Jiale; Cao, Zeyu; Tang, Yongchang; Feng, Chao; Huang, Feizhou

2018-06-05

Despite advances in surgery and chemotherapy, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor. In the present study, the role of S100A1 in the progression of HCC was investigated. Immunohistochemical staining was used to measure the expression of S100A1 in HCC tissues. S100A1 was knocked down by siRNA. A battery of experiments was used to evaluate the biology functions of S100A1. It was found that S100A1 was upregulated in HCC tissues, and its upregulation was associated with a large tumor size, low differentiation and shorter survival time. The biological experiments demonstrated that S100A1 functions as an oncogene in HCC. It was also found that S100A1 knockdown enhanced the inhibitory effects of cisplatin on HCC cells. The results showed that the downregulation of S100A1 induced the phosphorylation of yes‑associated protein (YAP), and treatment with CHX demonstrated that the downregulation of S100A1 accelerated YAP protein degradation. The downregulation of S100A1 did not alter the expression of mammalian sterile 20‑like kinase (MST)1/2 or phosphorylated MST1/2, but upregulated the phosphorylation of large tumor suppressor kinase 1 (LATS1). It was further confirmed that S100A1 interacted with LATS1. LATS1 depletion significantly reduced the effects of S100A1 on cell growth rate and apoptosis, and there was a positive correlation between phosphorylated LATS1 and S100A1 in clinical samples, indicating that LATS1 was responsible for the S100A1-induced changes in cancer cell growth and Hippo signaling. In conclusion, the results of the present study indicated that S100A1 functions as an oncogene and may be a biomarker for the prognosis of patients with HCC. S100A1 exerted its oncogenic function by interacting with LATS1 and activating YAP. S100A1 may serve as a target for novel therapies in HCC.

Oxygen uptake kinetics and energy system’s contribution around maximal lactate steady state swimming intensity

PubMed Central

Machado, Leandro; Fernandes, Ricardo Jorge; Greco, Camila Coelho

2017-01-01

The purpose of this study was to examine the oxygen uptake (V˙O2) kinetics and the energy systems’ contribution at 97.5, 100 and 102.5% of the maximal lactate steady state (MLSS) swimming intensity. Ten elite female swimmers performed three-to-five 30 min submaximal constant swimming bouts at imposed paces for the determination of the swimming velocity (v) at 100%MLSS based on a 7 x 200 m intermittent incremental protocol until voluntary exhaustion to find the v associated at the individual anaerobic threshold. V˙O2 kinetics (cardiodynamic, primary and slow component phases) and the aerobic and anaerobic energy contributions were assessed during the continuous exercises, which the former was studied for the beginning and second phase of exercise. Subjects showed similar time delay (TD) (mean = 11.5–14.3 s) and time constant (τp) (mean = 13.8–16.3 s) as a function of v, but reduced amplitude of the primary component for 97.5% (35.7 ± 7.3 mL.kg.min-1) compared to 100 and 102.5%MLSS (41.0 ± 7.0 and 41.3 ± 5.4 mL.kg.min-1, respectively), and τp decreased (mean = 9.6–10.8 s) during the second phase of exercise. Despite the slow component did not occur for all swimmers at all swim intensities, when observed it tended to increase as a function of v. Moreover, the total energy contribution was almost exclusively aerobic (98–99%) at 97.5, 100 and 102.5%MLSS. We suggest that well-trained endurance swimmers with a fast TD and τp values may be able to adjust faster the physiological requirements to minimize the amplitude of the slow component appearance, parameter associated with the fatigue delay and increase in exhaustion time during performance, however, these fast adjustments were not able to control the progressive fatigue occurred slightly above MLSS, and most of swimmers reached exhaustion before 30min swam. PMID:28245246

High pretransplantation soluble CD30 levels: impact in renal transplantation.

PubMed

Giannoli, C; Bonnet, M C; Perrat, G; Houillon, A; Reydet, S; Pouteil-Noble, C; Villar, E; Lefrançois, N; Morelon, E; Dubois, V

2007-10-01

In a retrospective study, the impact of the level of pretransplantation soluble CD30 molecule (sCD30) was evaluated on 3 year transplant survival, as well as the number and grade of acute rejection episodes among kidney recipients engrafted between 2000 and 2002. One hundred and ninety sera of 190 patients sampled on the cross-match day were tested for sCD30 concentrations using an enzyme-linked immunosorbent assay (ELISA) kit (Biotest). For the analysis, a sCD30 cutoff level of 100 U/mL was chosen: 87 (46%) recipients had a level >100, and 103 (54%) <100. All cases (5) of immunological graft loss showed a high sCD30 level. The rate of biopsy-proven acute rejection was 26% in the sCD30 >100 group versus 22% in the sCD30 <100 groups. Among the first graft population (n = 157), the rate was 27% for sCD30 >100 versus 20% for the lower level. The difference was more important for grade II acute rejection (Banff criteria): 6/87 (7%) showed high sCD30 versus 2/103 (2%) with sCD30 <100. This analysis became significant for anti-HLA immunization: 11 (13%) recipients developed anti-HLA class II antibodies in the first group (sCD30 >100) versus 1 (1%) in the second group (sCD30 <100; P < .01). A high pretransplantation sCD30 was not a significant risk factor for an acute rejection episode, but it seemed to be more predictive for antibody-mediated acute rejection and immunological graft loss. However, many recipients showed an increased pretransplantation concentration without any rejection episode or graft loss. Consequently, sCD30 pregraft measurements cannot be used as a predictor for acute kidney rejection among our transplant center, nor as an aid to adapt the immunosuppressive regimen.

Technology Insertion-Engineering Services Process Characterization Task Order No. 1. Book 2 of 3. Database Documentation Book. OO-ALC MANPGP (Wheels - WCD’S)

DTIC Science & Technology

1989-12-15

RElOVE MASKINE TAPE .00!91 .002 000 Al RCB-OH-W2 1.00 REMY WHL HLF F/PAINT CONVYOR .00833 .010 0040 E RWr- BBP -0 1.00 BALPOCE WEEL HALF .0773 .093 0050 5...16S601-819 16W6-35-3-2 15 ART SHE 160 PULTIPLE LA-10 L"L R/H AIM 9 1441--1-M -36A 7 472-M 1L--11. z.I-- PARK AN)E 161814, LEf-N sE. r& ffA t- 1450-00-. b

Thulium fiber laser induced vapor bubbles using bare, tapered, ball, hollow steel, and muzzle brake fiber optic tips

NASA Astrophysics Data System (ADS)

Gonzalez, David A.; Hardy, Luke A.; Hutchens, Thomas C.; Irby, Pierce B.; Fried, Nathaniel M.

2018-02-01

This study characterizes laser-induced vapor bubbles for five distal fiber optic tip configurations, to provide insight into stone retropulsion experienced during laser ablation of kidney stones. A TFL with 1908-nm wavelength delivered 34 mJ energy per pulse at 500-μs pulse duration through five different fibers: 100-μm-core/170-μm-OD bare fiber tip, 150-μm- to 300-μm-core tapered fiber tip, 100-μm-core/300-μm-OD ball tip fiber, 100-μm-core/340- μm-OD hollow steel tip fiber, and 100-μm-core/560-μm-OD muzzle brake fiber tip. A high speed camera with 10- μm spatial and 9.5-μs temporal resolution imaged vapor bubble dynamics. A needle hydrophone measured pressure transients in forward (0°) and side (90°) directions while placed at a 6.8 +/- 0.4 mm distance from fiber tip. Maximum bubble dimensions (width/length) averaged 0.7/1.5, 1.0/1.6, 0.5/1.1, 0.8/1.9, and 0.7/1.5 mm, for bare, tapered, ball, hollow steel, and muzzle tips, respectively (n=5). The hollow steel tip exhibited the most elongated vapor bubble shape, translating into increased forward pressure in this study and consistent with higher stone retropulsion in previous reports. Relative pressures (a.u.) in (forward/side) directions averaged 1.7/1.6, 2.0/2.0, 1.4/1.2, 6.8/1.1, and 0.3/1.2, for each fiber tip (n=5). For hollow steel tip, forward pressure was 4× higher than for bare fiber. For the muzzle brake fiber tip, forward pressure was 5× lower than for bare fiber. Bubble dimensions and pressure measurements demonstrated that the muzzle tip reduced forward pressure by partially venting vapors through side holes, consistent with lower stone retropulsion observed in previous reports.

Diagnostic reliability of an immunochromatographic test for Chagas disease screening at a primary health care centre in a rural endemic area

PubMed Central

Mendicino, Diego; Stafuza, Mariana; Colussi, Carlina; del Barco, Mónica; Streiger, Mirtha; Moretti, Edgardo

2014-01-01

Many patients with Chagas disease live in remote communities that lack both equipment and trained personnel to perform a diagnosis by conventional serology (CS). Thus, reliable tests suitable for use under difficult conditions are required. In this study, we evaluated the ability of personnel with and without laboratory skills to perform immunochromatographic (IC) tests to detect Chagas disease at a primary health care centre (PHCC). We examined whole blood samples from 241 patients and serum samples from 238 patients. Then, we calculated the percentage of overall agreement (POA) between the two groups of operators for the sensitivity (S), specificity (Sp) and positive (PPV) and negative (NPV) predictive values of IC tests compared to CS tests. We also evaluated the level of agreement between ELISAs and indirect haemagglutination (IHA) tests. The readings of the IC test results showed 100% agreement (POA = 1). The IC test on whole blood showed the following values: S = 87.3%; Sp = 98.8%; PPV = 96.9% and NPV = 95.9%. Additionally, the IC test on serum displayed the following results: S = 95.7%; Sp = 100%; PPV = 100% and NPV = 98.2%. Using whole blood, the agreement with ELISA was 96.3% and the agreement with IHA was 94.1%. Using serum, the agreement with ELISA was 97.8% and the agreement with IHA was 96.6%. The IC test performance with serum samples was excellent and demonstrated its usefulness in a PHCC with minimal equipment. If the IC test S value and NPV with whole blood are improved, then this test could also be used in areas lacking laboratories or specialised personnel. PMID:25466624

Elliptical-P cells in the avian perilymphatic interface of the Tegmentum vasculosum

NASA Technical Reports Server (NTRS)

Fermin, C. D.; Lee, D. H.; Martin, D. S.

1995-01-01

Elliptical cells (E-P) are present at the perilymphatic interface lumen (PIL) of the lagena. The E-P cells often separate from the tegmentum vasculosum (TV) and have touching processes that form a monolayer between the K+ rich perilymph and the Na+ rich endolymph, similar to the mammalian Reissner's membrane. We examined the TV of chicks (Gallus domesticus) and quantitated the expression of anti-S100 alphaalphabetabeta and S100 beta. There was a 30% increase of S100 beta saturation in the light cells facing the PIL when compared to other TV light cells. We show that: (1) the dimer anti- S100 alphaalphabetabeta and the monomer anti-S100 beta are expressed preferentially in the light cells and the E-P cells of TV; (2) expression of S100 beta is higher in light cells facing the PIL than in adjacent cells; (3) the expression of the dimer S100 alphaalphabetabeta and monomer S100 beta overlaps in most inner ear cell types, including the cells of the TV, most S100 alphaalphabetabeta positive cells express S 100 beta, but S100 beta positive cells do not always express S100 alphaalphabetabeta; and (4) the S100 beta expression in light cells, the abundant Na+-K+ ATPase on dark cells of the TV, and previously demonstrated co-localization of S100 beta/GABA in sensory cells suggest that S100 beta could have, in the inner ear, a dual neurotrophic-ionic modulating function.

Glial S100B Positive Vacuoles In Purkinje Cells: Earliest Morphological Abnormality In SCA1 Transgenic Mice

PubMed Central

VIG, Parminder J.S.; LOPEZ, Maripar E.; WEI, Jinrong; D’SOUZA, David R.; SUBRAMONY, SH; HENEGAR, Jeffrey; FRATKIN, Jonathan D.

2007-01-01

Spinocerebellar ataxia-1 (SCA1) is caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-1. The overexpression of mutant ataxin-1 in SCA1 transgenic mice results in the formation of cytoplasmic vacuoles in Purkinje neurons (PKN) of the cerebellum. PKN are closely associated with neighboring Bergmann glia. To elucidate the role of Bergmann glia in SCA1 pathogenesis, cerebellar tissue from 7 days to 6 wks old SCA1 transgenic and wildtype mice were used. We observed that Bergmann glial S100B protein is localized to the cytoplasmic vacuoles in SCA1 PKN. These S100B positive cytoplasmic vacuoles began appearing much before the onset of behavioral abnormalities, and were negative for other glial and PKN marker proteins. Electron micrographs revealed that vacuoles have a double membrane. In the vacuoles, S100B colocalized with receptors of advanced glycation end-products (RAGE), and S100B co-immunoprecipated with cerebellar RAGE. In SCA1 PKN cultures, exogenous S100B protein interacted with the PKN membranes and was internalized. These data suggest that glial S100B though extrinsic to PKN is sequestered into cytoplasmic vacuoles in SCA1 mice at early postnatal ages. Further, S100B may be binding to RAGE on Purkinje cell membranes before these membranes are internalized. PMID:18176630

A Biophysico-Computational Perspective of Breast Cancer Pathogenesis and Treatment Response

DTIC Science & Technology

2011-03-01

modification maps. Nat Rev Genet 8, 286-298 (2007). 51 Lo , P. K. & Sukumar, S. Epigenomics and breast cancer. Pharmacogenomics 9, 1879-1902 (2008). 52...P e rc e n t c e ll d e a th *** *** *** 0 7 14 21 28 0 100 200 300 400 Vector N-CoR2 Time after IR (days) C o lo n y s iz e ( m ) *** *** *** MDA...orchestrated processes.  In this respect, HOXA9 plays an important role in skeletal (41),  uro - genital tract (42), kidney (43), and mammary gland development

Oxide Evolution in ODS Steel Resulting From Friction Stir Welding

DTIC Science & Technology

2014-06-01

Master’s Thesis 4 . TITLE AND SUBTITLE OXIDE EVOLUTION IN ODS STEEL RESULTING FROM FRICTION STIR WELDING 5. FUNDING NUMBERS 6 . AUTHOR(S...temperatures, from [5]. ........... 6   Figure 4 .  The phase diagram for aluminum and yttrium oxide, from [13]. ......................8  Figure 5...millimeters per minute. FSW Conditions RPM IPM MMPM Heat Index 400 7 175 2.3 300 4 100 3 200 2 50 4 400 4 100 4 300 2 50 6 400 2 50 8 500 1 25

O2 uptake kinetics during exercise at peak O2 uptake.

PubMed

Scheuermann, Barry W; Barstow, Thomas J

2003-11-01

Compared with moderate- and heavy-intensity exercise, the adjustment of O2 uptake (VO2) to exercise intensities that elicit peak VO2 has received relatively little attention. This study examined the VO2 response of 21 young, healthy subjects (25 +/- 6 yr; mean +/- SD) during cycle ergometer exercise to step transitions in work rate (WR) corresponding to 90, 100, and 110% of the peak WR achieved during a preliminary ramp protocol (15-30 W/min). Gas exchange was measured breath by breath and interpolated to 1-s values. VO2 kinetics were determined by use of a two- or three-component exponential model to isolate the time constant (tau2) as representative of VO2 kinetics and the amplitude (Amp) of the primary fast component independent of the appearance of any VO2 slow component. No difference in VO2 kinetics was observed between WRs (tau90 = 24.7 +/- 9.0; tau100 = 22.8 +/- 6.7; tau110 = 21.5 +/- 9.2 s, where subscripts denote percent of peak WR; P > 0.05); nor in a subgroup of eight subjects was tau2 different from the value for moderate-intensity ( 0.05). As expected, the Amp increased with increasing WRs (Amp90 = 2,089 +/- 548; Amp100 = 2,165 +/- 517; Amp110 = 2,225 +/- 559 ml/min; Amp90 vs. Amp110, P < 0.05). However, the gain (G) of the VO2 response (deltaVO2/deltaWR) decreased with increasing WRs (G90 = 8.5 +/- 0.6; G100 = 7.9 +/- 0.6; G110 = 7.3 +/- 0.6 ml.min-1.W-1; P < 0.05). The Amp of the primary component approximated 85, 88, and 89% of peak Vo2 during 90, 100, and 110% WR transitions, respectively. The results of the present study demonstrate that, compared with moderate- and heavy-intensity exercise, the gain of the Vo2 response (as deltaVO2/DeltaWR) is reduced for exercise transitions in the severe-intensity domain, but the approach to this gain is well described by a common time constant that is invariant across work intensities. The lower deltaVO2/deltaWR may be due to an insufficient adjustment of the cardiovascular and/or pulmonary systems that determine O2 delivery to the exercising muscles or due to recruitment of motor units with lower oxidative capacity, after the onset of exercise in the severe-intensity domain.

Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.

PubMed

Vaithianathan, Soundarya; Raman, Siddarth; Jiang, Wenlei; Ting, Tricia Y; Kane, Maureen A; Polli, James E

2015-07-06

The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.

Vascular Physiology according to Clinical Scenario in Patients with Acute Heart Failure: Evaluation using the Cardio-Ankle Vascular Index.

