Plasma Osteopontin Levels Research Articles

Early Blood Biomarkers Distinguish Inflammation from Neonatal Hypoxic-Ischemia Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological outcomes. Reliable biomarkers which are both sensitive to hypoxic-ischemia and inflammation are critically needed. We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90min after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Two different HI severity groups (mild-HI with 75min hypoxia and severe-HI with 150min hypoxia) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN was significantly decreased (p < 0.001) but GFAP was slightly increased (p < 0.05) at 90min after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with the naïve group (all p < 0.05). Induced inflammation by LPS exaggerated neonatal HI brain injury. The plasma OPN and GFAP levels may be useful to differentiate HI alone groups from inflammation-sensitized HI groups or naïve group.

Osteopontin is a Prognostic Factor in Patients with Advanced Gastric Cancer.

Osteopontin (OPN), a phosphorylated sialoprotein, has been shown to overexpress in a variety of cancers and to contribute tumor progression and metastasis by increasing cell migration and adhesion. In the current study, we aimed to investigate the prognostic and predictive role of OPN in patients with advanced gastric cancer. A total of 42 consecutive chemonaive patients with advanced gastric cancer and 29 healthy controls were included. The patients were treated with a modified DCF regimen. The blood samples were obtained before each chemotherapy cycle from the patients and once from the healthy controls. The plasma OPN is measured by ELISA. The overall response and disease stabilization rates were 25% and 72%, respectively. The median serum OPN level of the patient group was significantly higher compared to healthy controls (176.9 ng/ml (range: 41.5 -521.4) vs 64.3 ng/ml (range 42.1-105.3 ng/ml), p<0.0001). The median overall survival time was 7.0 ± 1.1 (95% CI: 4.9-9.2) months and 1-year overall survival rate was 20.8%. The patients who responded to mDCF had lower plasma OPN levels than the non-responding ones (110.7±29.3 ng/mL, 211.9±24.4 ng/mL respectively, p=0.002). The performance status and the plasma OPN levels were found to be significant factors for overall survival in the multivariate analysis (p=0.004 and 0.016, respectively). The serum OPN seems to be a novel significant prognostic and predictive factor in patients with advanced gastric cancer who were treated with DCF regimen.

Patterns of Osteopontin Expression in Abusive Head Trauma Compared with Other Causes of Pediatric Traumatic Brain Injury

To examine levels of plasma osteopontin (OPN), a recently described neuroinflammatory biomarker, in children with abusive head trauma (AHT) compared with children with other types of traumatic brain injury (TBI). The study cohort comprised children aged <4years diagnosed with TBI and seen in the intensive care unit in a tertiary children's hospital. Patients were classified as having confirmed or suspected AHT or TBI by other mechanisms (eg, motor vehicle accidents), as identified by a Child Protection Team clinician. Serial blood samples were collected at admission and at 24, 48, and 72hours after admission. Levels of OPN were compared across groups. Of 77 patients identified, 24 had confirmed AHT, 12 had suspected AHT, and 41 had TBI. There were no differences in the Glasgow Coma Scale score between the patients with confirmed AHT and those with suspected AHT and those with TBI (median score, 4.5 vs 4 and 7; P=.39). At admission to the emergency department, OPN levels were significantly higher in children with confirmed AHT compared with the other 2 groups (mean confirmed AHT, 471.5ng/mL; median suspected AHT, 322.3ng/mL; mean TBI, 278.0ng/mL; P=.03). Furthermore, the adjusted mean trajectory levels of OPN were significantly higher in the confirmed AHT group compared with the other 2 groups across all subsequent time points (P = <.01). OPN is significantly elevated in children with confirmed AHT compared with those with suspected AHT and those with other types of TBI. OPN expression may help identify children with suspected AHT to aidresource stratification and triage of appropriate interventions for children who are potential victims of abuse.

Plasma Osteopontin Levels is Associated with Biochemical Markers of Kidney Injury in Patients with Leptospirosis.

