WorldWideScience

Sample records for prognostic marker ubiquitin

  1. Prognostic molecular markers in cancer - quo vadis?

    Science.gov (United States)

    Søland, Tine M; Brusevold, Ingvild J

    2013-09-01

    Despite the tremendous number of studies of prognostic molecular markers in cancer, only a few such markers have entered clinical practise. The lack of clinical prognostic markers clearly reflects limitations in or an inappropriate approach to prognostic studies. This situation should be of great concern for the research community, clinicians and patients. In the present review, we evaluate immunohistochemical prognostic marker studies in oral squamous cell carcinomas (OSCC) from 2006 to 2012. We comment upon general issues such as study design, assay methods and statistical methods, applicable to prognostic marker studies irrespective of cancer type. The three most frequently studied markers in OSCC are reviewed. Our analysis revealed that most new molecular markers are reported only once. To draw conclusions of clinical relevance based on the few markers that appeared in more than one study was problematic due to between-study heterogeneity. Currently, much valuable tissue material, time and money are wasted on irrelevant studies. © 2013 John Wiley & Sons Ltd.

  2. Prognostic markers of canine pyometra

    Directory of Open Access Journals (Sweden)

    M.C. Sant'Anna

    2014-12-01

    Full Text Available The pyometra is a disease that affects middle age and elderly female dogs during diestrus. Hormonal, microbiological, biochemical and hematological aspects are well described. However, few studies have evaluated the role of each in the prognosis of canine pyometra. The aim of this study was to identify markers associated with clinical worsening of dogs with pyometra. We prospectively evaluated 80 dogs with pyometra treated surgically. Group 1 consisted of dogs that were discharged within 48 hours after surgery and Group 2 consisted of those who required prolonged hospitalization or died. The findings of hematological, biochemical and blood lactate levels were compared between groups and variables such as bacterial multidrug resistance, systemic inflammatory response syndrome (SIRS, hyperlactatemia and increased creatinine were analyzed through the dispersion of frequencies between groups. Among the variables studied, the presence of SIRS and elevated serum creatinine >2.5mg/mL were effective in predicting the worsening of the disease and can be used as prognostic markers of canine pyometra.

  3. Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease.

    Science.gov (United States)

    Vinther-Jensen, T; Simonsen, A H; Budtz-Jørgensen, E; Hjermind, L E; Nielsen, J E

    2015-10-01

    Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene-expansion negative individuals using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry. Differences in peak intensity from SELDI-TOF spectra were evaluated. Levels of 10 peaks were statistically significantly different between manifest gene-expansion carriers and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P = 0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG-age product score (P = 0.019) in all gene-expansion carriers. Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset. © 2015 EAN.

  4. Prognostic DNA Methylation Markers for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Siri H. Strand

    2014-09-01

    Full Text Available Prostate cancer (PC is the most commonly diagnosed neoplasm and the third most common cause of cancer-related death amongst men in the Western world. PC is a clinically highly heterogeneous disease, and distinction between aggressive and indolent disease is a major challenge for the management of PC. Currently, no biomarkers or prognostic tools are able to accurately predict tumor progression at the time of diagnosis. Thus, improved biomarkers for PC prognosis are urgently needed. This review focuses on the prognostic potential of DNA methylation biomarkers for PC. Epigenetic changes are hallmarks of PC and associated with malignant initiation as well as tumor progression. Moreover, DNA methylation is the most frequently studied epigenetic alteration in PC, and the prognostic potential of DNA methylation markers for PC has been demonstrated in multiple studies. The most promising methylation marker candidates identified so far include PITX2, C1orf114 (CCDC181 and the GABRE~miR-452~miR-224 locus, in addition to the three-gene signature AOX1/C1orf114/HAPLN3. Several other biomarker candidates have also been investigated, but with less stringent clinical validation and/or conflicting evidence regarding their possible prognostic value available at this time. Here, we review the current evidence for the prognostic potential of DNA methylation markers in PC.