PubMed

Goto, Toshihiko; Wakami, Kazuaki; Mori, Kento; Kikuchi, Shohei; Fukuta, Hidekatsu; Ohte, Nobuyuki

2016-09-01

Increased aortic stiffness may be an important cause of acute heart failure (AHF). Clinical scenario (CS), which classifies the pathophysiology of AHF based on the initial systolic blood pressure (sBP), was proposed to provide the most appropriate therapy for AHF patients. In CS, elevated aortic stiffness, vascular failure, has been considered as a feature of patients categorized as CS1 (sBP > 140 mmHg at initial presentation). However, whether elevated aortic stiffness, vascular failure, is present in such patients has not been fully elucidated. Therefore, we assessed aortic stiffness in AHF patients using the cardio-ankle vascular index (CAVI), which is considered to be independent of instantaneous blood pressure. Sixty-four consecutive AHF patients (mean age, 70.6 ± 12.8 years; 39 men) were classified with CS, based on their initial sBP: CS1: sBP > 140 mmHg (n = 29); CS2: sBP 100-140 mmHg (n = 22); and CS3: sBP < 100 mmHg (n = 13). There were significant group differences in CAVI (CS1 vs. CS2 vs. CS3: 9.7 ± 1.4 vs. 8.4 ± 1.7 vs. 8.3 ± 1.7, p = 0.006, analysis of variance). CAVI was significantly higher in CS1 than in CS2 (p = 0.02) and CS3 (p = 0.04). CAVI did not significantly correlate with sBP at the time of measurement of CAVI (r = 0.24 and p = 0.06). Aortic stiffness assessed using blood pressure-independent methodology apparently increased in CS1 AHF patients. We conclude that vascular failure is a feature of CS1 AHF initiation.

Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women

PubMed Central

Rouillon, Steeve; Deshayes-Morgand, Chloé; Enjalbert, Line; Rabouan, Sylvie; Hardouin, Jean-Benoit; DisProSE, Group; Migeot, Virginie; Albouy-Llaty, Marion

2017-01-01

Endocrine disrupting chemicals (EDC) are environmental exposure factors that are rarely reported in clinical practice, particularly during pregnancy. This study aimed to describe women’s knowledge, attitudes and behaviors towards EDC exposure. A study was conducted in the French Department of Vienne between 2014 and 2016 and comprised semi-structured interviews with pregnant women, a focus group of professionals in perinatology and environmental health, and the administration of a psychosocial questionnaire comprising scores in 300 pregnant or in postpartum period women. The mean score of knowledge was 42.9 ± 9.8 out of 100 (from 13.5 to 75.7). Exposure attitude was determined by risk perception. Mean level of cues to action to reduce their EDC exposure was estimated at 56.9 ± 22.5 out of 100 (from 0 to 100). Anxiety was significantly increased after the questionnaire. Anxiety about EDC was associated with a high score of knowledge (OR = 2.30, 95% CI (1.12–4.71)) and with no pregnancy anxiety (OR = 0.57, 95% CI (0.34–0.95)). Our findings suggest that healthcare providers should consider pregnant women’s knowledge and perceptions, possibilities of action, and be careful not to increase their anxiety when advising them about EDC and environmental exposure. PMID:28878198

Physiological Responses and Performance Analysis Difference between Official and Simulated Karate Combat Conditions.

PubMed

Chaabène, Helmi; Mkaouer, Bessem; Franchini, Emerson; Souissi, Nafaa; Selmi, Mohamed Amine; Nagra, Yassine; Chamari, Karim

2014-03-01

This study aimed to compare physiological responses and time-motion analysis between official and simulated karate combat. Ten high-level karatekas participated in this study, which included official and simulated karate combat. Karatekas used more upper-limb attack techniques during official combat compared to simulated ones (6±3 vs 3±1; P=0.05, respectively). For official and simulated karate matches, the numbers of high-intensity actions (i.e. offensive and defensive fighting activity) were 14±6 and 18±5, respectively (P>0.05), lasting from <1s to 5s each. Total fighting activity phase was lower during official compared to simulated matches (21.0±8.2s vs 30.4±9.9s, P<0.01, respectively). Effort (10.0±2.8s) to rest (11.9±2.7s) ratio (E:R) was 1:1 and high-intensity actions (1.6±0.3s) to rest (11.9±2.7s) ratio was higher than 1:7 during simulated combat. During official karate match, the activity and rest duration were 10.0±3.4s and 16.2±4.1s, respectively (E:R ratio 1:1.5), while high-intensity actions were 1.5±0.3s, resulting in an E:R ratio of 1:11. Blood lactate concentration was higher during official (11.14±1.82 mmol.l(-1)) compared to simulated karate combat (7.80±2.66 mmol.l(-1)) (P<0.05). Subjective perceived exertion differed significantly between official and simulated combat (14±2 vs. 12±2; P<0.05, respectively). The majority of karatekas' perceived exertion was higher in the lower limb muscle groups irrespective of the karate combat condition. Official and simulated matches differ considerably, therefore coaches should create new strategies during training sessions to achieve the same effort and pause profile of competitive matches and/or that athletes should be submitted to frequent competitions to adapt themselves to the profile of this event.

Physiological Responses and Performance Analysis Difference between Official and Simulated Karate Combat Conditions

PubMed Central

Chaabène, Helmi; Mkaouer, Bessem; Franchini, Emerson; Souissi, Nafaa; Selmi, Mohamed Amine; Nagra, Yassine; Chamari, Karim

2013-01-01

Purpose This study aimed to compare physiological responses and time-motion analysis between official and simulated karate combat. Methods Ten high-level karatekas participated in this study, which included official and simulated karate combat. Results Karatekas used more upper-limb attack techniques during official combat compared to simulated ones (6±3 vs 3±1; P=0.05, respectively). For official and simulated karate matches, the numbers of high-intensity actions (i.e. offensive and defensive fighting activity) were 14±6 and 18±5, respectively (P>0.05), lasting from <1s to 5s each. Total fighting activity phase was lower during official compared to simulated matches (21.0±8.2s vs 30.4±9.9s, P<0.01, respectively). Effort (10.0±2.8s) to rest (11.9±2.7s) ratio (E:R) was 1:1 and high-intensity actions (1.6±0.3s) to rest (11.9±2.7s) ratio was higher than 1:7 during simulated combat. During official karate match, the activity and rest duration were 10.0±3.4s and 16.2±4.1s, respectively (E:R ratio 1:1.5), while high-intensity actions were 1.5±0.3s, resulting in an E:R ratio of 1:11. Blood lactate concentration was higher during official (11.14±1.82 mmol.l-1) compared to simulated karate combat (7.80±2.66 mmol.l-1) (P<0.05). Subjective perceived exertion differed significantly between official and simulated combat (14±2 vs. 12±2; P<0.05, respectively). The majority of karatekas’ perceived exertion was higher in the lower limb muscle groups irrespective of the karate combat condition. Conclusion Official and simulated matches differ considerably, therefore coaches should create new strategies during training sessions to achieve the same effort and pause profile of competitive matches and/or that athletes should be submitted to frequent competitions to adapt themselves to the profile of this event. PMID:24868428

Measures and Models for Estimating and Predicting Cognitive Fatigue

NASA Technical Reports Server (NTRS)

Trejo, Leonard J.; Kochavi, Rebekah; Kubitz, Karla; Montgomery, Leslie D.; Rosipal, Roman; Matthews, Bryan

2004-01-01

We analyzed EEG and ERPs in a fatiguing mental task and created statistical models for single subjects. Seventeen subjects (4 F, 18-38 y) viewed 4-digit problems (e.g., 3+5-2+7=15) on a computer, solved the problems, and pressed keys to respond (intertrial interval = 1 s). Subjects performed until either they felt exhausted or three hours had elapsed. Re- and post-task measures of mood (Activation Deactivation Adjective Checklist, Visual Analogue Mood Scale) confirmed that fatigue increased and energy decreased over time. We tested response times (RT); amplitudes of ERP components N1, P2, P300, readiness potentials; and amplitudes of frontal theta and parietal alpha rhythms for change as a function of time. For subjects who completed 3 h (n=9) we analyzed 12 15-min blocks. For subjects who completed at least 1.5 h (n=17), we analyzed the first-, middle-, and last 100 error-free trials. Mean RT rose from 6.7 s to 8.5 s over time. We found no changes in the amplitudes of ERP components. In both analyses, amplitudes of frontal theta and parietal alpha rose by 30% or more over time. We used 30-channel EEG frequency spectra to model the effects of time in single subjects using a kernel partial least squares classifier. We classified 3.5s EEG segments as being from the first 100 or the last 100 trials, using random sub-samples of each class. Test set accuracies ranged from 63.9% to 99.6% correct. Only 2 of 17 subjects had mean accuracies lower than 80%. The results suggest that EEG accurately classifies periods of cognitive fatigue in 90% of subjects.

Beach Profile Analysis System (BPAS). Volume VIII. Supporting Appendixes for BPAS User’s Guides.

DTIC Science & Technology

1982-06-01

V) 0 4)C CC0~ID ~C ~ C C~ a) L C C~ ~ C L- d C C C a . C.. -’ -C--C 0 ) w 0 0 (a) 0 (L 00.0V a) L)~a LCC Uda C - -La r CC-->C> C ) a ).C C...2+"- 21 14 1 4 1 a7Sooo2 IIoQ2’l 4 0# 1la+ t0+ 1ab # 37# 153s So* 185# .8. l8i 340 3 w 2 4 7+ 1# 1 + l o+t 174+ 1IS+ 100+ lab+ 147’ + 1 + 1 9Q a IIIa 1

Biomarkers S100B and neuron-specific enolase predict outcome in hypothermia-treated encephalopathic newborns*.

PubMed

Massaro, An N; Chang, Taeun; Baumgart, Stephen; McCarter, Robert; Nelson, Karin B; Glass, Penny

2014-09-01

To evaluate if serum S100B protein and neuron-specific enolase measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy. Prospective longitudinal cohort study. A level IV neonatal ICU in a freestanding children's hospital. Term newborns with moderate to severe neonatal encephalopathy referred for therapeutic hypothermia during the study period. Serum neuron-specific enolase and S100B were measured at 0, 12, 24, and 72 hours of hypothermia. Of the 83 infants enrolled, 15 (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development-II at 15 months. Outcomes were assessed in 49 of 68 survivors (72%) at a mean age of 15.2 ± 2.7 months. Neurodevelopmental outcome was classified by Bayley Scales of Infant Development-II Mental Developmental Index and Psychomotor Developmental Index scores, reflecting cognitive and motor outcomes, respectively. Four-level outcome classifications were defined a priori: normal = Mental Developmental Index/Psychomotor Developmental Index within 1 SD (> 85), mild = Mental Developmental Index/Psychomotor Developmental Index less than 1 SD (70-85), moderate/severe = Mental Developmental Index/Psychomotor Developmental Index less than 2 SD (< 70), or died. Elevated serum S100B and neuron-specific enolase levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and socioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were 2.5 (95% CI, 1.3-4.8) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase, and for motor outcome, 2.6 (95% CI, 1.2-5.6) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase. Serum S100B and neuron-specific enolase levels in babies with neonatal encephalopathy are associated with neurodevelopmental outcome at 15 months. These putative biomarkers of brain injury may help direct care during therapeutic hypothermia.

Solving the crystal structure of human calcium-free S100Z: the siege and conquer of one of the last S100 family strongholds.

PubMed

Calderone, V; Fragai, M; Gallo, G; Luchinat, C

2017-06-01

The X-ray structure of human apo-S100Z has been solved and compared with that of the zebrafish calcium-bound S100Z, which is the closest in sequence. Human apo-S100A12, which shows only 43% sequence identity to human S100Z, has been used as template model to solve the crystallographic phase problem. Although a significant buried surface area between the two physiological dimers is present in the asymmetric unit of human apo-S100Z, the protein does not form the superhelical arrangement in the crystal as observed for the zebrafish calcium-bound S100Z and human calcium-bound S100A4. These findings further demonstrate that calcium plays a fundamental role in triggering quaternary structure formation in several S100s. Solving the X-ray structure of human apo-S100Z by standard molecular replacement procedures turned out to be a challenge and required trying different models and different software tools among which only one was successful. The model that allowed structure solution was that with one of the lowest sequence identity with the target protein among the S100 family in the apo state. Based on the previously solved zebrafish holo-S100Z, a putative human holo-S100Z structure has been then calculated through homology modeling; the differences between the experimental human apo and calculated holo structure have been compared to those existing for other members of the family.

Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice.

PubMed

Wu, Hao; Brown, Eric V; Acharya, Nimish K; Appelt, Denah M; Marks, Alexander; Nagele, Robert G; Venkataraman, Venkat

2016-04-15

S100B is a calcium-sensor protein that impacts multiple signal transduction pathways. It is widely considered to be an important biomarker for several neuronal diseases as well as blood-brain barrier (BBB) breakdown. In this report, we demonstrate a BBB deficiency in mice that lack S100B through detection of leaked Immunoglobulin G (IgG) in the brain parenchyma. IgG leaks and IgG-binding to selected neurons were observed in S100B knockout (S100BKO) mice at 6 months of age but not at 3 months. By 9 months, IgG leaks persisted and the density of IgG-bound neurons increased significantly. These results reveal a chronic increase in BBB permeability upon aging in S100BKO mice for the first time. Moreover, coincident with the increase in IgG-bound neurons, autoantibodies targeting brain proteins were detected in the serum via western blots. These events were concurrent with compromise of neurons, increase of activated microglia and lack of astrocytic activation as evidenced by decreased expression of microtubule-associated protein type 2 (MAP2), elevated number of CD68 positive cells and unaltered expression of glial fibrillary acidic protein (GFAP) respectively. Results suggest a key role for S100B in maintaining BBB functional integrity and, further, propose the S100BKO mouse as a valuable model system to explore the link between chronic functional compromise of the BBB, generation of brain-reactive autoantibodies and neuronal dysfunctions. Copyright © 2016. Published by Elsevier B.V.

[Clinical evaluation of cefdinir 5% fine granules in pediatrics].

PubMed

Iwai, N; Nakamura, H; Taneda, Y; Miyazu, M; Kasai, K; Watanabe, Y

1991-10-01

Clinical evaluation in pediatrics on cefdinir (CFDN, FK482) (5% fine granules), a new oral cephem, was performed. 1. CFDN was administered to 112 pediatric patients with ages between 1 month to 13 years with various infections. Dose levels used were 3.0-8.9 mg/kg (mean 5.1 mg/kg) t.i.d. for 3-14 days (mean 6.7 days). The studied patients included 2 patients with scarlet fever, 6 with acute pharyngitis, 6 with acute rhinopharyngitis, 52 with acute purulent tonsillitis, 8 with acute bronchitis, 24 with acute pneumonia, 7 with acute urinary tract infections, 1 with acute vaginitis, and 6 with impetigo. Total doses ranged from 0.6 to 4.05 g. One hundred eleven of the 112 patients were evaluated for clinical efficacy and all the patients were evaluated for safety. 2. Clinical effects were excellent in 51 cases, good in 57, and fair in 3 with an extremely high efficacy rate of 97.3%. Efficacy rates were 100% in scarlet fever, acute pharyngitis, acute purulent tonsillitis, acute bronchitis, acute vaginitis and impetigo, and 83.3%, 95.7%, 85.7% in acute rhinopharyngitis, acute pneumonia, and acute urinary tract infections, respectively. Good clinical effects were observed regardless of diseases. 3. Causative organisms were identified in 79 cases, of which 71 were found to be monobacterial infections and 8 were found to be multi-bacterial infections. In mono-bacterial infections, clinical efficacies were 100% for those caused by Staphylococcus aureus/Streptococcus pyogenes/Streptococcus pneumoniae/beta-Streptococcus except those in A and B groups with an overall efficacy of 100% against Gram-positive cocci (GPC) and they were 89.5%, 100%, 100% for those caused by Haemophilus influenzae, Haemophilus parainfluenzae, and Escherichia coli, respectively, with an overall efficacy of 90.3% in Gram-negative rods (GNR). In multi-bacterial infections also, a clinical efficacy of 100% was obtained. 4. Bacteriological effects were studied for 89 strains in the 79 cases. The eradication rate for a few strains of S. pneumoniae was low, 25%, but it was 100% for S. aureus, with the same results for S. pyogenes, and beta-Streptococcus. The eradication rate on GPC was high 94.1%. Among GNR, 66.7% of E. coli, 50.0% of H. influenzae, and 71.4% of H. parainfluenzae was eradicated. The overall eradication rate for GNR was 55.3%, lower than that for GPC. Microbial substitutions were observed in 13 cases, with Haemophilus sp. replacing other bacteria. 5. Diarrhea and soft stools were noted in 4 and 2 patients, respectively. The severity of these side effects, however, was slight and it was possible to continue the CFDN treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Ansbach AAF, Katterback, Germany. Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts A-F

DTIC Science & Technology

1974-10-29

jAUG 100,C lQoo 99.8 98,1 90,0 8)92 66,1 47,0 23.7 7605 176 ( SEP 100.0 100 9C 100,0 9903 95.1 84q9 72,6 54 331,1 79.9 020 OCT 100O 100 ’, 100.0...10’. 20’. 30% 40% 50% 60’. 70% 80% 1 90,% HUMIDITY (OBS jAUG 00ൊ "°,o 00vo 100.0 100. 100.0 100.0 96.8 9o#3 57 9 . 93! Wo65 looov 11009 1oo LI o.1

Formation of Hg(II) tetrathiolate complexes with cysteine at neutral pH

DOE PAGES

Warner, Thomas; Jalilehvand, Farideh

2016-01-04

Mercury(II) ions precipitate from aqueous cysteine (H 2Cys) solutions containing H 2Cys/Hg(II) mole ratio ≥ 2.0 as Hg( S-HCys) 2. In absence of additional cysteine, the precipitate dissolves at pH ~12 with the [Hg( S, N-Cys) 2] 2- complex dominating. With excess cysteine (H 2Cys/Hg(II) mole ratio ≥ 4.0), higher complexes form and the precipitate dissolves at lower pH values. Previously, we found that tetrathiolate [Hg( S-Cys) 4] 6- complexes form at pH = 11.0; in this work we extend the investigation to pH values of physiological interest. We examined two series of Hg(II)-cysteine solutions in which C Hg(II) variedmore » between 8 – 9 mM and 80 – 100 mM, respectively, with H 2Cys/Hg(II) mole ratios from 4 to ~20. The solutions were prepared in the pH range 7.1 – 8.8, at the pH at which the initial Hg( S-HCys) 2 precipitate dissolved. The variations in the Hg(II) speciation were followed by 199Hg NMR, X-ray absorption and Raman spectroscopic techniques. Our results show that in the dilute solutions (C Hg(II) = 8 – 9 mM), mixtures of di-, tri- (major) and tetrathiolate complexes exist at moderate cysteine excess (C H2Cys ~ 0.16 M) at pH 7.1. In the more concentrated solutions (C Hg(II) = 80 – 100 mM) with high cysteine excess (C H2Cys > 0.9 M), tetrathiolate [Hg( S-cysteinate) 4] m-6 ( m = 0 – 4) complexes dominate in the pH range 7.3 – 7.8, with lower charge than for the [Hg( S-Cys) 4] 6- complex due to protonation of some ( m) of the amino groups of the coordinated cysteine ligands. In conclusion, the results of this investigation could provide a key to the mechanism of biosorption and accumulation of Hg(II) ions in biological / environmental systems.« less