Leptospirosis becomes severe, with a fatality rate of >10%, and manifests as severe lung injury accompanied by acute kidney injury. Using urine and blood samples of 112 patients with leptospirosis, osteopontin (OPN), galectin-9 (Gal-9) and other kidney-related biomarkers were measured to understand the pathological and diagnostic roles of OPN and Gal-9 in leptospirosis. Plasma levels of full-length (FL)-OPN (pFL-OPN) (p < 0.0001), pFL-Gal-9(p < 0.0001) and thrombin-cleaved OPN (p < 0.01) were significantly higher in patients with leptospirosis than in healthy controls (n = 30), as were levels of several indicators of renal toxicity: serum cystatin C (p < 0.0001), urine N-acetyl-β-glucosaminidase (NAG)/creatinine (p < 0.05), and urine clusterin/creatinine (p < 0.05). pFL-Gal-9 levels were negatively correlated with pFL-OPN levels (r = −0.24, p < 0.05). pFL-OPN levels were positively correlated with serum cystatin C (r = 0.41, p < 0.0001), urine NAG/creatinine (r = 0.35, p < 0.001), urine clusterin/creatinine (r = 0.33, p < 0.01), and urine cystatin C/creatinine (r = 0.33, p < 0.05) levels. In a group of patients with abnormally high creatinine levels, significantly higher levels of serum cystatin C (p < 0.0001) and pFL-OPN (p < 0.001) were observed. Our results demonstrate that pFL-OPN reflect kidney injury among patients with leptospirosis.

P1403PLASMA OSTEOPONTIN LEVELS DIRECTLY CORRELATE WITH INTACT PARATHYROID HORMONE AND ALKALINE PHOSPHATE LEVELS IN END STAGE RENAL DISEASE

Abstract Background and Aims Bone turnover disorders and reduction in bone mineral density are commonly observed in end stage renal disease (ESRD) patients. Osteopontin (OPN) is a glycol-phosphoprotein that stimulates osteoclast adhesion to bone. OPN may play a significant role in the pathways involved in bone turnover disorders. The objective of this study was: (1) to identify plasma levels of OPN in ESRD and normal populations, and (2) to elucidate if relationships exist between OPN and iPTH, and OPN and alkaline phosphatase. Method Plasma levels of OPN were measured via commercially available enzyme linked immunosorbent assays (ELISAs) in ESRD patients (n=92). A chart review was conducted on these patients to identify levels of intact parathyroid hormone (iPTH) and alkaline phosphatase at time of plasma draw. Additionally, levels of total calcium, albumin, calcium corrected for albumin, phosphorus, ferritin, white blood cell count (WBC), and platelet count (PLT CT) were identified at time of plasma draw via the chart review. OPN levels were also measured in normal control patient plasma (n = 49) purchased from George King Bio-Medical, Inc., Overland Park, KS. Results The ESRD cohort showed a statistically significant elevation of OPN plasma levels (p &amp;lt; 0.0001, Mann-Whitney t-test) compared to the normal group. Spearman correlation tests revealed a significant positive correlation of OPN with iPTH (p &amp;lt; 0.0001; r = 0.5606, 95% confidence interval = 0.3968 to 0.6898) and OPN with alkaline phosphatase (p &amp;lt; 0.0001; r = 0.4381, 95% confidence interval = 0.2494 to 0.5948) in the ESRD cohort. No statistically significant correlations were identified between OPN and total calcium, calcium corrected for albumin, albumin, phosphorus, ferritin, WBC, and PLT CT (p &amp;gt; 0.05). Conclusion OPN levels are significantly elevated in ESRD patients. Furthermore, OPN levels were also found to be positively correlated with the bone turnover biomarkers iPTH and alkaline phosphatase. These studies suggest that hyperparathyroidism secondary to ESRD increases circulating iPTH, stimulating osteoblast and osteoclast activation and differentiation that increases alkaline phosphatase and OPN production, ultimately resulting in increased bone turnover.