  5. Identification of Prostate Cancer Prognostic Markers

    Science.gov (United States)

    2016-10-01

    role in cellular energetics and growth. So far, our results suggest that genomic alterations may serve as prognostic markers that would improve the...shRNA vectors with better knockdown efficiency . Stable ECI1- knockdown cells would be ultimately used to perform rescue experiments for the phenotypes

  6. Expression and prognostic role of ubiquitination factor E4B in primary hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Xiao-Fei; Pan, Qiu-Zhong; Pan, Ke; Weng, De-Sheng; Wang, Qi-Jing; Zhao, Jing-Jing; He, Jia; Liu, Qing; Wang, Dan-Dan; Jiang, Shan-Shan; Zheng, Hai-Xia; Lv, Lin; Chen, Chang-Long; Zhang, Hong-Xia; Xia, Jian-Chuan

    2016-01-01

    Ubiquitination factor E4B (UBE4B) has been speculated to have contradictory functions upon tumorigenesis as an oncogene or tumor suppressor in different types of cancers. We investigated the expression and prognostic role of UBE4B in primary hepatocellular carcinoma (HCC) using cell lines and 149 archived HCC samples. Correlation between the functions of UBE4B in HCC was also explored. We used human HCC cell lines (HepG2, Hep3B, SK-Hep1, Huh7, SMMC-7721, BEL-7402) and a normal hepatocyte cell line (LO2) along with HCC samples from patients who had undergone resection for HCC previously at our hospital. A battery of methods (real-time quantitative polymerase chain reaction; Western blotting; immunohistochjemical analyses; cell proliferation and colony formation assays; cell migration and cell invasion assays) were employed to assess various aspects of UBE4B.We found that UBE4B expression was upregulated aberrantly at mRNA and protein levels in human primary HCC tissues. Amplified expression of UBE4B was highly correlated with poor outcome. Silencing of UBE4B expression by siRNA inhibited the proliferation, colony formation, migration and invasion of HCC cells in vitro, and resulted in significant apoptosis that was associated with downregulation of expression of Bcl-2 and upregulation of expression of total p53, p-p53, Bax and Cleaved-Caspase3 in HCC cells. Our findings suggested that UBE4B might have an oncogenic role in human primary HCC, and that it could be used as a prognostic marker (as well as a potential molecular target) for the treatment of HCC. © 2015 Wiley Periodicals, Inc.

  7. Prognostic laboratory markers of joint damage in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Lindqvist, E; Henriksen, Karen Eberhardt; Bendtzen, K

    2005-01-01

    To investigate whether determination of a set of laboratory markers at baseline provides prognostic information on joint damage in hands and feet in rheumatoid arthritis.......To investigate whether determination of a set of laboratory markers at baseline provides prognostic information on joint damage in hands and feet in rheumatoid arthritis....

  8. Ubiquitin

    DEFF Research Database (Denmark)

    Vinther-Jensen, T.; Simonsen, A. H.; Budtz-Jorgensen, E.

    2015-01-01

    BACKGROUND: Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies......, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. METHODS: This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene...... and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P = 0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG-age product score (P = 0.019) in all gene...

  9. Gc globulin as a diagnostic and prognostic marker in horses

    DEFF Research Database (Denmark)

    Pihl, Tina Holberg

    shown that very low concentration of plasma Gc-globulin are related to an increased risk of developing shock and lethal complications of trauma. Gc-globulin is thus a prognostic marker in intensive care medicine. It has been suggested that treatment with Gc-globulin to patients with severe tissue injury......-globulin concentrations in horses under clinical conditions have never previously been investigated. The Ph.D. project focuses on Gc-globulin as a prognostic marker in horses with acute abdominal pain....

  10. Cellular prognostic markers in hepatocellular carcinoma.

    Science.gov (United States)

    Buonaguro, Luigi; Tagliamonte, Maria; Petrizzo, Annacarmen; Damiano, Elvira; Tornesello, Maria Lina; Buonaguro, Franco M

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the five big killers worldwide and is frequently associated with chronic hepatitis B and C virus (HBV and HCV) infections. Tumor microenvironment consists of a complex network of cells and factors that plays a key role in the tumor progression and prognosis. This is true also for HCC. Several studies have shown strikingly strong correlation between HCC clinical prognosis and intratumoral infiltration of cells affecting tumor growth, invasion, angiogenesis and metastasis. None of such cells is yet validated for routine diagnostic and prognostic assessment. The present review aims at providing a state-of-the-art of such studies.