View of Endeavour touching down at Edwards AFB during STS-100's landing

NASA Image and Video Library

2001-05-01

STS100-S-024 (1 May 2001) --- The main landing gear on the space shuttle Endeavour touches down on a desert runway at Edwards Air Force Base in California to complete the STS-100 mission. Touchdown occurred at 9:11 a.m. (PDT), May 1, 2001. Onboard the shuttle were six NASA astronauts and a cosmonaut representing Rosaviakosmos. Photo credit: NASA

Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohan, Sepuru K., E-mail: mohansepuri@gmail.com; Gupta, Arun A., E-mail: ninja14gupta@gmail.com; Yu, Chin, E-mail: cyu.nthu@gmail.com

2013-05-03

Highlights: •The halo human S100A6 (C3S) NMR chemical shifts were assigned. •The interactions between S100A6m and RAGE V domain was investigated by ITC. •The residues involved in the S100A6m–RAGE V domain binding were mapped by {sup 1}H–{sup 15}N HSQC titration. •S100A6–RAGE V domain tetrameric complex model was generated from NMR studies. •The S100A6–RAGE V domain interface regions were elucidated based on HADDOCK model. -- Abstract: S100A6 is involved in several vital biological functions, such as calcium sensing and cell proliferation. It is a homodimeric protein that belongs to the S100 protein family. The receptor for advanced glycation end products (RAGE)more » has been shown to play a role in the progression of various disease conditions, such as diabetes and immune/inflammatory disorders. Information regarding the association of RAGE with S100 proteins at a molecular level is useful to understand the diversity of the RAGE signaling pathways. In this report, biomolecular NMR techniques were utilized for the resonance assignment of the C3S mutation in human S100A6 and characterizing its interaction with the RAGE V domain. Further binding affinity between S100A6m and the RAGE V domain was determined by isothermal titration calorimetric studies. HADDOCK was used to generate a heterotetramer model of the S100A6m–RAGE V domain complex. This model provides an important insights into the S100–RAGE cellular signaling pathway.« less

Sensitization of interferon-γ induced apoptosis in human osteosarcoma cells by extracellular S100A4

PubMed Central

Pedersen, Kjetil Boye; Andersen, Kristin; Fodstad, Øystein; Mælandsmo, Gunhild Mari

2004-01-01

Background S100A4 is a small Ca2+-binding protein of the S100 family with metastasis-promoting properties. Recently, secreted S100A4 protein has been shown to possess a number of functions, including induction of angiogenesis, stimulation of cell motility and neurite extension. Methods Cell cultures from two human osteosarcoma cell lines, OHS and its anti-S100A4 ribozyme transfected counterpart II-11b, was treated with IFN-γ and recombinant S100A4 in order to study the sensitizing effects of extracellular S100A4 on IFN-γ mediated apoptosis. Induction of apoptosis was demonstrated by DNA fragmentation, cleavage of poly (ADP-ribose) polymerase and Lamin B. Results In the present work, we found that the S100A4-expressing human osteosarcoma cell line OHS was more sensitive to IFN-γ-mediated apoptosis than the II-11b cells. S100A4 protein was detected in conditioned medium from OHS cells, but not from II-11b cells, and addition of recombinant S100A4 to the cell medium sensitized II-11b cells to apoptosis induced by IFN-γ. The S100A4/IFN-γ-mediated induction of apoptosis was shown to be independent of caspase activation, but dependent on the formation of reactive oxygen species. Furthermore, addition of extracellular S100A4 was demonstrated to activate nuclear factor-κB (NF-κB). Conclusion In conclusion, we have shown that S100A4 sensitizes osteosarcoma cells to IFN-γ-mediated induction of apoptosis. Additionally, extracellular S100A4 activates NF-κB, but whether these events are causally related remains unknown. PMID:15318945

S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages.

PubMed

Wang, Huaqing; Zhang, Leying; Zhang, Ian Y; Chen, Xuebo; Da Fonseca, Anna; Wu, Shihua; Ren, Hui; Badie, Sam; Sadeghi, Sam; Ouyang, Mao; Warden, Charles D; Badie, Behnam

2013-07-15

S100B is member of a multigenic family of Ca(2+)-binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM). We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100B(high)) or underexpressed (S100B(low)) S100B and compared their growth characteristics to intracranial wild-type (S100B(wt)) tumors. Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100B(low) tumors, S100B(wt) and S100B(high) intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100B(high) tumors. Furthermore, analysis of The Cancer Genome Atlas's glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding. These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy.

Oceans 1999 MTS/IEEE, Riding the Crest into the 21st Century

DTIC Science & Technology

1999-01-01

Universidade do Porto and Instituto de Sistemas e Robötica Rua dos Bragas, 4099 Porto Codex Portugal * Instituto Superior de Engenharia do Porto Rua de S...the TOC and the PAH-PCB’s. Fig. 7 is a comparison of the corrected Percentage (%) TOC and the Differential Bottom Loss. ü O t- o 01 $ c v...0) 0. 120 100 80 60 40 20 0 ► 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 Portion of Diff. BL for TOC (db) Fig. 7. Percentage

U.S. Naval Weather Service Command. Summary of Synoptic Meteorological Observations, North American Coastal Marine Areas - Revised. Pacific Coast. Volume 6. Area 36 - Point Arena, Area 37 - Eureka, Area 38 - Cape Blanco, Area 39 - Newport, Area 40 - Astoria, Area 41 - Vancouver Island SW

DTIC Science & Technology

1976-05-01

3.6 6.5 20.4 .0 4.0 422 100.0 PACE 122 r IPKIKitV) H4S-H73 (Ovei«-*LL) H87-1973 AUGUST USLS * ARE« 0037 EUR6KA »6HCJNT4CE...6 6.9 7.5 4.9 5.4 5!7 6.3 7.0 7.1 .0 .0 .0 3.4 3.» Soil 53.1 TOT OIS TOT PCT tal 6.5 13.1 U.I 20.0 U.l U.7 12.1 .0 4.1 100.0 2015

Purification and partial characterization of canine S100A12.

PubMed

Heilmann, Romy M; Suchodolski, Jan S; Steiner, Jörg M

2010-12-01

Canine S100A12 (cS100A12) is a calcium-binding protein of the S100 superfamily of EF-hand proteins, and its expression is restricted to neutrophils and monocytes. Interaction of S100A12 with the receptor for advanced glycation end products (RAGE) has been suggested to play a central role in inflammation. Moreover, S100A12 has been shown to represent a sensitive and specific marker for gastrointestinal inflammation in humans. Only human, porcine, bovine, and rabbit S100A12 have been purified to date, and an immunoassay for the quantification of S100A12 is available only for humans. Therefore, the aim of this study was to develop a protocol for the purification of S100A12 and to partially characterize this protein in the dog (Canis lupus familiaris) as a prelude to the development of an immunologic method for its detection and quantification in canine serum and fecal specimens. Leukocytes were isolated from canine whole blood by dextran sedimentation, and canine S100A12 was extracted from the cytosol fraction of these cells. Further purification of cS100A12 comprised of ammonium sulfate precipitation, hydrophobic interaction chromatography, and strong cation- and anion-exchange column chromatography. Canine S100A12 was successfully purified from canine whole blood. The relative molecular mass of the protein was estimated at 10,379.5 and isoelectric focusing revealed an isoelectric point of 6.0. The approximate specific absorbance of cS100A12 at 280 nm was determined to be 1.78 for a 1 mg/ml solution. The N-terminal AA sequence of the first 15 residues of cS100A12 was Thr-Lys-Leu-Glu-Asp-His-X-Glu-Gly-Ile-Val-Asp-Val-Phe-His, and revealed 100% identity with the predicted protein sequence available through the canine genome project. Sequence homology for the 14 N-terminal residues identified for cS100A12 with those of feline, bovine, porcine, and human S100A12 was 78.6%. We conclude that canine S100A12 can be successfully purified from canine whole blood using the described methods. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

In Vitro Scolicidal Effects of Salvadora persica Root Extract against Protoscolices of Echinococcus granulosus.

PubMed

Abdel-Baki, Abdel-Azeem S; Almalki, Esam; Mansour, Lamjed; Al-Quarishy, Saleh

2016-02-01

It has been known that Arak, Salvadora persica, has a number of medicinal properties. We tried to investigate in vitro scolicidal effect of root extracts of this plant against protoscolices from hydatid cysts of Echinococcus granulosus. Protoscolices were aseptically collected from sheep livers containing hydatid cysts. S. persica root extract was used in 10, 30, and 50 mg/ml concentration for 10, 20, and 30 min. The viability of protoscolices was ascertained by 0.1% eosin staining. Scolicidal activity of S. persica extract at a concentration of 10 mg/ml was 36.3%, 50.3%, and 70.8% after 10, 20, and 30 min of exposure, respectively. The scolicidal effect of this extract at a concentration of 30 mg/ml was 52.9%, 86.7%, and 100% after 10, 20, and 30 min of exposure, respectively. S. persica extract at a concentration of 50 mg/ml, meanwhile, killed 81.4%, 100%, and 100% of protoscolices after 10, 20, and 30 min, respectively. Also, the cytotoxic potential of S. persica was assessed on human liver cells (HepG2) using trypan blue exclusion test. No cytotoxic effect was observed on HepG2 cell line. The present study confirmed for the first time that the ethanolic extract of S. persica has high scolicidal power in vitro. However, in vivo effect of this material remains to be studied for treatment of echinococcosis in humans and herbivorous animals.

A Direct Synergistic Effect of Immunotherapy and Chemotherapy as a New Paradigm in Treatment of Breast Cancer

DTIC Science & Technology

2009-04-01

Untreated and TAX treated EL4 targets were labeled with DDAO-SE and loaded with control (C.P.) or specific (S.P.) peptide. The tumor cells were...C ell Vehicle treated EL4 cells 100 101 102 103 104 FL4-H: anti mouse granzyme B alexa647 0 100 200 300 400 500 # Cells 2.5297.5 100 101 102 103...mouse granzyme B alexa647 0 100 200 300 400 500 # Cells 7.292.8 Taxol treated EL4 cells 100 101 102 103 104 FL4-H: anti mouse granzyme B alexa647 0

Biomarkers of Brain Injury in Neonatal Encephalopathy Treated with Hypothermia

PubMed Central

Massaro, An N.; Chang, Taeun; Kadom, Nadja; Tsuchida, Tammy; Scafidi, Joseph; Glass, Penny; McCarter, Robert; Baumgart, Stephen; Vezina, Gilbert; Nelson, Karin B.

2012-01-01

Objective To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy. Study design Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7–10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis. Results Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5–7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures. Conclusion Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity. PMID:22494878

Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia.

PubMed

Massaro, An N; Chang, Taeun; Kadom, Nadja; Tsuchida, Tammy; Scafidi, Joseph; Glass, Penny; McCarter, Robert; Baumgart, Stephen; Vezina, Gilbert; Nelson, Karin B

2012-09-01

To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy. Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7-10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis. Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5-7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures. Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity. Copyright © 2012 Mosby, Inc. All rights reserved.

Relationship of the stretch-shortening cycle to sprint performance in trained female athletes.

PubMed

Hennessy, L; Kilty, J

2001-08-01

This study assessed the relationship of long and short stretch-shortening cycle test scores to sprint performances in trained female athletes. Seventeen trained, female, high school, competitive sprinters completed the following tests: countermovement jump for vertical distance (CMJ), bounce drop jump for height with minimum ground contact time (BDJ index), and ground contact time (GCT) during the BDJ and a 5-step bound (5B) test. Group mean and SD values were as follows: height, 167.7 +/- 3.7 cm; body mass, 59.9 +/- 7.2 kg; and percentage of body fat (PF), 20.3 +/- 1.8%. Sprint performances at 30-, 100-, and 300-m distances were assessed. Stretch-shortening cycle performance and sprint results (mean +/- SD) were as follows: CMJ, 33.8 +/- 3.8 cm; BDJ index, 166.7 +/- 24.7 cm/s; 5B test, 10.98 +/- 0.76 m; 30-m sprint, 4.58 +/- 0.17 seconds; 100-m sprint, 12.9 +/- 0.61 seconds; and 300-m sprint, 45.03 +/- 2.94 seconds. Correlations indicated that no relationship existed between PF and the dependent sprint variables. Significant correlations (p < 0.05) existed between CMJ and 30-m (r = -0.60), 100-m (r = -0.64), and 300-m (r = -0.55) sprint times; BDJ index and 30-m (r = -0.79) and 100-m (r = -0.75) sprint times; and 5B test and 300-m sprint time (r = -0.54). Multiple regression analysis found significant T values for BDJ index with 30- and 100-m sprints and CMJ and PF with 300 m. Results indicated that the BDJ index and CMJ tests were significantly related to sprint performances in female athletes.

Molecular basis for the interaction between stress-inducible phosphoprotein 1 (STIP1) and S100A1.

PubMed

Maciejewski, Andrzej; Prado, Vania F; Prado, Marco A M; Choy, Wing-Yiu

2017-05-16

Stress-inducible phosphoprotein 1 (STIP1) is a cellular co-chaperone, which regulates heat-shock protein 70 (Hsp70) and Hsp90 activity during client protein folding. Members of the S100 family of dimeric calcium-binding proteins have been found to inhibit Hsp association with STIP1 through binding of STIP1 tetratricopeptide repeat (TPR) domains, possibly regulating the chaperone cycle. Here, we investigated the molecular basis of S100A1 binding to STIP1. We show that three S100A1 dimers associate with one molecule of STIP1 in a calcium-dependent manner. Isothermal titration calorimetry revealed that individual STIP1 TPR domains, TPR1, TPR2A and TPR2B, bind a single S100A1 dimer with significantly different affinities and that the TPR2B domain possesses the highest affinity for S100A1. S100A1 bound each TPR domain through a common binding interface composed of α-helices III and IV of each S100A1 subunit, which is only accessible following a large conformational change in S100A1 upon calcium binding. The TPR2B-binding site for S100A1 was predominately mapped to the C-terminal α-helix of TPR2B, where it is inserted into the hydrophobic cleft of an S100A1 dimer, suggesting a novel binding mechanism. Our data present the structural basis behind STIP1 and S100A1 complex formation, and provide novel insights into TPR module-containing proteins and S100 family member complexes. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Comparison of hippocampal G protein activation by 5-HT(1A) receptor agonists and the atypical antipsychotics clozapine and S16924.

PubMed

Newman-Tancredi, A; Rivet, J-M; Cussac, D; Touzard, M; Chaput, C; Marini, L; Millan, M J

2003-09-01

This study employed [(35)S]guanosine 5'- O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT(1A) receptors with those of reference agonists at postsynaptic 5-HT(1A) receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, E(max), values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC(50)) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT(1A) receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT(1A) receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding, consistent with partial agonist properties. In [(35)S]GTPgammaS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT(1A) receptors, was more potent in the septum (pEC(50) approximately 6.5) than in the dentate gyrus of the hippocampus (pEC(50) approximately 5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 microM) did not enhance [(35)S]GTPgammaS labelling in any structure, S16924 (10 micro M) modestly increased [(35)S]GTPgammaS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 microM)-stimulated [(35)S]GTPgammaS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT(1A) receptors in the hippocampus. These data support a role of postsynaptic 5-HT(1A) receptors in the functional profiles of certain antipsychotic agents.

[Impacts of the different frequencies of electroacupunctrue on cognitive function in patients after abdominal operation under compound anesthesia of acupuncture and drugs].

PubMed

Lin, Shun-Yan; Gao, Ju; Yin, Zheng-Lu; Zhou, Luo-Jing; Chen, Xin

2013-12-01

To observe the impacts of different frequencies of electroacupuncture (EA) on post-operative cognitive function and the change in serum S-100beta protein under the compound anesthesia of acupuncture and drugs. One hundred and twenty-four patients of abdominal operation at selective time were randomized into a routine drug anesthesia group (group A, 24 cases), a meridian point 2 Hz group (group B, 26 cases), a me ridian point 2 Hz/100 Hz group (group C, 25 cases), a meridian point 100 Hz group (group D, 24 cases) and a transcutaneous acupoint electric stimulation 2 Hz/100 Hz group (group E, 25 cases). In group A, the endotrachea-lgeneral anesthesia was applied. In the rest groups, the acupuncture anesthesia was induced for 30 min before the endotracheal general anesthesia, at Baihui (GV 20), Yintang (GV 29) and Neiguan (PC 6), with G6805-2 electric acupuncture apparatus used. In group B, the continuous wave and 2Hz in frequency were selected. In group C, the disperse-dense wave and 2 Hz/100 Hz in frequency were selected. In group D, the continuous wave and 100 Hz in frequency were selected. In group E, the disperse-dense wave and 2 Hz/100 Hz in frequency were selected, and the electrode pads were stick on the acupoints and connected with the electric stimulation till the end of operation. Mini-mental state examination (MMSE) was adopted to evaluate and record the changes in cognitive function 1 day before operation and on the 3rd day after operation. The conditions of post-operative cognitive dysfunction (POCD) in the patients and the changes in serum S-100beta protein were monitored before and at the end of operation. The incidence rate of POCD on the 3rd day after operation was 41.7% (10/24) in group A. The incidence rates of POCD were 26.9% (7/26), 16.0% (4/25), 33.3% (8/24) and 16.0% (4/25) in group B, C, D and E separately. Compared with group A, the incidence rate of PCOD in group B, C, D and E were reduced (all P<0.05), the incidence rate in group C and E were lower than that in groups B and D (all P<0.05). At the end of operation, the level of serumS-100beta protein was (0.186 +/- 0.027) microg/L in group A, the levels were (0.165 +/- 0. 028) microg/L, (0.166 +/- 0.027) microg/L, (0.163 +/- 0.025) microg/L and (0.164 +/- 0.025) microg/L in group B, C, D and E separately. The levels of serum S-100beta protein in group B, C, D and E were lower than that in group A separately (all P<0.05). The general anesthesia assisted with EA at different frequencies reduces the incidence of cognitive dysfunctionand, decreases the level of serum S-100beta protein after intestinal cancer resection. The effects of the meridian point electric stimulation at 2 Hz/100 Hz and the transcutaneous electric stimulation at 2 Hz/100 Hz are the best. Hence, these two approaches of anesthesia deserve to be recommended practically.