Early osteopontin levels predict mortality in patients with septic shock

BackgroundInflammatory biomarkers could be useful to stratify the risk of sepsis adverse outcome and potentially improving the clinical management. Here, we investigated the prognostic role of the inflammatory molecule osteopontin (OPN) in patients with severe sepsis with and without septic shock. Material and methodsThis is a sub-analysis of 957 patients with sepsis/septic shock from the Albumin Italian Outcome Sepsis (ALBIOS) study. Alongside demographic, clinical, and laboratory data, we assessed plasmatic values of OPN at day 1, 2 and 7 after enrolment. The primary outcome was the predictive role of OPN values at day 1on death for any cause at 28 days after enrolment. ResultsPlasma OPN values at day 1 were higher in patients with septic shock and correlated with the severity of multi-organ dysfunction. Once categorized for 28-day mortality, survivors were characterized by lower OPN levels at each time point and statistically significant drop overtime (p<0.001 for all). Similarly, OPN reduction during the first 7 days was associated with reduced hospitalization and mortality overtime. Multivariate logistic and Cox regression models confirmed plasma OPN at day 1 as predictor of both 28- and 90-day mortality and infection resolution as well, independently of demographic, clinical and therapeutic variables. However, this prognostic value was limited to septic shock patients. ConclusionsIn patients with septic shock, OPN plasma levels at day 1 predict a poor clinical outcome. These results provide the rationale for future pathophysiological studies aimed at clarifying the mechanisms triggered by OPN in septic shock (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).

Osteopontin as novel biomarker for reversibility of pressure overload induced left ventricular hypertrophy.

Aim: The aim of this study was to evaluate the prognostic value of osteopontin (OPN) as a marker for left ventricular (LV)hypertrophy and its reversibility after surgical aortic valve replacement (SAVR). Patients & methods: Echocardiographic data and OPN plasma levels of 149 consecutive patients undergoing SAVR were obtained preoperatively and 3 months postoperatively. OPN was measured by Quantikine Human OPN immunoassay. Results: There was a significant correlation between higher OPN plasma levels and lower LV-mass regression. In patients receiving SAVR combined with coronary artery bypass grafting, high OPN plasma levels were also an indicator for eccentric hypertrophy phenotype. Conclusion: OPN may be a useful indicator for LV hypertrophy phenotype and could have a prognostic value to estimate LV-mass regression after SAVR.

Plasma levels of osteopontin from birth to adulthood.

Osteopontin (OPN) has been investigated as a biomarker for cancer and nonmalignant diseases during the last decades. Data about OPN as a potential biomarker in childhood diseases are still sparse, and reference values are not available in children. We aimed to establish reference values for children from birth to young adulthood and evaluate whether there are age-, gender-, and weight-specific differences. Umbilical cord blood and blood plasma samples of 117 children were collected in the Children's Hospital of Saarland University in Homburg/Saar. OPN levels were measured by ELISA, and statistical analysis was performed using SPSS software. Neonates, infants, toddlers, young children, adolescents, and adults were divided into the following six age groups: newborns (birth), infancy and toddlers (0-24 months), early childhood (3-6 years), middle childhood (7-11 years), adolescence (12-18 years), and adults (>18 years). Highest blood OPN levels were found in the group of 0-1 years of age. OPN blood levels declined significantly with age (Spearman r=-0.874; P<0.001). Our work is the first prospective and systematic study analyzing OPN cord blood and blood plasma levels in children of all ages. It is the first study yielding reference values for different age groups from birth to young adulthood. Our data give insight on how OPN in umbilical cord blood and OPN in blood plasma are physiologically influenced during childhood development and growth with high OPN levels after birth and a constant age-related decline until the age of 14, when OPN levels reach similar values to those measured in adults.

Plasma osteopontin levels in patients with acute kidney injury requiring dialysis: a study in a tertiary care institute in South India.

Osteopontin (OPN) is evolving as a novel biomarker of injury, overall survival and renal outcome in critically ill patients with acute kidney injury (AKI), requiring renal replacement therapy. We performed a prospective study on 35 consecutive patients of acute kidney injury requiring renal replacement therapy (AKIN stage 3). OPN levels were measured in the patients and in the controls. The relation between OPN and the severity of illness and its effect on the AKI and renal outcome were studied. There was a statistically significant elevation of OPN in patients of AKIN stage 3 in comparison to healthy controls (p = 0.001). The Sequential Organ Function Assessment (SOFA) scores were found to be higher in septic group in comparison to non-septic group and it was statistically significant (p = 0.014). There was significant correlation between SOFA scoring and OPN levels suggesting its association with severity (r = 0.382, p = 0.023). In our study, OPN was found to be a valuable marker of severity of injury, its association with sepsis and renal recovery, in patients with acute kidney injury needing renal replacement therapy.