  11. Clinical prognostic markers in stage IIIC melanoma.

    Science.gov (United States)

    Madu, Max F; Schopman, Jaap H H; Berger, Danique M S; Klop, Willem M C; Jóźwiak, Katarzyna; Wouters, Michel W J M; van der Hage, Jos A; van Akkooi, Alexander C J

    2017-08-01

    Although the EORTC 18071-trial has shown a clear survival benefit for adjuvant ipilimumab, accurately selecting patients for this toxic adjuvant therapy is important. We aimed to identify prognostic factors for death and disease recurrence in AJCC stage IIIC melanoma patients. Retrospective analysis of patients who underwent lymph node dissection (LND) for stage IIIC melanoma in our institution between 2000 and 2016. Baseline characteristics, melanoma-specific survival (MSS), and disease-free survival (DFS) were assessed, and prognostic factors for recurrence and survival were analyzed using uni- and multivariable analysis. A total of 205 patients were included. Median follow-up was 20 months (interquartile range 11-43 months), median MSS was 28 months, and median DFS was 11 months. Five-year MSS was 33% and 5-year DFS was 23%. N3 (≥4 involved lymph nodes) and extracapsular extension (ECE) carried an increased risk of disease recurrence after LND and death by melanoma. Patients with both N3 and ECE had virtually no long-term survival. Although survival for patients with stage IIIC is poor in general, patients with both N3 disease and ECE constitute the group with the worst prognosis and should be considered for adjuvant therapy with ipilimumab or any other future effective adjuvant therapy (study). © 2017 Wiley Periodicals, Inc.

  12. Prognostic markers for diet-induced weight loss in obese women

    DEFF Research Database (Denmark)

    Astrup, A; Buemann, B; Gluud, C

    1995-01-01

    To identify prognostic metabolic and hormonal markers for long-term weight loss outcome in obese women.......To identify prognostic metabolic and hormonal markers for long-term weight loss outcome in obese women....

  13. Prognostic markers and DNA methylation profiling in lymphoid malignancies

    OpenAIRE

    Bhoi, Sujata

    2017-01-01

    In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confi...

  14. Molecular Pathology: Prognostic and Diagnostic Genomic Markers for Myeloid Neoplasms.

    Science.gov (United States)

    Kuo, Frank C

    2016-09-01

    Application of next-generation sequencing (NGS) on myeloid neoplasms has expanded our knowledge of genomic alterations in this group of diseases. Genomic alterations in myeloid neoplasms are complex, heterogeneous, and not specific to a disease entity. NGS-based panel testing of myeloid neoplasms can complement existing diagnostic modalities and is gaining acceptance in the clinics and diagnostic laboratories. Prospective, randomized trials to evaluate the prognostic significance of genomic markers in myeloid neoplasms are under way in academic medical centers. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers.

    LENUS (Irish Health Repository)

    Jansen, Michael

    2010-07-01

    Over the past 10 years, there has been an increasing use of molecular markers in the assessment and management of adult malignant gliomas. Some molecular signatures are used diagnostically to help pathologists classify tumours, whereas others are used to estimate prognosis for patients. Most crucial, however, are those markers that are used to predict response to certain therapies, thereby directing clinicians to a particular treatment while avoiding other potentially deleterious therapies. Recently, large-scale genome-wide surveys have been used to identify new biomarkers that have been rapidly developed as diagnostic and prognostic tools. Given these developments, the pace of discovery of new molecular assays will quicken to facilitate personalised medicine in the setting of malignant glioma.

  16. Role of Phosphorylated Neurofilament H as a diagnostic and prognostic marker in traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Moh Omar Ghonemi

    2013-09-01

    Conclusion: Phosphorylated Neurofilament H can be used as a diagnostic and prognostic marker in patients with TBI as seen by the presence of significant correlations between the marker levels and different clinical and radiological tools.