The prognostic value of serum S100B in patients with cutaneous melanoma: a meta-analysis.

PubMed

Mocellin, Simone; Zavagno, Giorgio; Nitti, Donato

2008-11-15

S100B protein detected in the serum of patients with cutaneous melanoma has been long reported as a prognostic biomarker. However, no consensus exists on its implementation in the routine clinical setting. This study aimed to comprehensively and quantitatively summarize the evidence on the suitability of serum S100B to predict patients' survival. Twenty-two series enrolling 3393 patients with TNM stage I to IV cutaneous melanoma were reviewed. Standard meta-analysis methods were applied to evaluate the overall relationship between S100B serum levels and patients' survival (meta-risk). Serum S100B positivity was associated with significantly poorer survival (hazard ratio [HR] = 2.23, 95% CI: 1.92-2.58, p < 0.0001). Between-study heterogeneity was significant, which appeared to be related mainly to dissemination bias and the inclusion of patients with stage IV disease. Considering stage I to III melanoma (n = 1594), the meta-risk remained highly significant (HR = 2.28, 95% CI: 1.8-2.89; p < 0.0001) and studies' estimates were homogeneous. Subgroup analysis of series reporting multivariate survival analysis supported S100B as a prognostic factor independent of the TNM staging system. Our findings suggest that serum S100B detection has a clinically valuable independent prognostic value in patients with melanoma, with particular regard to stage I-III disease. Further investigation focusing on this subset of patients is justified and warranted before S100B can be implemented in the routine clinical management of melanoma. (c) 2008 Wiley-Liss, Inc.

Front view of Endeavour prior to touching down at Edwards AFB during STS-100's landing

NASA Image and Video Library

2001-05-01

STS100-S-025 (1 May 2001) --- The space shuttle Endeavour is only seconds away from main gear touchdown on a desert runway at Edwards Air Force Base in California to complete the STS-100 mission. Touchdown occurred at 9:11 a.m. (PDT), May 1, 2001. Onboard the shuttle were six NASA astronauts and a cosmonaut representing Rosaviakosmos. Photo credit: NASA

Profile view of Endeavour prior to touching down at Edwards AFB during STS-100's landing

NASA Image and Video Library

2001-05-01

STS100-S-023 (1 May 2001) --- The space shuttle Endeavour is only seconds away from main gear touchdown on a desert runway at Edwards Air Force Base in California to complete the STS-100 mission. Touchdown occurred at 9:11 a.m. (PDT), May 1, 2001. Onboard the shuttle were six NASA astronauts and a cosmonaut representing Rosaviakosmos. Photo credit: NASA

Global Epidemiology of Head and Neck Cancers: A Continuing Challenge.

PubMed

Gupta, Bhawna; Johnson, Newell W; Kumar, Narinder

2016-01-01

Head and neck cancers (HNCs) continue to remain a significant public health burden worldwide, causing significant mortality and morbidity despite significant clinical advances enabling their early diagnosis and treatment. We used data from the GLOBOCAN 2012, Cancer Incidence in Five Continents, World Health Organization Mortality Database and Surveillance, Epidemiology, and End Results programmes to describe the current epidemiology of HNCs. Estimated age-standardised incidence/mortality rates for cancers of the lip and oral cavity among males and females (7.0/2.3 and 2.6/0.6 per 100,000 per annum) in more developed regions are higher compared to those in less developed regions (5.0/2.8 and 2.5/1.4 per 100,000 per annum). Similarly, the estimated rates for cancers of the tonsils and pharynx among males (7.5/2.5 per 100,000 per annum) and females (2.7/0.5 per 100,000 per annum) are reported to be the highest in Western Europe, whereas these rates for cancer of the larynx among males (7.9/4.0 per 100,000 per annum) and females (0.9/0.5 per 100,000 per annum) are reported to be the highest in the Caribbean. Cancer of the nasopharynx represents a significant HNC burden in the Asia-Pacific region and Northern Africa. The current and future estimated burden of HNCs is shifting to less developed regions which may be ill equipped to deal with this increasing burden. This needs urgent attention of policy makers through effective cancer control policy implementation with population-based interventions. © 2016 S. Karger AG, Basel.

Human calprotectin affects the redox speciation of iron.

PubMed

Nakashige, Toshiki G; Nolan, Elizabeth M

2017-08-16

We report that the metal-sequestering human host-defense protein calprotectin (CP, S100A8/S100A9 oligomer) affects the redox speciation of iron (Fe) in bacterial growth media and buffered aqueous solution. Under aerobic conditions and in the absence of an exogenous reducing agent, CP-Ser (S100A8(C42S)/S100A9(C3S) oligomer) depletes Fe from three different bacterial growth media preparations over a 48 h timeframe (T = 30 °C). The presence of the reducing agent β-mercaptoethanol accelerates this process and allows CP-Ser to deplete Fe over a ≈1 h timeframe. Fe-depletion assays performed with metal-binding-site variants of CP-Ser show that the hexahistidine (His 6 ) site, which coordinates Fe(ii) with high affinity, is required for Fe depletion. An analysis of Fe redox speciation in buffer containing Fe(iii) citrate performed under aerobic conditions demonstrates that CP-Ser causes a time-dependent increase in the [Fe(ii)]/[Fe(iii)] ratio. Taken together, these results indicate that the hexahistidine site of CP stabilizes Fe(ii) and thereby shifts the redox equilibrium of Fe to the reduced ferrous state under aerobic conditions. We also report that the presence of bacterial metabolites affects the Fe-depleting activity of CP-Ser. Supplementation of bacterial growth media with an Fe(iii)-scavenging siderophore (enterobactin, staphyloferrin B, or desferrioxamine B) attenuates the Fe-depleting activity of CP-Ser. This result indicates that formation of Fe(iii)-siderophore complexes blocks CP-mediated reduction of Fe(iii) and hence the ability of CP to coordinate Fe(ii). In contrast, the presence of pyocyanin (PYO), a redox-cycling phenazine produced by Pseudomonas aeruginosa that reduces Fe(iii) to Fe(ii), accelerates Fe depletion by CP-Ser under aerobic conditions. These findings indicate that the presence of microbial metabolites that contribute to metal homeostasis at the host/pathogen interface can affect the metal-sequestering function of CP.

Evaluating the Environmental Impact, Cost, and Performance of Biobased Alternatives

DTIC Science & Technology

2007-05-01

r r r. r ASTM D 445: At 40°C: 38.5 • 45.5 cStDAt 100°C: min 4.8 est MIL -H- 81019 I r r r. r r r. ASTM D 445: At 100°(: 2.5 x 10-6 m’l/s, minD...r. r r mm>/s(cSt)DGrade 2 btw 41.4 and 50.6 mm 2 /sDGrade 3 btw 6 1.2 and 74.8 mm 2 /sDGrade 4 r. r r btw 135 and 165 mm’/s MIL -H- 19457 I r r...At 40°C: 7.0 x 10-6 m>/s, minD At -54°C: 800 x 10-6 m 2 /s, max D At ·70°C: 0.008 m 2 /s, m~x MIL -PRF-32073 I r. r r r. r r ASTM D 445: At 40°C

Ranking benchmarks of top 100 players in men's professional tennis.

PubMed

Reid, Machar; Morris, Craig

2013-01-01

In men's professional tennis, players aspire to hold the top ranking position. On the way to the top spot, reaching the top 100 can be seen as a significant career milestone. National Federations undertake extensive efforts to assist their players to reach the top 100. However, objective data considering reasonable ranking yardsticks for top 100 success in men's professional tennis are lacking. Therefore, it is difficult for National Federations and those involved in player development to give empirical programming advice to young players. By taking a closer look at the ranking history of professional male tennis players, this article tries to provide those involved in player development a more objective basis for decision-making. The 100 names, countries, birthdates and ranking histories of the top 100 players listed in the Association of Tennis Professionals (ATP) at 31 December 2009 were recorded from websites in the public domain. Descriptive statistics were reported for the ranking milestones of interest. Results confirmed the merits of the International Tennis Federation's junior tour with 91% of the top 100 professionals earning a junior ranking, the mean peak of which was 94.1, s=148.9. On average, top 100 professionals achieved their best junior rankings and earned their first ATP point at similar ages, suggesting that players compete on both the junior and professional tours during their transition. Once professionally ranked, players took an average 4.5, s=2.1 years to reach the ATP top 100 at the mean age of 21.5, s=2.6 years, which contrasts with the mean current age of the top 100 of 26.8, s=3.2. The best professional rankings of players born in 1982 or earlier were positively related to the ages at which players earned their first ATP point and then entered the top 100, suggesting that the ages associated with these ranking milestones may have some forecasting potential. Future work should focus on the change in top 100 demographics over time as well as the evaluation of the interaction between rankings and tournament play.

Isotretinoin therapy changes the expression of antimicrobial peptides in acne vulgaris.

PubMed

Borovaya, Alena; Dombrowski, Yvonne; Zwicker, Stephanie; Olisova, Olga; Ruzicka, Thomas; Wolf, Ronald; Schauber, Jürgen; Sárdy, Miklós

2014-10-01

In acne vulgaris, antimicrobial peptides (AMPs) could play a dual role; i.e., protective by acting against Propionibacterium acnes, pro-inflammatory by acting as signalling molecules. The cutaneous expression of 15 different AMPs was investigated in acne patients; furthermore, the impact of isotretinoin therapy on AMP expression was analysed in skin biopsies from 13 patients with acne vulgaris taken before, during and after a 6-month treatment cycle with isotretinoin using quantitative real-time polymerase chain reaction. Cutaneous expression of the AMPs cathelicidin, human β-defensin-2 (HBD-2), lactoferrin, lysozyme, psoriasin (S100A7), koebnerisin (S100A15), and RNase 7 was upregulated in untreated acne vulgaris, whereas α-defensin-1 (HNP-1) was downregulated compared to controls. While relative expression levels of cathelicidin, HBD-2, lactoferrin, psoriasin (S100A7), and koebnerisin (S100A15) decreased during isotretinoin treatment, only those of cathelicidin and koebnerisin returned to normal after 6 months of isotretinoin therapy. The increased expression of lysozyme and RNase 7 remained unaffected by isotretinoin treatment. The levels of granulysin, RANTES (CCL5), perforin, CXCL9, substance P, chromogranin B, and dermcidin were not regulated in untreated acne patients and isotretinoin had no effect on these AMPs. In conclusion, the expression of various AMPs is altered in acne vulgaris. Isotretinoin therapy normalizes the cutaneous production of distinct AMPs while the expression of others is still increased in healing acne. Considering the antimicrobial and pro-inflammatory role of AMPs, these molecules could serve as specific targets for acne therapy and maintenance of clinical remission.

Differences in Poisoning Mortality in the United States, 2003–2007: Epidemiology of Poisoning Deaths Classified as Unintentional, Suicide or Homicide

PubMed Central

Muazzam, Sana; Swahn, Monica H.; Alamgir, Hasanat; Nasrullah, Muazzam

2012-01-01

Introduction Poisoning, specifically unintentional poisoning, is a major public health problem in the United States (U.S.). Published literature that presents epidemiology of all forms of poisoning mortalities (i.e., unintentional, suicide, homicide) together is limited. This report presents data and summarizes the evidence on poisoning mortality by demographic and geographic characteristics to describe the burden of poisoning mortality and the differences among sub-populations in the U.S. for a 5-year period. Methods Using mortality data from the Center for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System, we presented the age-specific and age-adjusted unintentional and intentional (suicide, homicide) poisoning mortality rates by sex, age, race, and state of residence for the most recent years (2003–2007) of available data. Annual percentage changes in deaths and rates were calculated, and linear regression using natural log were used for time-trend analysis. Results There were 121,367 (rate=8.18 per 100,000) unintentional poisoning deaths. Overall, the unintentional poisoning mortality rate increased by 46.9%, from 6.7 per 100,000 in 2003 to 9.8 per100.000 in 2007, with the highest mortality rate among those aged 40–59 (rate=15.36), males (rate=11.02) and whites (rate=8.68). New Mexico (rate=18.2) had the highest rate. Unintentional poisoning mortality rate increased significantly among both sexes, and all racial groups except blacks (p<0.05 time-related trend for rate). Among a total of 29,469 (rate=1.97) suicidal poisoning deaths, the rate increased by 9.9%, from 1.9 per 100,000 in 2003 to 2.1 per 100,000 in 2007, with the highest rate among those aged 40–59 (rate=3.92), males (rate=2.20) and whites (rate=2.24). Nevada (rate=3.9) had the highest rate. Mortality rate increased significantly among females and whites only (p<0.05 time-related trend for rate). There were 463 (rate=0.03) homicidal poisoning deaths and the rate remained the same during 2003–2007. The highest rates were among aged 0–19 (rate=0.05), males (rate=0.04) and blacks (rate=0.06). Conclusion Prevention efforts for poisoning mortalities, especially unintentional poisoning, should be developed, implemented and strengthened. Differences exist in poisoning mortality by age, sex, location, and these findings underscore the urgency of addressing this public health burden as this epidemic continues to grow in the U.S. PMID:22900120

Microstructure and properties of hard and optically transparent HfO2 films prepared by high-rate reactive high-power impulse magnetron sputtering

NASA Astrophysics Data System (ADS)

Patterson, Burkley Delesdernier

Hafnium Dioxide (HfO2) has an extraordinary high bulk modulus, high hardness, high chemical stability, high melting point and high thermal stability. This material can be used as protective coatings for application involving high temperature environments. HfO2 films were fabricated on Si using high-rate reactive high-power impulse magnetron sputtering (HiPIMS) using different deposition-averaged target power density and voltage pulse durations t1. Five HfO2 films were prepared with (1) t1 = 25 mus, =7.6 Wcm-2 (T25S7), (2) t 1 = 100 mus, =7.2 Wcm-2 (T100S7), (3) t1 = 200 mus, =7.3 Wcm-2 (T200S7), (4) t1 = 200 mus, =18 Wcm-2 (T200S18) and (5) t1 = 200 mus, =54 Wcm-2 (T200S54). Atomic force microscopy (AFM) images of the T200S54, T200S18 and T200S7 films exhibit a coarser granular structure with a similar grain size varying from 25 nm to 120 nm in diameter and an average grain size of ˜70 nm. AFM images of the T25S7 and T100S7 films show smaller granular structures compared to the other three films. Transmission electron microscopy (TEM) studies show that all films are composed of an interlayer next to the Si interface followed by a nano-columnar structure layer. The interlayer structure of the films consists of a population of lower density nanoscale regions. A reduction in t1 and in films T200S54, T200S18, T200S7 and T100S7 caused an increase in the interlayer thickness and a decrease in the width of the nano-columnar structures from ˜46 nm to ˜21 nm. This microstructural change was accompanied by a concomitant change of the grain boundary structure from tight and interlocking in films T200S54 and T200S18, to rough and thicker (˜1 nm) boundaries in films T200S7 and T100S7. Film T25S7 exhibited an entirely different microstructure composed of a multilayered interlayer (˜3 nm) and nano-columnar (˜15 nm) structure. Films prepared with large t1 (200 mus) have a monoclinic HfO 2 structure and that with small t1 (25 mus) an orthorhombic HfO 2 structure. Film prepared with an intermediate t1 value (100 mus) exhibited a mixture of both monoclinic and orthorhombic phases. A high hardness of 17.6-17.0 GPa was shown for films with a monoclinic HfO2 structure. The films exhibited a refractive index of 2.02-2.11 and an extinction coefficient between ≥≤2x10-3 and 0.1x10-3 (both at a wavelength of 550 nm). High optical quality was achieved for films T200S54 and T200S18 owing to the presence of a dense microstructure with sharp and interlocking grain boundaries.

Rickettsia amblyommatis infecting ticks and exposure of domestic dogs to Rickettsia spp. in an Amazon-Cerrado transition region of northeastern Brazil.

PubMed

Costa, Francisco B; da Costa, Andréa P; Moraes-Filho, Jonas; Martins, Thiago F; Soares, Herbert S; Ramirez, Diego G; Dias, Ricardo A; Labruna, Marcelo B

2017-01-01

This study was performed in Maranhão state, a transition area two Brazilian biomes, Amazon and Cerrado. During 2011-2013, 1,560 domestic dogs were sampled for collection of serum blood samples and ticks in eight counties (3 within the Amazon and 5 within the Cerrado). A total of 959 ticks were collected on 150 dogs (9.6%). Rhipicephalus sanguineus sensu lato (s.l.) was the most abundant tick (68% of all collected specimens), followed by Amblyomma cajennense sensu lato (s.l.) (12.9%), Amblyomma parvum (9.2%), and Amblyomma ovale (5.2%). Other less abundant species (<1%) were Amblyomma oblongoguttatum, Rhipicephalus microplus, Haemaphysalis juxtakochi, and Amblyomma rotundatum. Females of A. cajennense s.l. ticks were morphologically identified as A. cajennense sensu stricto (s.s.) or A. sculptum. Molecular analyses of 779 canine ticks revealed three Rickettsia species: Rickettsia amblyommatis in 1% (1/100) A. cajennense s.l., 'Candidatus Rickettsia andeanae' in 20.7% (12/58) A. parvum, Rickettsia bellii in 6.8% (3/44) A. ovale and 100% (1/1) A. rotundatum ticks. An additional collection of A. sculptum from horses in a Cerrado area, and A. cajennense s.s. from pigs in an Amazon area revealed R. amblyommatis infecting only the A. cajennense s.s. ticks. Serological analysis of the 1,560 canine blood samples revealed 12.6% canine seroreactivity to Rickettsia spp., with the highest specific seroreactivity rate (10.2%) for R. amblyommatis. Endpoint titers to R. amblyommatis were significantly higher than those for the other Rickettsia antigens, suggesting that most of the seroreactive dogs were exposed to R. amblyommatis-infected ticks. Highest canine seroreactivity rates per locality (13.1-30.8%) were found in Amazon biome, where A. cajennense s.s. predominated. Lowest seroreactivity rates (1.9-6.5%) were found in Cerrado localities that were further from the Amazon, where A. sculptum predominated. Multivariate analyses revealed that canine seroreactivity to Rickettsia spp. or R. amblyommatis was statistically associated with rural dogs, exposed to Amblyomma ticks.