Association of Circulating Osteopontin Levels With Lower Extremity Arterial Disease in Subjects With Type 2 Diabetes Mellitus: A Cross-Sectional Observational Study

Osteopontin (OPN) is involved in the atherosclerotic and inflammatory process. In this article, we examined the relationship between circulating OPN levels with lower extremity arterial disease (LEAD) in individuals with type 2 diabetes mellitus (T2DM). Seventy individuals with T2DM and 66 individuals without T2DM were recruited. Diagnosis of LEAD was based on the absence of triphasic waveform on the pedal arteries. Plasma OPN levels were determined by Luminex Multiplex immunoassay. LEAD was present in 34 (48.6%) patients with T2DM. In the diabetes cohort, individuals with LEAD had higher plasma OPN concentrations than those without LEAD (geometric mean [95% confidence intervals]; 43.4 [37.5-50.4] vs 26.1 [22.9-29.8] ng/mL, respectively, P < .001). Multivariable analysis showed that presence of LEAD independently associated with higher OPN levels in subjects with T2DM, with marginal statistical significance (P = .049). In both cohorts, plasma OPN concentrations were negatively associated with ankle-brachial index values (P < .05). In the total sample, there was a gradual increase of OPN levels across subgroups with triphasic, biphasic, and monophasic/blunted waveforms (P < .001). In conclusion, plasma OPN levels are associated with the presence and severity of LEAD in subjects with T2DM. Further studies are needed to investigate the role of OPN in the pathogenesis and progression of LEAD.

Evaluation of plasma Osteopontin level in relapsing- remitting multiple sclerosis patients compared to healthy subjects in Isfahan Province

Background: Multiple sclerosis (MS) is known as a neuroinflammatory disease of the central nervous system (CNS). The neuroinflammation may induce pro-inflammatory cytokines such as Osteopontin (OPN). OPN plays an important role in the inflammation by modulating the T helper1 (Th1) and Th17 responses. Since the exact immune pathogenesis of MS is complex and not well defined and many factors are involved, the need to detect more contributing biomarkers may help in setting new therapeutic strategies.Objective: This study tried to compare plasma OPN levels in relapsing- remitting multiple sclerosis (RRMS) patients during the remission phase with healthy subjects in Isfahan province.Materials and methods: In a case-control study, plasma was collected from the 40 RRMS as well as 38 (age and sex matched) healthy individuals as a control group. PlasmaOPN level was measured and compared between the two groups by Enzyme-linked immunosorbent assays (ELISA).Result: Statistical analysis revealed that plasma OPN level was markedly higher in the case group (RRMS patients during the remission phase) compared with the control group (P- value = 0.039). Our results also showed that there was no statistically significant difference in mean of plasma OPN level among RRMS patients who were treated with interferon (IFN)-ß and those who were not (P- value = 0.332). There was also no correlation between OPN plasma level and EDSS score (r = 0.037, P- value = 0.835), age of onset (r = 0.161, P- value = 0.357) and duration of disease (r = 0.121, P- value = 0.490).Conclusion: Higher OPN plasma level in studied patients suggests that OPN increased in RRMS patients who were in remission phase. It could be hypothesized that plasma OPN level may be increased as part of the pro-inflammatory cytokine milieu taking place in MS patients. OPN may not be specific marker for MS, but targeting it might present promising therapeutic effect to MS patients.

