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Anthracycline chemotherapy is commonly used to treat breast cancer yet may increase the level of matrix metalloproteinases (MMP) -2 and -9, which increase the risk of atherosclerosis. While exercise has been shown to reduce the level of MMP in patients with diabetes, high intensity interval training (HIIT) has not been utilized to improve level of MMP in women with breast cancer receiving anthracycline chemotherapy. Thirty women were randomized to either 8-week HIIT or control (CON) group. The CON group was offered the HIIT intervention after 8 weeks. MMP-1, -2 -7, -9, tissue inhibitor of MMP (TIMP) -1, and-2 were measured at baseline and post-intervention. Repeated measures ANCOVA and paired t-test were performed to assess changes in MMP and TIMP. Post-intervention, no significant between-group differences were observed for MMP and TIMP. However, within-group decrease in MMP-9 was observed in the HIIT group [104.3(51.9) to 65.2(69.1); P = 0.01]. MMP-9 in the CON group was not significantly changed [115.5(47.2) to 90.4(67.9);]. MMP-2 significantly increased in both the HIIT group [76.6(11.2) to 83.2(13.1); P = 0.007) and the CON group [69.0(8.9) to 77.6(11.1) P = 0.003). It is unclear whether an 8-week HIIT intervention influences MMP-9 in breast cancer patients undergoing anthracycline chemotherapy. Additional investigations are required to understand the exercise-induced changes in MMP-2 and -9 in women undergoing anthracycline chemotherapy.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.

Ovarian cancer (OC) has an extremely unfavourable prognosis. This is due to its asymptomatic course and lack of screening tests. Therefore, new methods are needed to diagnose OC. The aim of this study was to evaluate the concentrations and diagnostic utility of selected matrilysins and stromelysins in the diagnosis of OC in comparison with the classical markers CA125 and HE4. The study group included 100 patients with serous OC, 70 with serous cysts (BL), and 50 healthy women (HW). Selected MMPs were determined by ELISA, routine markers by CMIA. Ovarian cancer patients have elevated concentrations of MMP-7, MMP-26, MMP-10 as well as CA125 and HE4 in the total group and subgroups (stage I + II, and III + IV). The highest values of diagnostic parameters—SP, SE, NPV, PPV, and ACC, as compared to CA125 and HE4, were observed for MMP-7. Performing ROC analyses showed that the highest AUC values were observed for MMP-7, CA125, and HE4, in the whole group of patients and divided into stages I and II according to FIGO. Performing ROC analyses for groups III and IV according to FIGO was associated with an increase in AUC for the MMPs studied. Of the MMPs tested, MMP-7, MMP-26, and MMP-10 have the highest potential in diagnostics of serous ovarian cancer patients.

Metalloproteinases (MMPs) play a significant role in cancer pathogenesis. We investigated the levels of MMP-7, MMP-26, MMP-3, and MMP-10 in comparison with the levels of a tumor marker (CA125) in the plasma of postmenopausal patients in early stages of endometrial cancer (EC) compared with control groups: patients with benign lesions (myoma uteri) and healthy controls. Plasma MMP levels were determined by ELISA and CA125 by CMIA methods. The study showed that plasma MMP-7 levels were significantly higher in EC patients compared to both control groups, whereas MMP-3 and MMP-26 levels were significantly higher in EC patients than in healthy women. MMP-7 showed the highest diagnostic sensitivity (SE), specificity (SP), positive (PPV) and negative predictive value (NPV), and diagnostic power (AUC) compared to other MMPs or CA125 in EC patients overall and patients with stage I and II EC. A combined analysis showed higher SE, NPV, and AUC levels in total EC patients and stage I and II EC patients—with the highest values for the combination MMP-7+CA125 (96%, 92%, 95%; 95%, 96%, and 98%; 0.9420, 0.9158, and 0.9693, respectively) or MMP-26 with CA125 (86%, 86%, and 86%; 59%, 73%, 73%; 0.8219, 0.8086, and 0.8353, respectively). The results suggest the usefulness of MMPs, especially MMP-7 and MMP-26, in combined panels with CA125 in diagnosing EC patients.

Background Matrixmetalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases which are involved in angiogenesis, tumor invasion and metastatic formation. Up to date, the prognostic relevance of MMPs in serum of patients with colon cancer remains unknown. Thus, we wanted to assess an expression pattern of MMPs in a homogenous cohort of colon cancer patients to assess their potential as prognostic biomarkers. Methods Differences in the expression pattern of MMP7, MMP10 and MMP12 in 78 serum specimens of patients with an adenocarcinoma of the colon and serum specimens of a healthy control group were assessed using Luminex-100 technologies. Subsequently, we correlated these results with histopathological and clinical data of the patients. Results Luminex based expression analysis revealed a significant overexpression of MMP7 and an overexpression of MMP10 and MMP12 in the sera of colon cancer patients compared to the healthy control group. Patients with vascular invasion showed a significantly higher MMP12 expression than V0-staged patients. Moreover overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera displayed a significantly impaired overall survival. Multivariate analysis revealed high MMP10 serum levels to be an independent adverse prognostic marker in colon cancer patients. Conclusions Expression patterns of MMP7, MMP10 and MMP12 in colon cancer patients´ sera are different compared to serum specimens of healthy individuals. Furthermore, overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera correlates with a dismal prognosis and may help to stratify patients into different risk groups.