Rickettsia amblyommatis infecting ticks and exposure of domestic dogs to Rickettsia spp. in an Amazon-Cerrado transition region of northeastern Brazil

PubMed Central

Costa, Francisco B.; da Costa, Andréa P.; Moraes-Filho, Jonas; Martins, Thiago F.; Soares, Herbert S.; Ramirez, Diego G.; Dias, Ricardo A.

2017-01-01

This study was performed in Maranhão state, a transition area two Brazilian biomes, Amazon and Cerrado. During 2011–2013, 1,560 domestic dogs were sampled for collection of serum blood samples and ticks in eight counties (3 within the Amazon and 5 within the Cerrado). A total of 959 ticks were collected on 150 dogs (9.6%). Rhipicephalus sanguineus sensu lato (s.l.) was the most abundant tick (68% of all collected specimens), followed by Amblyomma cajennense sensu lato (s.l.) (12.9%), Amblyomma parvum (9.2%), and Amblyomma ovale (5.2%). Other less abundant species (<1%) were Amblyomma oblongoguttatum, Rhipicephalus microplus, Haemaphysalis juxtakochi, and Amblyomma rotundatum. Females of A. cajennense s.l. ticks were morphologically identified as A. cajennense sensu stricto (s.s.) or A. sculptum. Molecular analyses of 779 canine ticks revealed three Rickettsia species: Rickettsia amblyommatis in 1% (1/100) A. cajennense s.l., ‘Candidatus Rickettsia andeanae’ in 20.7% (12/58) A. parvum, Rickettsia bellii in 6.8% (3/44) A. ovale and 100% (1/1) A. rotundatum ticks. An additional collection of A. sculptum from horses in a Cerrado area, and A. cajennense s.s. from pigs in an Amazon area revealed R. amblyommatis infecting only the A. cajennense s.s. ticks. Serological analysis of the 1,560 canine blood samples revealed 12.6% canine seroreactivity to Rickettsia spp., with the highest specific seroreactivity rate (10.2%) for R. amblyommatis. Endpoint titers to R. amblyommatis were significantly higher than those for the other Rickettsia antigens, suggesting that most of the seroreactive dogs were exposed to R. amblyommatis-infected ticks. Highest canine seroreactivity rates per locality (13.1–30.8%) were found in Amazon biome, where A. cajennense s.s. predominated. Lowest seroreactivity rates (1.9–6.5%) were found in Cerrado localities that were further from the Amazon, where A. sculptum predominated. Multivariate analyses revealed that canine seroreactivity to Rickettsia spp. or R. amblyommatis was statistically associated with rural dogs, exposed to Amblyomma ticks. PMID:28594882

Calprotectin in rheumatic diseases.

PubMed

Ometto, Francesca; Friso, Lara; Astorri, Davide; Botsios, Costantino; Raffeiner, Bernd; Punzi, Leonardo; Doria, Andrea

2017-04-01

Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker. Impact statement Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.

Effect of Hot Water Blanching Time and Drying Temperature on the Thin Layer Drying Kinetics of and Anthocyanin Degradation in Black Carrot (Daucus carota L.) Shreds.

PubMed

Garba, Umar; Kaur, Sawinder; Gurumayum, Sushma; Rasane, Prasad

2015-09-01

This study was conducted to investigate the effect of blanching treatment (98 °C for 3 and 6 min) and air drying temperature of 40, 50 and 60 °C on the thin layer drying characteristics such as drying time, drying rate constant, effective moisture diffusivity and activation energy, as well as on anthocyanin content of black carrot shreds. It was observed that drying temperature affected the drying rate but blanching did not have an effect on drying time. Three thin layer drying models, i.e. Page, Lewis and Henderson-Pabis were evaluated. The goodness of these models was evaluated based on the coefficient of determination (R 2 ), root mean square error, reduced chi square (χ 2 ) and standard error. Page model showed the best fit to the drying data. The effective diffusivity ranges of 1.4·10 -9 to 2.6·10 -9 m 2 /s, 1.3·10 -9 to 2.1·10 -9 m 2 /s and 1.5·10 -9 to 2.2·10 -9 m 2 /s after 3 or 6 min of blanching and control samples respectively were calculated using Fick's second law. The activation energy of 37.5, 26.0 and 34.6 kJ/(mol·K) of the control samples and samples blanched for 3 or 6 min respectively was determined from the Arrhenius plot. The blanching treatment affected the anthocyanin content to a great extent. The anthocyanin content of (231.7±2.9) and (278.8±7.8) mg per 100 g was recorded in samples blanched for 3 and 6 min and then dried at 60 °C, and (153.0±4.3) and (247.0±5.5) mg per 100 g was recorded at 40 °C as compared to the control of (580.1±1.3) at 60 °C and (466.7±1.1) mg per 100 g at 40 °C.

The Role of Newly Discovered Exotoxin (S Toxin) in Pseudomonas aeruginosa Infections

DTIC Science & Technology

1979-08-01

sodium or potassium phosphate 6.0-8.0 N-2-hydroxyethylpiperazine-N’-2-ethanesulfonic acid (HEPES) 6.5-8.5 tris 7.0-9.5 sodium borate 7.5-9.5 sodium...was found to be variable with respect to whether sodium or potassium phosphate buffer was used. With sodium phosphate, virtually all the enzyme...activity bound was eluted between 20-100.2M phosphate at pH 6.8. With the potassium salt, elution occurs at 400-?00mM KP04. Since very little protein was

Small molecule inhibitors of Ca 2+-S100B reveal two protein conformations

DOE PAGES

Cavalier, Michael C.; Ansari, Mohd. Imran; Pierce, Adam D.; ...

2016-01-04

The drug pentamidine inhibits calcium-dependent complex formation with p53 ( CaS100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure–activity relationship (SAR) studies were therefore completed in this study with 23 pentamidine analogues, and X-ray structures of CaS100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the “FF-gate”. For symmetric pentamidine analogues ( CaS100B· 5a, CaS100B· 6b) a channel between sites 1 and 2 on S100B was occluded bymore » residue Phe88, but for an asymmetric pentamidine analogue ( CaS100B· 17), this same channel was open. Finally, the CaS100B· 17 structure illustrates, for the first time, a pentamidine analog capable of binding the “open” form of the “FF-gate” and provides a means to block all three “hot spots” on CaS100B, which will impact next generation CaS100B·p53 inhibitor design.« less

Small molecule inhibitors of Ca 2+-S100B reveal two protein conformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cavalier, Michael C.; Ansari, Mohd. Imran; Pierce, Adam D.

The drug pentamidine inhibits calcium-dependent complex formation with p53 ( CaS100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure–activity relationship (SAR) studies were therefore completed in this study with 23 pentamidine analogues, and X-ray structures of CaS100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the “FF-gate”. For symmetric pentamidine analogues ( CaS100B· 5a, CaS100B· 6b) a channel between sites 1 and 2 on S100B was occluded bymore » residue Phe88, but for an asymmetric pentamidine analogue ( CaS100B· 17), this same channel was open. Finally, the CaS100B· 17 structure illustrates, for the first time, a pentamidine analog capable of binding the “open” form of the “FF-gate” and provides a means to block all three “hot spots” on CaS100B, which will impact next generation CaS100B·p53 inhibitor design.« less

Sprint Start Kinetics of Amputee and Non-Amputee Sprinters

PubMed Central

Willwacher, Steffen; Herrmann, Volker; Heinrich, Kai; Funken, Johannes; Strutzenberger, Gerda; Goldmann, Jan-Peter; Braunstein, Björn; Brazil, Adam; Irwin, Gareth; Potthast, Wolfgang; Brüggemann, Gert-Peter

2016-01-01

The purpose of this study was to explore the relationship between the forces applied to the starting blocks and the start performances (SPs) of amputee sprinters (ASs) and non-amputee sprinters (NASs). SPs of 154 male and female NASs (100-m personal records [PRs], 9.58–14.00 s) and 7 male ASs (3 unilateral above knee, 3 unilateral below knee, 1 bilateral below knee; 100 m PRs, 11.70–12.70 s) with running specific prostheses (RSPs) were analysed during full-effort sprint starts using instrumented starting blocks that measured the applied forces in 3D. Using the NAS dataset and a combination of factor analysis and multiple regression techniques, we explored the relationship between force characteristics and SP (quantified by normalized average horizontal block power). Start kinetics were subsequently compared between ASs and NASs who were matched based on their absolute 100 m PR and their 100 m PR relative to the world record in their starting class. In NASs, 86% of the variance in SP was shared with five latent factors on which measured parameters related to force application to the rear and front blocks and the respective push-off directions in the sagittal plane of motion were loaded. Mediolateral force application had little influence on SP. The SP of ASs was significantly reduced compared to that of NASs matched on the basis of relative 100-m PR (−33.8%; d = 2.11, p < 0.001), while a non-significant performance reduction was observed when absolute 100-m PRs were used (−17.7%; d = 0.79, p = 0.09). These results are at least partially explained by the fact that force application to the rear block was clearly impaired in the affected legs of ASs. PMID:27846241

Sprint Start Kinetics of Amputee and Non-Amputee Sprinters.

PubMed

Willwacher, Steffen; Herrmann, Volker; Heinrich, Kai; Funken, Johannes; Strutzenberger, Gerda; Goldmann, Jan-Peter; Braunstein, Björn; Brazil, Adam; Irwin, Gareth; Potthast, Wolfgang; Brüggemann, Gert-Peter

2016-01-01

The purpose of this study was to explore the relationship between the forces applied to the starting blocks and the start performances (SPs) of amputee sprinters (ASs) and non-amputee sprinters (NASs). SPs of 154 male and female NASs (100-m personal records [PRs], 9.58-14.00 s) and 7 male ASs (3 unilateral above knee, 3 unilateral below knee, 1 bilateral below knee; 100 m PRs, 11.70-12.70 s) with running specific prostheses (RSPs) were analysed during full-effort sprint starts using instrumented starting blocks that measured the applied forces in 3D. Using the NAS dataset and a combination of factor analysis and multiple regression techniques, we explored the relationship between force characteristics and SP (quantified by normalized average horizontal block power). Start kinetics were subsequently compared between ASs and NASs who were matched based on their absolute 100 m PR and their 100 m PR relative to the world record in their starting class. In NASs, 86% of the variance in SP was shared with five latent factors on which measured parameters related to force application to the rear and front blocks and the respective push-off directions in the sagittal plane of motion were loaded. Mediolateral force application had little influence on SP. The SP of ASs was significantly reduced compared to that of NASs matched on the basis of relative 100-m PR (-33.8%; d = 2.11, p < 0.001), while a non-significant performance reduction was observed when absolute 100-m PRs were used (-17.7%; d = 0.79, p = 0.09). These results are at least partially explained by the fact that force application to the rear block was clearly impaired in the affected legs of ASs.

Should an increase in cerebral neurochemicals following head kicks in full contact karate influence return to play?

PubMed

Graham, M R; Pates, J; Davies, B; Cooper, S M; Bhattacharya, K; Evans, P J; Baker, J S

2015-12-01

Cerebral neurochemicals are markers of traumatic brain injury (TBI). The aim of the study was to determine whether kicks to the head (KTH) in full contact karate significantly increased serum concentrations of protein S-100B, and neurone specific enolase (NSE). Kicks to the body (KTB) were also quantified to asses muscle tissue injury. Muscle damage was assessed by analysis of serum total creatine kinase (CK). Twenty-four full contact karate practitioners were observed and filmed during actual competition and divided into two main groups post event: (1) Kicks to the head and body group (KTH): n = 12; mean ± SD; age, 30.4 ± 6.7 years; height, 1.74 ± 0.1 m; weight, 79.1 ± 2.1 kg; and (2): Kicks to the body group (KTB): n = 12; mean ± SD; age, 28.2 ± 6.5 years; height, 1.75 ± 0.1 m; weight, 79.2 ± 1.7 kg. The KTH group received direct kicks to the head, while group KTB received kicks and punches to the body. Blood samples were taken before and immediately post-combat for analysis of serum S-100B, NSE, CK and cardiac troponin. Significant increases in serum concentrations of S-100B (0.12 ± 0.17 vs. 0.37 ± 0.26, µg.L(-1)) and NSE (11.8 ± 4.1 vs. 20.2 ± 9.1 ng.mL(-1)) were encountered after combat in the KTH group and CK (123 ± 53 vs. 184 ± 103 U.L(-1)) in the KTB group (all P <0.05). Head kicks in full contact karate cause elevation of neurochemical markers associated with damaged brain tissue. The severity of injury is related to the early post-traumatic release of protein S-100B and NSE. The early kinetics and appearance post injury can reflect intracranial pathology, and suggest S-100B and NSE are extremely sensitive prognostic markers of TBI. © The Author(s) 2015.

11 CFR 100.57 - Funds received in response to solicitations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 100.57 is vacated. See Final Order, EMILY's List v. FEC, No. 05-0049 (D.D.C. Nov. 30, 2009). [69 FR....S.C. 431) Definition of Contribution (2 U.S.C. 431(8)) § 100.57 Funds received in response to...

Diet Therapy Career Ladder, AFSC 926XO.

DTIC Science & Technology

1985-12-01

ACCORDING TO PHYSICIAN’S OR DIETITIAN’S GUIDELINES AND AFR 160-8 50% 5.81 F171 PREPARE PUDDINGS 49% 5.74 F159 PREPARE DEHYDRATED FOODS (E.G., INSTANT MASHED...COOKING TECHNIQUES 100 F143 COOK POULTRY 100 F135 CLEAN FOOD PRIOR TO COOKING OR SERVING 100 F159 PREPARE DEHYDRATED FOODS (E.G., INSTANT MASHED POTATOES...FOR COOKING OR SERVING 100 ~, F142 COOK PASTA, SUCH AS NOODLES OR SPAGHETTI 100 F166 PREPARE GRAVIES 100 F176 SAM4PLE FOODS BY TASTE AND SMELL 100

Carbon-armored Co9S8 nanoparticles as all-pH efficient and durable H2-evolving electrocatalysts.

PubMed

Feng, Liang-Liang; Li, Guo-Dong; Liu, Yipu; Wu, Yuanyuan; Chen, Hui; Wang, Yun; Zou, Yong-Cun; Wang, Dejun; Zou, Xiaoxin

2015-01-14

Splitting water to produce hydrogen requires the development of non-noble-metal catalysts that are able to make this reaction feasible and energy efficient. Herein, we show that cobalt pentlandite (Co9S8) nanoparticles can serve as an electrochemically active, noble-metal-free material toward hydrogen evolution reaction, and they work stably in neutral solution (pH 7) but not in acidic (pH 0) and basic (pH 14) media. We, therefore, further present a carbon-armoring strategy to increase the durability and activity of Co9S8 over a wider pH range. In particular, carbon-armored Co9S8 nanoparticles (Co9S8@C) are prepared by direct thermal treatment of a mixture of cobalt nitrate and trithiocyanuric acid at 700 °C in N2 atmosphere. Trithiocyanuric acid functions as both sulfur and carbon sources in the reaction system. The resulting Co9S8@C material operates well with high activity over a broad pH range, from pH 0 to 14, and gives nearly 100% Faradaic yield during hydrogen evolution reaction under acidic (pH 0), neutral (pH 7), and basic (pH 14) media. To the best of our knowledge, this is the first time that a transition-metal chalcogenide material is shown to have all-pH efficient and durable electrocatalytic activity. Identifying Co9S8 as the catalytically active phase and developing carbon-armoring as the improvement strategy are anticipated to give a fresh impetus to rational design of high-performance noble-metal-free water splitting catalysts.

S100A4 Mediates Endometrial Cancer Invasion and is a Target of TGF-β1 Signaling

PubMed Central

Xie, Ran; Schlumbrecht, Matthew; Shipley, Gregory L.; Xie, Susu; Bassett, Roland L.; Broaddus, Russell R.