Beneficial effects of anti-RANKL antibody in depression-like phenotype, inflammatory bone markers, and bone mineral density in male susceptible mice after chronic social defeat stress

Multiple lines of evidence suggest a link between depression and osteoporosis in elderly people. Receptor activator of nuclear factor-κB ligand (RANKL) plays a role in the pathology of osteoporosis, and anti-RANKL antibody has been used in the treatment of osteoporosis. In this study, we investigated whether anti-mouse RANKL antibody could attenuate depression-like phenotypes, inflammatory bone markers and bone mineral density (BMD) in male susceptible mice after chronic social defeat stress (CSDS). We measured plasma levels of inflammatory bone markers, including osteoprotegerin (OPG), RANKL, and osteopontin. A single intravenous injection of anti-RANKL (2 mg/kg) elicited rapid antidepressant effects in CSDS susceptible mice. Furthermore, anti-RANKL significantly improved the increased plasma levels of RANKL and decreased OPG/RANKL ratio in CSDS susceptible mice. Moreover, anti-RANKL significantly attenuated the decreased BMD in CSDS susceptible mice. Interestingly, there is a positive correlation between anhedonia-like behavior and OPG/RANKL ratio in mice. These findings demonstrate that anti-RANKL may have beneficial effects in depression-like phenotype and abnormalities in bone functions of CSDS susceptible mice. It is, therefore, likely that anti-human RANKL antibody (i.e., Denosumab) would be a potential therapeutic drug for depression and osteoporosis.

Preliminary observation of chemokine expression in patients with Stanford type A aortic dissection

Stanford type A Aortic dissection (TAAD) is a deadly cardiovascular disease but the relationship between inflammatory cytokines and disease pathogenesis is still unclear. Observation of the changes of different chemokines may help to explore the etiology of TAAD much further. Clinical data was collected from TAAD patients (TAAD group) and healthy controls (HC group) in our institute between October 2013 and December 2014. Blood sample was harvested from each subject of two groups. The expression levels of eighty chemokines were examined by protein array technology. Then we tested the expressions of macrophage inflammatory protein 1β (MIP-1β), epithelial neutrophil activating peptide 78 (ENA-78), interleukin 16 (IL-16), interferon inducible protein 10 (IP-10), and FMS-like tyrosine kinase 3 (Flt-3) ligand by using luminex technology. Osteopontin (OPN) and monocyte chemotaxis protein (MCP) levels were analyzed by ELISA kits. The mean age of TAAD group is 49.9 ± 11.2 and 48.7 ± 9.9 in HC group, respectively. 76.0% of TAAD patients and 72.0% of healthy controls were male. MIP-1β and ENA-78 expression in TAAD group were significantly lower than that in HC group, while significant increasing IL-16 level was found. Plasma levels of OPN in TAAD group increased remarkably compared with HC group, but MCP-1 and MCP-2 expression significantly decreased. No correlation was shown between serum CRP levels and plasma level of these cytokines by using Spearman analysis. ROC analysis showed that OPN could be indicators for TAAD diagnosis with sensitivity of 0.92 and specificity of 0.99. Our results provide a reasonable way to focus on the chemokines in understanding the pathogenesis of human TAAD.

Increased plasma osteopontin levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus

Nonalcoholic fatty liver disease (NAFLD) commonly occurs in patients with type 2 diabetes mellitus (T2DM). Osteopontin (OPN) is a multifunctional protein with pleiotropic physiological functions. This study aimed to investigate the interrelation between circulating OPN and NAFLD in T2DM patients. Overall, 249 subjects were classified into 4 groups: 53 patients with NAFLD and T2DM; 57 with newly diagnosed T2DM; 59 with NAFLD; and 80 healthy age- and sex-matched controls. Serum OPN was measured by ELISA. The OPN distribution in the pooled data was divided into quartiles; significant trends across increasing quartiles were estimated by the Cochran-Armitage trend test. Compared with the controls, circulating OPN concentrations were significantly elevated in NAFLD patients and T2DM patients with or without NAFLD. Serum OPN levels were higher in the overweight/obese group than that in the lean group. Circulating OPN levels were positively correlated with CRP, age, BMI, SBP, DBP, HbA1c, UA, TGs, WBCs, neutrophils, FBG, and HOMA-IR and negatively correlated with ADP, albumin and HDL. Age, albumin, HbA1c, HDL and hsCRP were independently related to circulating OPN. The relative risks for NAFLD, T2DM and T2DM with NAFLD increased significantly along with increasing OPN quartiles based on the Cochran-Armitage trend test. OPN is an optimal predictor in the diagnosis of T2DM with NAFLD and T2DM and may contribute to the aggravation of the metabolic state.