BackgroundWe investigated the utilities of the liver-to-psoas apparent diffusion coefficient ratios (LTPAR) yielded by diffusion-weighted magnetic resonance imaging (DWMRI) and the age-adjusted serum matrix metalloproteinase-7 (MMP-7) for the diagnosis of biliary atresia (BA) in cholestatic infants.MethodsIn total, 170 cholestatic infants were recruited, of whom 50 (29.41%) were diagnosed with BA after cholestatic workups. The LTPAR and MMP7 levels were assessed.ResultsThe LTPAR was significantly lower in BA infants, and the age-adjusted MMP7 ratio was significantly higher, compared to other cholestatic infants (both p < 0.001). Receiver operating characteristic curve analysis yielded a cutoff > 0.1 ng/mL.day for the age-adjusted MMP-7 ratio, and an LTPAR < 1.01 for the optimal prediction of BA (both p < 0.001). Univariate logistic regression analysis revealed that both an age-adjusted MMP-7 ratio > 0.1 ng/mL.day and an LTPAR < 1.01 were significant predictors of BA among cholestatic infants (odds ratio = 30.98 and 13.28; p < 0.001 and < 0.001, respectively). The significance of the age-adjusted MMP-7 ratio and the LTPAR persisted on multivariate logistic regression analysis after adjusting for sex and the serum gamma-glutamyl transferase level (p < 0.001 and < 0.001, respectively). The negative predictive values (NPVs) for BA were 91.49% and 94.17%, respectively, for the LTPAR and age-adjusted MMP-7 ratio.ConclusionThe age-adjusted MMP-7 ratio and the LTPAR are both significant non-invasive predictors of BA. The consideration of both serum and imaging parameters may enhance BA diagnostic performance in cholestatic infants.

Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process. Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50-69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined. Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality. Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.

Background/Objectives: Peripheral artery disease (PAD) is associated with an increased risk of major adverse cardiovascular events (MACE), such as myocardial infarction and stroke, which are the top mortality causes in the PAD population. However, the identification of reliable biomarkers for predicting MACE in PAD patients remains limited. Proteins involved in extracellular matrix (ECM) remodeling have been implicated in atherosclerosis and may serve as potential indicators of cardiovascular risk. This study aimed to evaluate a panel of circulating proteins involved in ECM remodeling to identify those predictive of 2-year MACE in individuals with PAD. Methods: A prospective cohort of 465 PAD patients was enrolled and followed for 24 months. At baseline, plasma levels of nine ECM-related proteins were quantified. The outcome of interest was a 2-year MACE, defined as a composite of myocardial infarction, stroke, or mortality. Protein level differences between MACE vs. non-MACE patients were analyzed using Mann–Whitney U tests. Cox proportional hazards models, adjusted for baseline variables (including known cerebrovascular and coronary disease), were used to determine the independent associations between each protein and 2-year MACE. Subgroup analyses were conducted for diabetic and female patients, who are known to be at high risk for adverse events. Results: The mean age of the participants was 71 (SD 10) years, with 31.1% identifying as female and 47.2% having diabetes. Over two years, 84 patients (18.1%) experienced MACE. Among the proteins analyzed, matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-7 (MMP-7) were significantly elevated in those who developed MACE compared to those who did not: MMP-10 (710.60 pg/mL [SD 46.09] vs. 672.40 pg/mL [SD 45.04], p = 0.032) and MMP-7 (5.20 pg/mL [SD 4.11] vs. 4.76 pg/mL [SD 3.86], p = 0.048). Both independently correlated with 2-year MACE after adjustment for all baseline factors: MMP-10 (HR 1.32, 95% CI 1.16–1.51, p = 0.023) and MMP-7 (HR 1.17, 95% CI 1.05–2.68, p = 0.026). Subgroup analyses revealed that MMP-10 was associated with MACE in diabetic patients (HR 1.18, 95% CI 1.13–1.53, p = 0.019), while MMP-7 was associated with MACE among females (HR 1.31, 95% CI 1.15–1.69, p = 0.009). Conclusions: MMP-10 and MMP-7 emerged as independent biomarkers for prognosticating 2-year MACE in PAD patients, suggesting their utility in systemic cardiovascular risk stratification. Measuring these proteins could enhance clinical decision-making by identifying high-risk individuals with PAD who may benefit from multidisciplinary vascular evaluation and intensified treatment strategies, ultimately aiming to reduce cardiovascular complications in the PAD population.