2009-01-01

The molecular mechanisms of endometrial cancer invasion are poorly understood. S100A4, also known as FSP1 (fibroblast specific protein 1), has long been known to be a molecular marker of fibrosis in a variety of different fibrotic diseases of the lungs, liver, kidney, and heart. We demonstrate here that increased expression of S100A4 is associated with advanced stage endometrial cancer and decreased recurrence free survival. To verify the essential role of S100A4 in invasiveness of endometrial cancer, S100A4 expression was down-regulated by RNAi in HEC-1A cells, which resulted in undetectable S100A4 protein and significantly decreased migration and invasion. Due to the established connection between TGF-β1 and S100A4 induction in experimental models of kidney and liver fibrosis, we next examined whether TGF-β1 could also regulate S100A4 in endometrial cancer cells. TGF-β1 stimulated endometrial cancer cell migration and invasion with a concomitant increase in S100A4 protein. Induction of S100A4 was associated with the activation of Smads. TGF -β1 mediated endometrial cancer cell motility was inhibited by S100A4 siRNA. In aggregate, these results suggest that S100A4 is a critical mediator of invasion in endometrial cancer and is upregulated by the TGF-β1 signaling pathway. These results also suggest that endometrial cancer cell invasion and fibrosis share common molecular mechanisms. PMID:19506550

S100A4 amplifies TGF-β-induced epithelial–mesenchymal transition in a pleural mesothelial cell line

PubMed Central

Ning, Qian; Li, Feiyan; Wang, Lei; Li, Hong; Yao, Yan; Hu, Tinghua; Sun, Zhongmin

2018-01-01

Pleural fibrosis can dramatically lower the quality of life. Numerous studies have reported that epithelial–mesenchymal transition (EMT) regulated by transforming growth factor-β (TGF-β) is involved in fibrosis. However, the molecular mechanism is inadequately understood. Fibroblast-specific protein-1 (S100A4) is a target of TGF-β signaling. In our previous study, we have reported that S100A4 is highly expressed in pleural fibrosis. Thus, we suggest that S100A4 took part in the TGF-β-induced EMT in pleural fibrosis. In this study, we determined the expression of S100A4 and EMT-related markers in Met-5A cells (pleural mesothelial cells) treated with TGF-β or TGF-β inhibitor by real-time PCR and western blot. In order to explore the role of S100A4, we used siRNA to knock down the expression of S100A4 in cell model. We found that the expression of epithelial cell marker was decreased and the mesenchymal cell marker increased with S100A4 upregulation after treatment with TGF-β. Moreover, the changes of EMT-related event were restricted when the expression of S100A4 was knocked down. Conversely, S100A4 can partially rescue the EMT-related expression changes induced by TGF-β inhibitor. These findings suggest that S100A4 expression is induced by the TGF-β pathway, and silencing S100A4 expression can inhibit the process of TGF-β-induced EMT. PMID:29141874

Effects of dietary cation-anion difference on intake, milk yield, and blood components of the early lactation cow.

PubMed

Chan, P S; West, J W; Bernard, J K; Fernandez, J M

2005-12-01

Early lactation Holsteins cows (15 primiparous and 18 multiparous) were offered rations with dietary cation-anion difference, calculated as mEq (Na + K - Cl - S)/100 g of feed dry matter (DCAD:S), of 20, 35, or 50 mEq from d 0 (calving) to 42 d postpartum (August 20, 2000 to January 9, 2001) to determine the effects of increasing DCAD:S on dry matter intake (DMI), milk yield, and blood metabolites. For DCAD:S of 20, 35, and 50, DMI was 3.30, 3.38, 2.96 kg/100 kg of body weight (BW); milk yield was 25.5, 24.2, and 22.4 kg/d, respectively. No differences were observed for concentration or yield of milk fat or milk protein. Serum Ca, P, Mg, Na, K, Cl, cation-anion difference, insulin, and glucose did not differ with DCAD. Serum HCO3- was 26.07, 25.88, and 27.64 mEq/L for 20, 35, and 50 DCAD:S. Serum Ca, Mg, Na, and K concentrations were greater for primiparous cows (9.52 mg/dL, 2.35 mg/dL, 140.03 mEq/L, 4.66 mEq/L, respectively) than for multiparous cows (9.27 mg/dL, 2.12 mg/dL, 137.63 mEq/L, 4.46 mEq/ L, respectively). A DCAD:S between 23 and 33 mEq/100 g of dry matter (DM) appears to be adequate during cool weather for the milk yield that occurred in the present study based on DMI (kg/100 kg of BW), whereas DCAD:S of 50 mEq/100 g of DM may be excessive and could be too alkaline or unpalatable, resulting in decreased DMI (kg/100 kg of BW).

Surgical injury: comparing open surgery and laparoscopy by markers of tissue damage.

PubMed

Máca, Jan; Peteja, Matúš; Reimer, Petr; Jor, Ondřej; Šeděnková, Věra; Panáčková, Lucie; Ihnát, Peter; Burda, Michal; Ševčík, Pavel

2018-01-01

Major abdominal surgery (MAS) is high-risk intervention usually accompanied by tissue injury leading to a release of signaling danger molecules called alarmins. This study evaluates the surgical injury caused by two fundamental types of gastrointestinal surgical procedures (open surgery and laparoscopy) in relation to the inflammation elicited by alarmins. Patients undergoing MAS were divided into a mixed laparoscopy group (LPS) and an open surgery group (LPT). Serum levels of alarmins (S100A8, S100A12, HMGB1, and HSP70) and biomarkers (leukocytes, C-reactive protein [CRP], and interleukin-6 [IL-6]) were analyzed between the groups. The secondary objectives were to compare LPT and LPS cancer subgroups and to find the relationship between procedure and outcome (intensive care unit length of stay [ICU-LOS] and hospital length of stay [H-LOS]). A total of 82 patients were analyzed. No significant difference was found in alarmin levels between the mixed LPS and LPT groups. IL-6 was higher in the LPS group on day 2 ( p =0.03) and day 3 ( p =0.04). Significantly higher S100A8 protein levels on day 1 ( p =0.02) and day 2 ( p =0.01) and higher S100A12 protein levels on day 2 ( p =0.03) were obtained in the LPS cancer subgroup. ICU-LOS and H-LOS were longer in the LPS cancer subgroup. The degree of surgical injury elicited by open MAS as reflected by alarmins is similar to that of laparoscopic procedures. Nevertheless, an early biomarker of inflammation (IL-6) was higher in the laparoscopy group, suggesting a greater inflammatory response. Moreover, the levels of S100A8 and S100A12 were higher with a longer ICU-LOS and H-LOS in the LPS cancer subgroup.

Vector Competence of Anopheles kleini and Anopheles sinensis (Diptera: Culicidae) From the Republic of Korea to Vivax Malaria-Infected Blood From Patients From Thailand.

PubMed

Ubalee, Ratawan; Kim, Heung-Chul; Schuster, Anthony L; McCardle, Patrick W; Phasomkusolsil, Siriporn; Takhampunya, Ratree; Davidson, Silas A; Lee, Won-Ja; Klein, Terry A

2016-11-01

In total, 1,300 each of Anopheles kleini Rueda and Anopheles sinensis Wiedemann sensu stricto (s.s.) females (colonized from the Republic of Korea) and Anopheles dirus Peyton & Harrison (Thai strain) were allowed to feed on blood from Thai malaria patients naturally infected with Plasmodium vivax The overall oocyst infection rates for An. dirus, An. kleini, and An. sinensis s.s. were 77.4, 46.1, and 45.9%, respectively. The mean number of oocysts was significantly higher for An. dirus (82.7) compared with An. kleini (6.1) and An. sinensis s.s. (8.6), whereas the mean number of oocysts for An. kleini and An. sinensis s.s. was similar. The overall sporozoite infection rates for An. dirus, An. kleini, and An. sinensis s.s. dissected on days 14-15, 21, and 28 days post-feed were significantly higher for An. dirus (90.0%) than An. kleini (5.4%), whereas An. kleini sporozoite rates were significantly higher than An. sinensis s.s. (<0.1%). The overall sporozoite indices for positive females with +3 (100-1,000 sporozoites) and +4 (>1,000 sporozoites) salivary gland indices were significantly higher for An. dirus (85.7%), compared with An. kleini (47.1%). Only one An. sinensis s.s. had sporozoites (+2; >10-100 sporozoites). These results indicate that An. kleini is a competent vector of vivax malaria. Although An. sinensis s.s. develops relatively high numbers of oocysts, it is considered a very poor vector of vivax malaria due to a salivary gland barrier. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

QuickStats: Age-Adjusted Death Rates* Attributable to Alcohol-Induced Causes,† by Race/Ethnicity - United States, 1999-2015.

PubMed

2017-05-12

In 2015, mortality from alcohol-induced causes reached the highest rate during 1999-2015 of 9.1 deaths per 100,000 U.S. standard population. Alcohol-induced death rates for the Hispanic population remained the highest (9.9 per 100,000 U.S. standard population), followed by the non-Hispanic white population (9.6). For the non-Hispanic black population, the alcohol-induced death rate decreased 33% from 1999 to 2015, while the rate increased by 50% during the same period for the non-Hispanic white population. Overall, from 1999 to 2015, mortality from alcohol-induced causes increased 28% (7.1 to 9.1).

An orthologue of the host-defense protein psoriasin (S100A7) is expressed in frog skin.

PubMed

Matthijs, Severine; Hernalsteens, Jean-Pierre; Roelants, Kim

2017-02-01

Host-defense peptides and proteins are vital for first line protection against bacteria. Most host-defense peptides and proteins common in vertebrates have been studied primarily in mammals, while their orthologues in non-mammalian vertebrates received less attention. We found that the European Common Frog Rana temporaria expresses a protein in its skin that is evolutionarily related to the host-defense protein S100A7. This prompted us to test if the encoded protein, which is an important microbicidal protein in human skin, shows similar activity in frogs. The R. temporaria protein lacks the zinc-binding sites that are key to the antimicrobial activity of human S100A7 at neutral pH. However, despite being less potent, the R. temporaria protein does compromise bacterial membranes at low pH, similar to its human counterpart. We postulate that, while amphibian S100A7 likely serves other functions, the capacity to compromise bacterial cell membranes evolved early in tetrapod evolution. Copyright © 2016 Elsevier Ltd. All rights reserved.

Time-dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes.

PubMed

Lasič, Eva; Galland, Fabiana; Vardjan, Nina; Šribar, Jernej; Križaj, Igor; Leite, Marina Concli; Zorec, Robert; Stenovec, Matjaž

2016-10-01

Astrocytes, the most heterogeneous glial cells in the central nervous system, contribute to brain homeostasis, by regulating a myriad of functions, including the clearance of extracellular debris. When cells are damaged, cytoplasmic proteins may exit into the extracellular space. One such protein is S100B, which may exert toxic effects on neighboring cells unless it is removed from the extracellular space, but the mechanisms of this clearance are poorly understood. By using time-lapse confocal microscopy and fluorescently labeled S100B (S100B-Alexa 488 ) and fluorescent dextran (Dextran 546 ), a fluid phase uptake marker, we examined the uptake of fluorescently labeled S100B-Alexa 488 from extracellular space and monitored trafficking of vesicles that internalized S100B-Alexa 488 . Initially, S100B-Alexa 488 and Dextran 546 internalized with distinct rates into different endocytotic vesicles; S100B-Alexa 488 internalized into smaller vesicles than Dextran 546 . At a later stage, S100B-Alexa 488 -positive vesicles substantially co-localized with Dextran 546 -positive endolysosomes and with acidic LysoTracker-positive vesicles. Cell treatment with anti-receptor for advanced glycation end products (RAGE) antibody, which binds to RAGE, a 'scavenger receptor', partially inhibited uptake of S100B-Alexa 488 , but not of Dextran 546 . The dynamin inhibitor dynole 34-2 inhibited internalization of both fluorescent probes. Directional mobility of S100B-Alexa 488 -positive vesicles increased over time and was inhibited by ATP stimulation, an agent that increases cytosolic free calcium concentration ([Ca 2+ ] i ). We conclude that astrocytes exhibit RAGE- and dynamin-dependent vesicular mechanism to efficiently remove S100B from the extracellular space. If a similar process occurs in vivo, astroglia may mitigate the toxic effects of extracellular S100B by this process under pathophysiologic conditions. This study reveals the vesicular clearance mechanism of extracellular S100B in astrocytes. Initially, fluorescent S100B internalizes into smaller endocytotic vesicles than dextran molecules. At a later stage, both probes co-localize within endolysosomes. S100B internalization is both dynamin- and RAGE-dependent, whereas dextran internalization is dependent on dynamin. Vesicle internalization likely mitigates the toxic effects of extracellular S100B and other waste products. © 2016 International Society for Neurochemistry.

The Most-Cited Works in Severe Traumatic Brain Injury: A Bibliometric Analysis of the 100 Most-Cited Articles.

PubMed

Li, Lei; Ma, Xiaoye; Pandey, Sajan; Deng, Xianyu; Chen, Songyu; Cui, Daming; Gao, Liang

2018-05-01

There is an abundance of works published on severe traumatic brain injury (sTBI). Bibliometric analyses aim to provide a macroscopic view of research activities regarding sTBI and are helpful in determining the most impactful studies within this field. We performed a generalized search using the database of Web of Science, organized the references by the number of citations, and reviewed full length-articles for the top-100 most-cited articles on sTBI. The articles were classified according to focus. The top-100 articles were cited on average 326.4 times per paper. The Journal of Neurosurgery published the greatest number of top-100 cited articles (9 of 100). Authors from the United States published the majority (67%) of the most-cited articles. The most popular categories were "reviews and guidelines" and "etiology and epidemiology." The present study provides a cross-sectional summary of the 100 most-cited articles on sTBI, highlighting areas of research needing further investigation and development. Copyright © 2018 Elsevier Inc. All rights reserved.

Performances of antibiotic screening tests in determining the persistence of penicillin residues in ewe's milk.

PubMed

Berruga, M I; Yamaki, M; Althaus, R L; Molina, M P; Molina, A

2003-11-01

Milk collected at 12-h intervals throughout 6 days from three groups of Manchega ewes (n = 12 per group), treated intramuscularly with beta-lactams (benzyl penicillin procaine, ampicillin, and amoxicillin, respectively), was evaluated for antibiotic residue persistence with four microbial inhibitor tests (BRT MRL, CH ATK P&S, Delvotest SP, and Eclipse 100ov) and one enzymatic test (Penzym 100). Antibiotic depletion time was established using a logistic regression model. A clear effect (P < 0.0001) of milking order on the response of all tests was observed with the three antibiotics, but no significant effects were found for milk yield. Except with Eclipse 100ov, positive tests were observed after the recommended withdrawal period of benzyl penicillin procaine (five milkings) from 2% (Delvotest SP) to 11% (CH ATK P&S). There were almost no positive responses beyond the withdrawal period (six milkings) of ampicillin, except for the Penzym 100 test (7%). Residues of amoxicillin were found to persist beyond the six milkings established as the withdrawal period, from 2.8% (Eclipse 100ov) to 72.4% (CH ATK P&S) of positive cases. Higher frequencies of doubtful cases were found with BRT MRL and Delvotest SP assays with the three beta-lactams. Positive and doubtful results could be obtained when milk samples from individual ewes were analyzed using BRT MRL, CH ATK P&S, Delvotest SP, and Penzym 100 tests, even if farmers follow the antibiotic withdrawal periods.

Prevalence of exocrine pancreatic insufficiency in patients with chronic pancreatitis without follow-up. PANCR-EVOL Study.

PubMed

Marra-Lopez Valenciano, Carlos; Bolado Concejo, Federico; Marín Serrano, Eva; Millastre Bocos, Judith; Martínez-Moneo, Emma; Pérez Rodríguez, Esperanza; Francisco González, María; Del Pozo-García, Andrés; Hernández Martín, Anaiansi; Labrador Barba, Elena; Orera Peña, María Luisa; de-Madaria, Enrique

2018-02-01

Exocrine pancreatic insufficiency (EPI) is an important complication of chronic pancreatitis (CP). Guidelines recommend to rule out EPI in CP, to detect those patients who would benefit from pancreatic enzyme replacement therapy. The aim of this study was to evaluate the prevalence of EPI in patients with CP without follow-up in the last 2 years and to describe their nutritional status and quality of life (QoL). This was a cross-sectional, multicenter Spanish study. CP patients without follow-up by a gastroenterologist or surgeon in at least 2 years were included. EPI was defined as fecal elastase test <200mcg/g. For nutritional assessment, laboratory and anthropometric data were obtained. QoL was investigated using the EORTC QLQ-C30 questionnaire. 64 patients (mean age 58.8±10.3 years, 85.9% men) from 10 centers were included. Median time since diagnosis of CP was 58.7 months [37.7-95.4]. Forty-one patients (64.1%) had EPI. Regarding nutritional status, the following differences were observed (EPI vs. Non-EPI): BMI (23.9±3.5kg/m 2 vs. 25.7±2.5, p=0.03); glucose (121 [96-189] mg/dL vs. 98 [90-116], p=0.006); HbA1c 6.6% [6.0-8.4] vs. 5.5 [5.3-6.0], p=0.0005); Vitamin A (0.44mg/L [0.35-0.57] vs. 0.53 [0.47-0.63], p=0.048) and Vitamin E (11.2±5.0μg/ml vs. 14.4±4.3, p=0.03). EPI group showed a worse EORTC QLQ-C30 score on physical (93.3 [66.7-100] vs. 100 [93.3-100], p=0.048) and cognitive function (100 [83.3-100] vs. 100 [100-100], p=0.04). Prevalence of EPI is high in patients with CP without follow-up. EPI group had higher levels of glucose, lower levels of vitamins A and E and worse QoL. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Hyaluronan–cisplatin conjugate nanoparticles embedded in Eudragit S100-coated pectin/alginate microbeads for colon drug delivery

PubMed Central

Tsai, Shiao-Wen; Yu, Ding-Syuan; Tsao, Shu-Wei; Hsu, Fu-Yin

2013-01-01

Hyaluronan–cisplatin conjugate nanoparticles (HCNPs) were chosen as colon-targeting drug-delivery carriers due to the observation that a variety of malignant tumors overexpress hyaluronan receptors. HCNPs were prepared by mixing cisplatin with a hyaluronan solution, followed by dialysis to remove trace elements. The cells treated with HCNPs showed significantly lower viability than those treated with cisplatin alone. HCNPs were entrapped in Eudragit S100-coated pectinate/alginate microbeads (PAMs) by using an electrospray method and a polyelectrolyte multilayer-coating technique in aqueous solution. The release profile of HCNPs from Eudragit S100-coated HCNP-PAMs was pH-dependent. The percentage of 24-hour drug release was approximately 25.1% and 39.7% in pH 1.2 and pH 4.5 media, respectively. However, the percentage of drug released quickly rose to 75.6% at pH 7.4. Moreover, the result of an in vivo nephrotoxicity study demonstrated that Eudragit S100-coated HCNP-PAMs treatment could mitigate the nephrotoxicity that resulted from cisplatin. From these results, it can be concluded that Eudragit S100-coated HCNP-PAMs are promising carriers for colonspecific drug delivery. PMID:23861585

[Non-invasive ventilation improves comfort in pediatric palliative care patients].