Inhibition of inflammatory-molecule synthesis in THP-1 cells stimulated with phorbol 12-myristate 13-acetate by brefelamide derivatives

Plasma osteopontin (OPN) levels are elevated in tuberculosis patients and may involve granuloma formation. New inhibitors using brefelamide, an aromatic amide isolated from Dictyostelium cellular slime molds that may inhibit OPN transcription in A549 cells at 1 μM concentration, were synthesized as compounds C, D, and E. Their inhibitory activity against OPN synthesis in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells was confirmed using enzyme-linked immunosorbent assay (ELISA), a multicolor immune-fluorescent microscope, and western blot. In the ELISA performed using full-length OPN, each compound showed significant inhibition in culture supernatants with half maximal inhibitory concentration (IC50) values of 1.6, 1.8, and 2.2 μM for C, D, and E, respectively. In another ELISA to detect the immune-related form of OPN, IC50 values were 0.6, 1.2, and 2.5 μM for compounds C, D, and E, respectively. The decreases in OPN expression and synthesis were confirmed using immunofluorescence and western blot studies using compound-treated cells or cell lysates. Luminex assay of the supernatants of PMA-treated THP-1 cells showed significant reduction in the synthesis of interleukin (IL)-1β, galectin-9, and tumor necrosis factor (TNF)-α. Elucidation of the detailed mechanisms of the biological activities of these compounds would be necessary; however, they may be used in clinical trials for infectious diseases, inflammatory disorders, and cancer.

Correlation of plasma osteopontin and osteocalcin with lower renal function in dental patients with carotid artery calcification and tooth loss

ObjectivesTo investigate plasma osteopontin (OPN) and osteocalcin (OCN) levels in dental patients with carotid artery calcification (CAC) and determine the correlations between these proteins and renal function and tooth loss. MethodsThe health parameters and number of teeth of 99 participants were recorded. Panoramic radiographs were taken for CAC evaluation, and OPN and OCN levels were measured. ResultsNone of the participants had overt kidney disease, and 14 (14.14%) had CAC. The age, sex, and health profiles of patients with CAC were not different from those without CAC. The OPN and OCN levels in participants with CAC were higher than in those without (p = 0.026 and p = 0.025, respectively). The OPN levels were correlated with the estimated glomerular filtration rate (eGFR) (p = 0.021) and tooth loss (p = 0.027). The OCN levels were correlated with the eGFR (p = 0.002), tooth loss (p = 0.023), blood urea nitrogen (p = 0.040), and creatinine levels (p = 0.031). The median tooth loss in individuals with an eGFR <60 mL/min/1.73 m2 was higher than that of individuals with an eGFR ≥60 mL/min/1.73 m2 (p = 0.033). In individuals with CAC, tooth loss correlated more strongly with the eGFR, and the correlation between OPN and OCN levels was more apparent. ConclusionDental patients with CAC and increased tooth loss have a greater tendency for decreased renal function, which may be associated with OPN and OCN; thus, these patients should be referred for investigation.

High glucose upregulates osteopontin expression by FoxO1 activation in macrophages.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE-/- mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt -1918 ~ -713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.

Plasma osteopontin levels, but not its myocardial expression, reflect heart failure severity in recently diagnosed dilated cardiomyopathy.