PubMed

Bosch-Alcaraz, A

2014-01-01

To analyze the appropriate use of non-invasive ventilation and its contribution to improving comfort in pediatric palliative care patients. This is a descriptive cross-sectional study comprising 55 palliative care patients from San Juan de Dios Hospital in Barcelona. The effectiveness was evaluated using a register of socio-demographic, clinical-ventilatory and oxymetric parameters, the comfort and dyspnea's grade using Silverman Anderson scale, and pain level using pediatric scales. The effectiveness of the technique was proved by a decreased heart rate (133.53±25.8 vs. 111.04±23.1; p<0.0001), respiratory rate (35.02±12.9 vs. 25.63±5.7; p<0.0001) and an increase of partial oxygen saturation (95.7±2.9 vs. 96.87±7.2; p<0.0001) and partial oxygen saturation/fraction of inspired oxygen ratio (297.12±113.4 vs. 336.97±100.7; p<0.0001). Dyspnea and pain levels improved in 100% of the patients. The therapy was effective and the comfort improved in 100% of the patients. Copyright © 2013 Elsevier España, S.L.U. y SEEIUC. All rights reserved.

Reports of the U.S. - U.S.S.R. Weddell Polynya Expedition, October-November 1981. Volume 6. Upper-Air Data.

DTIC Science & Technology

1983-05-01

65 0 7 *.’• 7P 72 66 i-3 r.f 5? 50 «» 36 25 E IMi 1 IE*: Hr-.n (KG/«•»3 > i|6 iEC -J sprt r (8/° ) O.7708 0.6677 0.751" 0•652 2...16974. 73.5 17025 . 72.9 17077. 72.3 1712t?. 71.7 1718ü. 71.1 17233. 70.5 17277. 73.0 17331. o9.4 I <c > —1 1 • ’- -el.f -fei. I -11.1...10.3 99.9 100. 0.1903 0.1743 0.7829 4416. 527.9 -35.5 12.1 12.1 -35.5 KC. 0.2123 0.1936 0.7740 4464. 524.3 -3 5.6 12.5 12.6 99.9 ISO . 0.2093 0.191C

A 4-Week Neuromuscular Training Program and Gait Patterns at the Ankle Joint

PubMed Central

Coughlan, Garrett; Caulfield, Brian

2007-01-01

Context: Previous research into the rehabilitation of ankle sprains has primarily focused on outcome measures that do not replicate functional activities, thus making it difficult to extrapolate the results relative to the weight-bearing conditions under which most ankle sprains occur. Objective: To measure the effects of a training program on gait during walking and running in an active athletic population. Design: Matched-pairs, controlled trial. Setting: University motion analysis laboratory. Patients or Other Participants: Ten subjects from an athletic population (7 healthy, 3 with functional ankle instability: age = 25.8 ± 3.9 years, height = 177.6 ± 6.1 cm, mass = 66.8 ± 7.4 kg) and 10 controls matched for age, sex, activity, and ankle instability (7 healthy, 3 with functional ankle instability: age = 27.4 ± 5.8 years, height = 178.7 ± 10.8 cm, mass = 71.6 ± 10.0 kg). Intervention(s): A 4-week neuromuscular training program undertaken by the treatment group. Main Outcome Measure(s): We measured ankle position and velocity in the frontal (x) and sagittal (y) planes in all subjects during treadmill walking and running for the periods 100 milliseconds before heel strike, at heel strike, and 100 milliseconds after heel strike. Results: A 4-week neuromuscular training program resulted in no significant changes in ankle position or velocity during treadmill walking and running. Conclusions: The mechanisms by which neuromuscular training improves function in normal subjects and those with functional ankle instability do not appear to result in measurable changes in gait kinematics. Our findings raise issues regarding methods of ankle sprain rehabilitation and the measurement of their effectiveness in improving functional activities. Further research in a larger population with functional ankle instability is necessary. PMID:17597944

S100β is associated with cognitive impairment in childhood-onset systemic lupus erythematosus patients.

PubMed

Lapa, A T; Postal, M; Sinicato, N A; Bellini, B S; Fernandes, P T; Marini, R; Appenzeller, S

2017-04-01

Objective To investigate serologic S100β protein levels in childhood-onset SLE patients (cSLE) and to elucidate their association with disease activity and neuropsychiatric (NP) manifestations. Methods We included 71 cSLE patients (67 females; median age 18 years; range 9-37 and 53 (47 females; median age of 20 years; range 6-29) age and sex matched healthy controls. Neurological manifestations were analysed according to the American College of Rheumatology (ACR) criteria. Cognitive evaluation was performed in all participants using Wechsler Intelligence Scale for Children (WISC-III) and Wechsler Adult Intelligence Scale (WAIS), according to age, and validated in Portuguese. SLE patients were further assessed for clinical and laboratory SLE manifestations, disease activity (SLE Disease Activity Index (SLEDAI)), damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)) and current drug exposures. Sera S100β protein levels were measured by enzyme-linked immunosorbent assay using commercial kits. Results The median S100β protein level was 116.55 pg/mL (range 1.53-468.50) in cSLE and 54.98 pg/mL (range 0.69-181.00) in healthy controls ( p < 0.001). An association was observed between S100β protein and NP manifestations ( p = 0.03). The S100β protein levels was associated with cognitive impairment in cSLE patients ( p = 0.006). Conclusions S100β protein levels are increased in cSLE with cognitive impairment. S100β may be considered a potential biomarker that underlies central nervous system (CNS) dysfunction, especially cognitive impairment.

S100A4 interacts with p53 in the nucleus and promotes p53 degradation.

PubMed

Orre, L M; Panizza, E; Kaminskyy, V O; Vernet, E; Gräslund, T; Zhivotovsky, B; Lehtiö, J

2013-12-05

S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild-type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin-induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes.

Low Frequency Seismo-Acoustic Propagation in a Sloping Ocean Environment: Measured Results and Numerical Predictions

DTIC Science & Technology

1987-11-01

15407 - 1525,1 m/s Cp = 1900 m/ s , op = 0,2, p= 1.8 L . Cp = 2340 m/ s . Op = 02, p= 1,9 Cp = 3000 m/ s . Op = 02, P = 2,2 Cj = 1500 m/s, oj = 02 Cp...4300 m/ s , op = 005, p = 24 Cc = 2150 m/s, o^ = 01 20 Figure 5. Geoacoustic input parameters for SAFARI model. 0.0 10.0 30.0 30.0 RANGE IKM

Serum S100B protein concentration in brain-dead organ donors: a pilot study.

PubMed

Krzych, Łukasz J; Czempik, Piotr Filip; Saucha, Wojciech; Kokocińska, Danuta; Knapik, Piotr

2015-01-01

Protein S100B is considered to be a marker of brain damage, but there is a paucity of data regarding the utility of its assessment in brain-dead organ donors. The aim of the study was to compare serum protein S100B concentrations between brain-dead organ donors and patients with a confirmed permanent neurological deficit but without signs of brain death. The concentration of serum S100B protein was measured in 12 brain-dead organ donors (including 7 males with a median age of 40 years). All measurements were taken when brain death was confirmed by the commission. Twenty-nine patients (including 13 males with a median age of 63 years) who died in the medical ICU with confirmed permanent brain injury without signs of brain death acted as controls. In these patients, S-100B protein measurements were performed upon ICU admission. In brain-dead organ donors, the median values of serum S100B protein were much higher in comparison to the control group (median and IQR, respectively: 5.04 μg L⁻¹; 1.775-6.765 vs 0.897 μg L⁻¹; 0.324-1.880, P < 0.001). S100B serum values > 1.81 μg L⁻¹ predicted brain death with the highest accuracy (AUROC = 0.83; 95% CI 0.68-0.93; P < 0.001). Concentrations of serum S100B protein in brain-dead organ donors are extremely high and may support the diagnosis of brain death. This fact may be of value when the presence of reflex movements (frequently reported despite brain death) might delay determination of brain death and result in the failure of organ donation.

Cancer Detection Rates in a Population-Based, Opportunistic Screening Model, New Delhi, India

PubMed Central

Shridhar, Krithiga; Dey, Subhojit; Bhan, Chandra Mohan; Bumb, Dipika; Govil, Jyostna; Dhillon, Preet K

2017-01-01

Background In India, cancer accounts for 7.3% of DALY’s, 14.3% of mortality with an age-standardized incident rate of 92.4/100,000 in men and 97.4/100,000 in women and yet there are no nationwide screening programs. Materials and Methods We calculated age-standardized and age-truncated (30-69 years) detection rates for men and women who attended the Indian Cancer Society detection centre, New Delhi from 2011-12. All participants were registered with socio-demographic, medical, family and risk factors history questionnaires, administered clinical examinations to screen for breast, oral, gynecological and other cancers through a comprehensive physical examination and complete blood count. Patients with an abnormal clinical exam or blood result were referred to collaborating institutes for further investigations and follow-up. Results A total of n=3503 were screened during 2011-12 (47.8% men, 51.6% women and 0.6% children <15 years) with a mean age of 47.8 yrs (±15.1 yrs); 80.5% were aged 30-69 years and 77.1% had at least a secondary education. Tobacco use was reported by 15.8%, alcohol consumption by 11.9% and family history of cancer by 9.9% of participants. Follow-up of suspicious cases yielded 45 incident cancers (51.1% in men, 48.9% in women), consisting of 55.5% head and neck (72.0% oral), 28.9% breast, 6.7% gynecological and 8.9% other cancer sites. The age-standardized detection rate for all cancer sites was 340.8/100,000 men and 329.8/100,000 women. Conclusions Cancer screening centres are an effective means of attracting high-risk persons in low-resource settings. Opportunistic screening is one feasible pathway to address the rising cancer burden in urban India through early detection. PMID:25773793

High-performance liquid chromatographic determination of pyridostigmine bromide, nicotine, and their metabolites in rat plasma and urine.

PubMed

Abu-Qare, A W; Abou-Donia, M B

2001-07-01

This study reports on the development of a rapid and simple method for the determination of the antinerve agent drug pyridostigmine bromide (3-dimethylaminocarbonyloxy-N-methyl pyridinium bromide) (PB), its metabolite N-methyl-3-hydroxypyridinium bromide, nicotine (S-1-methyl-5-(3-pyridyl)-2-pyrrolidine), and its metabolites nornicotine (2-(3-pyridyl)pyrrolidine) and cotinine (S-1-methyl-5-(3-pyridyl)-2-pyrrolidone) in rat plasma and urine. The compounds are extracted and eluted by methanol and acetonitrile using C18 Sep-Pak cartridges and separated using high-performance liquid chromatography by a gradient of methanol, acetonitrile, and water (pH 3.2) at a flow rate of 0.8 mL/min in a period of 14 min. UV detection was at 260 nm for nicotine and its metabolites and at 280 nm for PB and its metabolite. The limits of detection ranged between 20 and 70 ng/mL, and the limits of quantitation were 50-100 ng/mL. The average percent recovery of five spiked plasma samples were 85.7 +/- 7.3%, 80.4 +/- 5.8%, 78.9 +/- 5.4%, 76.7 +/- 6.4%, and 79.7 +/- 5.7% and for urine were 85.9 +/- 5.9%, 75.5 +/- 6.9%, 82.6 +/- 7.9%, 73.6 +/- 5.9%, and 77.7 +/- 6.3% for nicotine, nornicotine, cotinine, PB, and N-methyl-3-hydroxypyridinium bromide, respectively. The calibration curves for standard solutions of the compounds of peak areas and concentration are linear for a range between 100 and 1,000 ng/mL. This method is applied in order to analyze the previously mentioned chemicals and metabolites following their oral administration in rats.

Role of S100A12 in the pathogenesis of osteoarthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakashima, Motoshige; Sakai, Tadahiro, E-mail: tadsakai@med.nagoya-u.ac.jp; Hiraiwa, Hideki

Highlights: Black-Right-Pointing-Pointer This is the first report of S100A12 expression in human OA articular cartilages. Black-Right-Pointing-Pointer Exogenous S100A12 increased the production of MMP13 and VEGF in OA chondrocytes. Black-Right-Pointing-Pointer Soluble RAGE suppressed the increased production of MMP13 and VEGF. Black-Right-Pointing-Pointer p38MAPK and NF-{kappa}B inhibitors abrogated S100A12-induced MMP13 and VEGF production. Black-Right-Pointing-Pointer S100A12 may contribute to OA progression by increasing MMP13 and VEGF production. -- Abstract: S100A12 is a member of the S100 protein family, which are intracellular calcium-binding proteins. Although there are many reports on the involvement of S100A12 in inflammatory diseases, its presence in osteoarthritic cartilage has not beenmore » reported. The purpose of this study was to investigate the expression of S100A12 in human articular cartilage in osteoarthritis (OA) and to evaluate the role of S100A12 in human OA chondrocytes. We analyzed S100A12 expression by immunohistochemical staining of cartilage samples obtained from OA and non-OA patients. In addition, chondrocytes were isolated from knee cartilage of OA patients and treated with recombinant human S100A12. Real-time RT-PCR was performed to analyze mRNA expression. Protein production of matrix metalloproteinase 13 (MMP-13) and vascular endothelial growth factor (VEGF) in the culture medium were measured by ELISA. Immunohistochemical analyses revealed that S100A12 expression was markedly increased in OA cartilages. Protein production and mRNA expression of MMP-13 and VEGF in cultured OA chondrocytes were significantly increased by treatment with exogenous S100A12. These increases in mRNA expression and protein production were suppressed by administration of soluble receptor for advanced glycation end products (RAGE). Both p38 mitogen-activated protein kinase (MAPK) and nuclear factor-{kappa}B (NF-{kappa}B) inhibitors also suppressed the increases in mRNA expression and protein production of MMP-13 and VEGF. We demonstrated marked up-regulation of S100A12 expression in human OA cartilages. Exogenous S100A12 increased the production of MMP-13 and VEGF in human OA chondrocytes. Our data indicate the possible involvement of S100A12 in the development of OA by up-regulating MMP-13 and VEGF via p38 MAPK and NF-{kappa}B pathways.« less

Gene expression profiling reveals distinct molecular signatures associated with the rupture of intracranial aneurysm.

PubMed

Nakaoka, Hirofumi; Tajima, Atsushi; Yoneyama, Taku; Hosomichi, Kazuyoshi; Kasuya, Hidetoshi; Mizutani, Tohru; Inoue, Ituro

2014-08-01

The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA. We determined gene expression levels of 8 RIAs, 5 unruptured IAs, and 10 superficial temporal arteries with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns, using clustering methods. The clustering analysis identified 4 groups: superficial temporal arteries and unruptured IAs were aggregated into their own clusters, whereas RIAs segregated into 2 distinct subgroups (early and late RIAs). Comparing gene expression levels between early RIAs and unruptured IAs, we identified 430 upregulated and 617 downregulated genes in early RIAs. The upregulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (S100A8, S100A9, and S100A12). The downregulated genes suggest mechanical weakness of aneurysm walls. The expressions of Krüppel-like family of transcription factors (KLF2, KLF12, and KLF15), which were anti-inflammatory regulators, and CDKN2A, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also downregulated. We demonstrate that gene expression patterns of RIAs were different according to the age of patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets. © 2014 American Heart Association, Inc.

A Collaboration Network Model Of Cytokine-Protein Network

NASA Astrophysics Data System (ADS)

Zou, Sheng-Rong; Zhou, Ta; Peng, Yu-Jing; Guo, Zhong-Wei; Gu, Chang-Gui; He, Da-Ren

2008-03-01

Complex networks provide us a new view for investigation of immune systems. We collect data through STRING database and present a network description with cooperation network model. The cytokine-protein network model we consider is constituted by two kinds of nodes, one is immune cytokine types which can be regarded as collaboration acts, the other one is protein type which can be regarded as collaboration actors. From act degree distribution that can be well described by typical SPL (shifted power law) functions [1], we find that HRAS, TNFRSF13C, S100A8, S100A1, MAPK8, S100A7, LIF, CCL4, CXCL13 are highly collaborated with other proteins. It reveals that these mediators are important in cytokine-protein network to regulate immune activity. Dyad in the collaboration networks can be defined as two proteins and they appear in one cytokine collaboration relationship. The dyad act degree distribution can also be well described by typical SPL functions. [1] Assortativity and act degree distribution of some collaboration networks, Hui Chang, Bei-Bei Su, Yue-Ping Zhou, Daren He, Physica A, 383 (2007) 687-702

Enteric glial-derived S100B protein stimulates nitric oxide production in celiac disease.

PubMed

Esposito, Giuseppe; Cirillo, Carla; Sarnelli, Giovanni; De Filippis, Daniele; D'Armiento, Francesco Paolo; Rocco, Alba; Nardone, Gerardo; Petruzzelli, Raffaella; Grosso, Michela; Izzo, Paola; Iuvone, Teresa; Cuomo, Rosario

2007-09-01

Enteric glia participates to the homeostasis of the gastrointestinal tract. In the central nervous system, increased expression of astroglial-derived S100B protein has been associated with the onset and maintaining of inflammation. The role of enteric glial-derived S100B protein in gastrointestinal inflammation has never been investigated in humans. In this study, we evaluated the expression of S100B and its relationship with nitric oxide production in celiac disease. Duodenal biopsy specimens from untreated and on gluten-free diet patients with celiac disease and controls were respectively processed for S100B and inducible nitric oxide synthase (iNOS) protein expression and nitrite production. To evaluate the direct involvement of S100B in the inflammation, control biopsy specimens were exposed to exogenous S100B, and iNOS protein expression and nitrite production were measured. We also tested gliadin induction of S100B-dependent inflammation in cultured biopsy specimens deriving from on gluten-free diet patients in the absence or presence of the specific S100B antibody. S100B messenger RNA and protein expression, iNOS protein expression, and nitrite production were significantly increased in untreated patients but not in on gluten-free diet patients vs controls. Addition of S100B to control biopsy specimens resulted in a significant increase of iNOS protein expression and nitrite production. In celiac disease patients but not in controls biopsy specimens, gliadin challenge significantly increased S100B messenger RNA and protein expression, iNOS protein expression, and nitrite production, but these effects were completely inhibited by S100B antibody. Enteric glial-derived S100B is increased in the duodenum of patients with celiac disease and plays a role in nitric oxide production.

Base (100-year) flood elevations for selected sites in Marion County, Missouri

USGS Publications Warehouse

Southard, Rodney E.; Wilson, Gary L.

1998-01-01

The primary requirement for community participation in the National Flood Insurance Program is the adoption and enforcement of floodplain management requirements that minimize the potential for flood damages to new construction and avoid aggravating existing flooding conditions. This report provides base flood elevations (BFE) for a 100-year recurrence flood for use in the management and regulation of 14 flood-hazard areas designated by the Federal Emergency Management Agency as approximate Zone A areas in Marion County, Missouri. The one-dimensional surface-water flow model, HEC-RAS, was used to compute the base (100-year) flood elevations for the 14 Zone A sites. The 14 sites were located at U.S., State, or County road crossings and the base flood elevation was determined at the upstream side of each crossing. The base (100-year) flood elevations for BFE 1, 2, and 3 on the South Fork North River near Monroe City, Missouri, are 627.7, 579.2, and 545.9 feet above sea level. The base (100-year) flood elevations for BFE 4, 5, 6, and 7 on the main stem of the North River near or at Philadelphia and Palmyra, Missouri, are 560.5, 539.7, 504.2, and 494.4 feet above sea level. BFE 8 is located on Big Branch near Philadelphia, a tributary to the North River, and the base (100-year) flood elevation at this site is 530.5 feet above sea level. One site (BFE 9) is located on the South River near Monroe City, Missouri. The base (100-year) flood elevation at this site is 619.1 feet above sea level. Site BFE 10 is located on Bear Creek near Hannibal, Missouri, and the base (100-year) elevation is 565.5 feet above sea level. The four remaining sites (BFE 11, 12, 13, and 14) are located on the South Fabius River near Philadelphia and Palmyra, Missouri. The base (100-year) flood elevations for BFE 11, 12, 13, and 14 are 591.2, 578.4, 538.7, and 506.9 feet above sea level.

Expression of S100 protein and protective effect of arundic acid on the rat brain in chronic cerebral hypoperfusion.

PubMed

Ohtani, Ryo; Tomimoto, Hidekazu; Wakita, Hideaki; Kitaguchi, Hiroshi; Nakaji, Kayoko; Takahashi, Ryosuke

2007-03-02

S100 protein is expressed primarily by astroglia in the brain, and accumulates in and around the ischemic lesions. Arundic acid, a novel astroglia-modulating agent, is neuroprotective in acute cerebral infarction, whereas the protective effects remain unknown during chronic cerebral hypoperfusion. Rats undergoing chronic cerebral hypoperfusion were subjected to a bilateral ligation of the common carotid arteries, and were allowed to survive for 3, 7 and 14 days. The animals received a daily intraperitoneal injection of 5.0, 10.0 or 20.0 mg/kg of arundic acid, or vehicle, for 14 days. Alternatively, other groups of rats received a delayed intraperitoneal injection of 20.0 mg/kg of arundic acid or vehicle, which started from 1, 3 or 7 days after ligation and continued to 14 days. The degree of white matter (WM) lesions and the numerical density of S100 protein-immunoreactive astroglia were estimated. In the WM of rats with vehicle injections, the number of S100 protein-immunoreactive astroglia increased significantly after chronic cerebral hypoperfusion as compared to the sham-operation. A dosage of 10.0 and 20.0 mg/kg of arundic acid suppressed the numerical increase in S100 protein-immunoreactive astroglia and the WM lesions. These pathological changes were suppressed with delayed treatment up to 7 days in terms of astroglial activation, and up to 3 days in terms of the WM lesions. The protective effects of arundic acid against WM lesions were demonstrated in a dose-dependent manner, and even after postischemic treatments. These results suggest the potential usefulness of arundic acid in the treatment of cerebrovascular WM lesions.

S100A6 Protein Negatively Regulates CacyBP/SIP-Mediated Inhibition of Gastric Cancer Cell Proliferation and Tumorigenesis

PubMed Central

Zhang, Kun; Liang, Jie; Chuai, Yucai; Li, Yuan; Wang, Xiaoming

2012-01-01

Calcyclin-binding protein (CacyBP/SIP), identified on the basis of its ability to interact with S100 proteins in a calcium-dependent manner, was previously found to inhibit the proliferation and tumorigenesis of gastric cancer cells in our laboratory. Importantly, the effects of S100 proteins on the biological behavior of CacyBP/SIP in gastric cancer remain unclear. Herein, we report the construction of eukaryotic expression vectors for wild-type CacyBP/SIP and a truncated mutant lacking the S100 protein binding domain (CacyBP/SIPΔS100). The expressions of the wild-type and truncated recombinant proteins were demonstrated by transfection of MKN45 gastric cancer cells. Co-immunoprecipitation assays demonstrated interaction between S100A6 and wild-type CacyBP/SIP in MKN45 cells. Removal of the S100 protein binding domain dramatically reduced the affinity of CacyBP/SIP for S100 proteins as indicated by reduced co-immunoprecipitation of S100A6 by CacyBP/SIPΔS100. The MTT assay, FACS assay, clonogenic assay and tumor xenograft experiment were performed to assess the effect of CacyBP/SIP on cell growth and tumorigenesis in vitro and in vivo. Overexpression of CacyBP/SIP inhibited the proliferation and tumorigenesis of MKN45 gastric cancer cells; the proliferation and tumorigenesis rates were even further reduced by the expression of CacyBP/SIPΔS100. We also showed that S100 proteins negatively regulate CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation, through an effect on β-catenin protein expression and transcriptional activation of Tcf/LEF. Although the underlying mechanism of action requires further investigation, this study provides new insight into the interaction between S100 proteins and CacyBP/SIP, which might enrich our knowledge of S100 proteins and be helpful for our understanding of the development of gastric cancer. PMID:22295074

Willingness to pay for an Ebola vaccine during the 2014-2016 ebola outbreak in West Africa: Results from a U.S. National sample.

PubMed

Painter, Julia E; von Fricken, Michael E; Viana de O Mesquita, Suyane; DiClemente, Ralph J

2018-01-15

The 2014-2016 Ebola virus outbreak in West Africa led to advances in the development of vaccines against Ebola. This study examined factors associated with willingness to pay for an Ebola vaccine among a U.S. national sample during the recent Ebola outbreak. From April 30-May 8, 2015, a national survey was conducted using the GfK Group's KnowlegePanel®. Main outcome measures included willingness to pay at least $1; more than $50; and more than $100 for an Ebola vaccine. Analyses were conducted using weighted multivariable logistic regression. Among participants (N = 1,447), 583 (40.3%) would not pay for an Ebola vaccine; 864 (59.7%) would pay at least $1. Among those willing to pay at least $1: 570 (66.0%) would pay $1-50; 174 (20.1%) would pay $51-100; and 120 (13.9%) would pay more than $100. Willingness to pay at least $1 for an Ebola vaccine was associated with international travel; interest in getting an Ebola vaccine; and beliefs that the U.S. government should spend money to control Ebola and assume worldwide leadership in confronting emerging epidemics. Willingness to pay more than $50 was associated with similar variables. Willingness to pay more than $100 was associated with international travel; interest in getting an Ebola vaccine; information seeking; and beliefs that the U.S. government should assume worldwide leadership in confronting emerging epidemics. International travel and interest in an Ebola vaccine were key predictors of willingness to pay across all price points. Understanding willingness to pay for vaccines against emerging infectious diseases remains critical.

S100A4 amplifies TGF-β-induced epithelial-mesenchymal transition in a pleural mesothelial cell line.

PubMed

Ning, Qian; Li, Feiyan; Wang, Lei; Li, Hong; Yao, Yan; Hu, Tinghua; Sun, Zhongmin

2018-02-01

Pleural fibrosis can dramatically lower the quality of life. Numerous studies have reported that epithelial-mesenchymal transition (EMT) regulated by transforming growth factor-β (TGF-β) is involved in fibrosis. However, the molecular mechanism is inadequately understood. Fibroblast-specific protein-1 (S100A4) is a target of TGF-β signaling. In our previous study, we have reported that S100A4 is highly expressed in pleural fibrosis. Thus, we suggest that S100A4 took part in the TGF-β-induced EMT in pleural fibrosis. In this study, we determined the expression of S100A4 and EMT-related markers in Met-5A cells (pleural mesothelial cells) treated with TGF-β or TGF-β inhibitor by real-time PCR and western blot. In order to explore the role of S100A4, we used siRNA to knock down the expression of S100A4 in cell model. We found that the expression of epithelial cell marker was decreased and the mesenchymal cell marker increased with S100A4 upregulation after treatment with TGF-β. Moreover, the changes of EMT-related event were restricted when the expression of S100A4 was knocked down. Conversely, S100A4 can partially rescue the EMT-related expression changes induced by TGF-β inhibitor. These findings suggest that S100A4 expression is induced by the TGF-β pathway, and silencing S100A4 expression can inhibit the process of TGF-β-induced EMT. © American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

High Voltage Design Guide. Volume IV. Aircraft

DTIC Science & Technology

1983-01-01

35.5 35.5 354 XS 80 42.5 M 46 05 70.5 70.5 70.5 70.5 70.5 70.5 70.5 70.5 70.5 100 90. 60.0 74 8 9 89 as Be 89 Be 89 s9 s9 20 98.0 103 120 160 168 170 170...THE GAS PRESSURE IS 1 ATM. 41 400 400 350 SF6 -N2 1 100%SF 6 350 SF6 .AIR 2= 50% SF 6 UNIFORM FIELD .00 3- 20% SF6 D4=I 3%SF, 00 1cm SPACING 5 A0...BREAKDOWN VOLTAGES AS A FIGURE 118 BREAKDOWN VOLTAGES AS A FUNCTION OF GAS PRESSURE FUNCTION OF GAS PRESSURE MIXTURES FOR SF6 -AR MIXTURES 400 SF 6 "C02 350

Improved efficacy of intramuscular weekly administration of clodronate 200 mg (100 mg twice weekly) compared with 100 mg (once weekly) for increasing bone mineral density in postmenopausal osteoporosis.

PubMed

Frediani, Bruno; Bertoldi, Ilaria; Pierguidi, Serena; Nicosia, Antonella; Picerno, Valentina; Filippou, Georgios; Cantarini, Luca; Galeazzi, Mauro

2013-03-01

Clodronate is a bisphosphonate used for the treatment of postmenopausal osteoporosis and all conditions characterized by excess bone resorption. We have previously reported that intramuscular (IM) therapy with clodronate at a dose of 100 mg/week displays significant effects on bone mineral density (BMD) although a plateau effect is observed after 1 year of treatment. Previous reports indicate that the densitometric effects of bisphosphonates directly correlate with the drug dosage and suggest that using IM clodronate at doses higher than 100 mg/week may result in improved efficacy. However, to the best of our knowledge, this has never been proved. The primary endpoint of the study was the effect on BMD of IM clodronate 100 mg once weekly or 100 mg twice weekly in patients with postmenopausal osteoporosis. The incidence of non-traumatic vertebral fractures and adverse events was also reported. The present study was a randomized, open-label, parallel-group trial conducted between January 2007 and December 2009 in the Osteoporosis and Osteoarticular Instrumental Diagnosis Centre (University of Siena, Siena, Italy). The study involved 60 women, aged 57-78 years, with a history of postmenopausal osteoporosis for more than 5 years. Patients were randomized to receive IM clodronate 100 mg once weekly (Group A, 30 patients) or 100 mg twice weekly (Group B, 30 patients), for 2 years. Significant increases compared with baseline in BMD were observed for both groups at 1 and 2 years, with significantly higher increases for Group B compared with Group A. Group B displayed a BMD increase (± SD) at the lumbar spine of +4.0 % (± 2.1) and +5.9 % (± 2.0) at 1 and 2 year(s), respectively, compared with +2.8 % (± 1.7) and +3.5 % (± 2.2), respectively, observed for Group A. Similarly, Group B showed better performance compared with Group A for BMD increase at the femoral neck, with an observed increase of +3.5 % (± 1.7) and +5.4 % (± 1.8) at 1 and 2 year(s), respectively, compared with a change of +2.3 % (± 1.9) and +2.5 % (± 1.9), respectively, registered in Group A. Consistently, the BMD increase measured at the total femur was significantly higher for Group B [+3.4 % (± 1.9) and +4.9 % (± 2.1) at years 1 and 2, respectively] compared with Group A [+1.6 % (± 0.9) and +2.4 % (± 1.9) at years 1 and 2, respectively]. When the change in BMD from year 1 to year 2 was compared, a significant increase of BMD was seen in Group B in all the analysed regions, contrary to that observed for Group A where a plateau effect resulted in no significant change from year 1 to year 2. Three non-traumatic vertebral fractures occurred during the study: two in Group A and one in Group B. The present study indicates the superior performance of IM clodronate 200 mg weekly (100 mg twice weekly) compared with 100 mg once weekly in BMD in women with postmenopausal osteoporosis. This work demonstrated that administration of twice the drug dosage in a week significantly improved the efficacy of the treatment without inducing serious adverse events. Therefore, IM clodronate 200 mg weekly may be considered a valid therapeutic choice for the treatment of postmenopausal osteoporosis.

Overexpression of the S100A2 protein as a prognostic marker for patients with stage II and III colorectal cancer

PubMed Central

MASUDA, TAIKI; ISHIKAWA, TOSHIAKI; MOGUSHI, KAORU; OKAZAKI, SATOSHI; ISHIGURO, MEGUMI; IIDA, SATORU; MIZUSHIMA, HIROSHI; TANAKA, HIROSHI; UETAKE, HIROYUKI; SUGIHARA, KENICHI

2016-01-01

We aimed to identify a novel prognostic biomarker related to recurrence in stage II and III colorectal cancer (CRC) patients. Stage II and III CRC tissue mRNA expression was profiled using an Affymetrix Gene Chip, and copy number profiles of 125 patients were generated using an Affymetrix 250K Sty array. Genes showing both upregulated expression and copy number gains in cases involving recurrence were extracted as candidate biomarkers. The protein expression of the candidate gene was assessed using immunohistochemical staining of tissue from 161 patients. The relationship between protein expression and clinicopathological features was also examined. We identified 9 candidate genes related to recurrence of stage II and III CRC, whose mRNA expression was significantly higher in CRC than in normal tissue. Of these proteins, the S100 calcium-binding protein A2 (S100A2) has been observed in several human cancers. S100A2 protein overexpression in CRC cells was associated with significantly worse overall survival and relapse-free survival, indicating that S100A2 is an independent risk factor for stage II and III CRC recurrence. S100A2 overexpression in cancer cells could be a biomarker of poor prognosis in stage II and III CRC recurrence and a target for treatment of this disease. PMID:26783118

75 FR 7929 - Airworthiness Directives; Empresa Brasileira de Aeronautica S.A. (EMBRAER) Model ERJ 190-100 LR...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-23

... Directives; Empresa Brasileira de Aeronautica S.A. (EMBRAER) Model ERJ 190-100 LR, -100 IGW, -100 STD, -200 STD, -200 LR, and -200 IGW Airplanes AGENCY: Federal Aviation Administration (FAA), Department of... applies to Empresa Brasileira de Aeronautica S.A. (EMBRAER) Model ERJ 190-100 LR, -100 IGW, -100 STD, -200...

Implementation of a Shallow Groundwater Temperature Manipulation: Linking Hydrogeology, Biogeochemistry, and Aquatic Ecology

NASA Astrophysics Data System (ADS)

Wilson, K. P.; Williams, D. D.

2004-05-01

Integration of the fields of hydrogeology, biogeochemistry, and meiofaunal and microbial ecology is being used for a shallow groundwater temperature manipulation which simulates global climate change predictions. This study is being conducted on a first order spring-stream, Valley Spring, (southern Ontario, Canada) the headwater of which has been longitudinally divided to a sediment depth of -100 cm. To examine groundwater flow paths and hydraulic conductivity, and to collect physicochemical parameters and nutrient samples, a series of nested piezometers have been installed along three transects across the stream channel. Each nest evaluates water characteristics at depths of -20, -40, -60, -80, and -100 cm. Meiofaunal and microbial samples are collected, using a standpipe corer at the same depths as the piezometer openings. Sampling started in June 2002 and heating of one side of the groundwater began in March 2004. Hydraulic conductivity is heterogeneous with depth ranging from 0.0004 cm/s at -20 cm to 0.00002 cm/s at -100cm, but relatively uniform laterally, ranging from 0.0004 cm/s at 1 m to 0.0003 cm/s at 3 m from the stream channel. Pre-manipulation water temperatures decrease with depth in the summer, ranging from 14.5° C at the surface to 12.5° C at -100 cm. In contrast, temperature increases from 13.1 at the surface to 14.5° C at -100 cm in the fall. Temperature during the winter and spring are within 1.0° C from the surface to -100 cm, but range from 9.0-9.5° C in the winter and 8.0-7.0° C in the spring, respectively. Pre-manipulation nitrate concentrations are higher in winter (0.45 mg/l) then in summer (0.28 mg/l) and decrease with depth. Ammonia shows an inverse relationship, with lower concentrations in winter than summer (0.19 and 0.32 mg/l, respectively) and increase with depth. Dissolved organic carbon (DOC) also shows an increase with depth, ranging from 1.6 mg/l at the surface to 6.23 mg/l at -100 cm. Pre-manipulation meiofaunal abundance shows no difference between seasons but higher densities at -20cm then at all other depths. The most common meiofaunal taxa include Harpacticoida, Nematoda, Ostracoda, Chironomidae, Collembola, and Hydracarina. Plecoptera and Hymenoptera larvae are also found on occasion above -60 cm.