Elevated levels of the extracellular matrix glycoprotein osteopontin (OPN) may be detected in both myocardium and plasma under various pathological conditions affecting the heart. Several studies demonstrated increased plasma OPN levels in patients with heart failure due to dilated cardiomyopathy (DCM), while other studies showed high OPN expression levels in the myocardium of such patients. However, very little is known about OPN levels in both plasma and myocardium of the same individual with DCM. Therefore, we aimed to compare plasma OPN levels and levels of myocardial OPN expression in patients with recent-onset DCM (Ro-DCM). We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain natriuretic peptide (BNP), and troponinI levels in 25patients with Ro-DCM. Furthermore, all subjects underwent transthoracic echocardiography, selective coronary angiography, and endomyocardial biopsy (EMB) for the assessment of myocardial OPN expression. No significant correlation between myocardial OPN expression and clinical, biochemical, or echocardiographic parameters was found. In log transformation analysis, plasma OPN levels correlated significantly with BNP levels (r = 0.46, p = 0.031), with CRP levels (r = 0.52, p = 0.015), and with early diastolic mitral annular velocity (r = -0.57, p = 0.009). There was aborderline association between the plasma OPN log value and New York Heart Association class (p = 0.053). Plasma OPN levels reflect heart failure severity in patients with Ro-DCM. Myocardial OPN expression is not associated with either plasma OPN levels or markers of heart failure in these individuals.

Abstract 3313: Plasma levels of MMP7 are significantly increased in patients with colorectal cancer compared to benign disease colon pathology

Abstract Introduction: MMP-7 (matrilysin), a matrix metalloproteinase (MMP) family member, is expressed in epithelial cells and some cancers. MMP7 is capable of activating pro-collagenases and digesting extracellular matrix (ECM) proteins. MMP7 supports connective tissue remodeling and regulates intestinal host defense and innate immunity. Increased MMP7 expression is associated with inflammation, tumorgenesis, and metastasis. MMP7 regulates neutrophil recruitment at sites of neoangiogenesis. MMP7 is capable of activating pro-MMP-1,-2,and-9, and osteopontin. Preoperative (preop) colorectal cancer patient’s plasma levels of MMP2, MMP3 and osteopontin have been shown to be higher than benign disease patient’s preop levels. MMP7 overexpression is reported in many malignancies (colorectal cancer (CRC) included). This study’s purpose was to compare PreOp plasma MMP7 levels in CRC and benign colon disease (BCP) patients (pts). Method: Pts undergoing colorectal resection for CRC or BCP who were prospectively enrolled in an IRB approved tissue/data bank for whom plasma samples were available were studied. Clinical, demographic and pathological data were reviewed. Plasma MMP7 levels were determined via ELISA in duplicate and reported as median +95%CI (ng/ml). Expression levels were determined in tumors and paired normal colon tissues in a subgroup of study pts by QRT-PCR. The candidacy of MMP7 as a diagnostic marker for CRC was validated by the receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) results. The Mann-Whitney test was used for statistical analysis. Results: A total of 120 CRC (72% colon, 28% rectal) and 120 BCP pts (adenoma 33%, diverticulitis 52%, other 15%) were studied. The male: female ratios in both groups were similar but CRC pts were older. The CRC stage distribution was stage 1,30%; stage 2,27%, stage 3,33%, stage 4,10%. The median plasma MMP7 level was significantly higher in the CRC group than in the BCP group(3.69,CI: 3.39,4.07vs 2.79, CI: 2.51,3.2;P=&amp;lt; 0.001). The AUC for the ROC curve (AUC) for plasma MMP7 in association with a CRC diagnosis was 0.698 (sensitivity 48%, specificity 80%). All CRC tumors tested showed elevated MMP7 expression vs. paired normal tissue. Conclusion: The median PreOp plasma MMP7 level was 33% higher in CRC vs. BCP group. The AUC results suggest MMP7 may have value as a CRC prognostic marker, perhaps, in combination with other protein markers. High MMP7 levels may be related to tumor vascularization and inflammation associated with the cancer. Further studies that assess larger populations are needed to further assess preop MMP7 levels. Citation Format: HMC Shantha Kumara, Dasuni N. Gamage, Neil Mitra, Carl S. Winkler, Sandhu K. Jaspreet, Xiaohong Yan, Vesna Cekic, Hiromichi Miyagaki, Nipa D. Gandhi, Richard L. Whelan. Plasma levels of MMP7 are significantly increased in patients with colorectal cancer compared to benign disease colon pathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3313.

Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis.

Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.