  17. Galectin-3, a prognostic marker--and a therapeutic target?

    Science.gov (United States)

    Pereira, Ana Rita; Menezes Falcão, Luiz

    2015-03-01

    The natriuretic peptides BNP and NT-proBNP are currently the most commonly used biomarkers in heart failure, but they have limitations. There is thus a need to identify new biomarkers that may prove useful, alone or in combination, for screening, diagnosis and prognosis. Galectin-3 is a protein involved in a variety of cellular signaling pathways and is found in many tissues. Its expression is low in normal hearts but elevated in fibrotic hearts. Among other effects, it promotes fibroblast proliferation and collagen synthesis, contributing to the cardiac remodeling that is central to the development and progression of heart failure. Heart failure associated with elevated galectin-3 (>17.8 ng/ml) affects 30-50% of patients with chronic heart failure, and is a marker of worse prognosis, with higher rates of short-term rehospitalization and mortality. It is thought that galectin-3 inhibition, or even genetic disruption, may reverse or delay disease progression. Galectin-3 appears to have greater prognostic value than natriuretic peptides when assessed separately, however, when combined their prognostic value is even higher. Galectin-3, associated with BNP or NT-proBNP, may help improve the diagnosis and prognosis of heart failure. Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  18. Intraventricular conduction delay: a prognostic marker in chronic heart failure.

    Science.gov (United States)

    Shamim, W; Francis, D P; Yousufuddin, M; Varney, S; Pieopli, M F; Anker, S D; Coats, A J

    1999-07-31

    Chronic heart failure (CHF) is associated with high mortality, and there are several established clinical and laboratory parameters that predict mortality in CHF. The purpose of this study was (a) to identify the best ECG parameter that predicts mortality, (b) to evaluate the prognostic marker of ECG against well-established indicators of prognosis. Relevant data from 241 CHF patients were analysed retrospectively. Cardiopulmonary exercise testing and radionuclide ventriculogram were also performed where possible. The mean follow-up period was 31 months. On univariate analysis by the Cox proportional Hazard method, intraventricular conduction delay (IVCD) [P<0.0001, hazard ratio 1.017 (1.011-1.024)] and QTc [P<0.0001, hazard ratio 1.012 (1.006-1.017)] were identified as predictors of mortality. On bivariate analysis, IVCD and MVO2 were better predictors when combined together. A model based on multivariate analysis showed that IVCD, MVO2 and left ventricular ejection fraction (LVEF) were the best predictors of mortality. The addition of plasma sodium, age and NYHA class had no added benefit on the predictive power of the model. Further analysis of IVCD and QTc showed that, for different cut-off values, IVCD is better than QTc, and that there is a graded increase in mortality with increasing value of IVCD. We have found that IVCD is an important ECG predictor of prognosis in patients with CHF.

  19. FGFR Family Members Protein Expression as Prognostic Markers in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma

    NARCIS (Netherlands)

    Koole, Koos; Clausen, Martijn J. A. M.; van Es, Robert J. J.; van Kempen, Pauline M. W.; Melchers, Lieuwe J.; Koole, Ron; Langendijk, Johannes A.; van Diest, Paul J.; Roodenburg, Jan L. N.; Schuuring, Ed; Willems, Stefan M.

    Introduction Fibroblast growth factor receptor family member proteins (FGFR1-4) have been identified as promising novel therapeutic targets and prognostic markers in a wide spectrum of solid tumors. The present study investigates the expression and prognostic value of four FGFR family member

  20. Development of a Prognostic Marker for Lung Cancer Using Analysis of Tumor Evolution

    Science.gov (United States)

    2017-08-01

    together. Phylogenetic analysis For phylogenetic analysis , we selected 21,285 variant sites with no missing information for all samples ( read ...AWARD NUMBER: W81XWH-15-1-0243 TITLE: Development of a Prognostic Marker for Lung Cancer Using Analysis of Tumor Evolution PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER Development of a Prognostic Marker for Lung Cancer Using Analysis of Tumor Evolution 5b. GRANT NUMBER 5c. PROGRAM

  1. Malignant Pleural Mesothelioma Prognostic Marker: A Review of ...

    African Journals Online (AJOL)

    The first proves the utilization of osteopontin and mesothelin for diagnostic and prognostic assessment of MPM in patients previously exposed to asbestos and those with pleural metastasis. The second proves that immunohistochemical analysis identified osteopontin to have a prognostic role from its expression in MPM.

  2. Serum Clusterin as a Prognostic Marker of Chronic Spontaneous Urticaria.

    Science.gov (United States)

    Kim, Ji-Hye; Lee, Hyung-Young; Ban, Ga-Young; Shin, Yoo-Seob; Park, Hae-Sim; Ye, Young-Min

    2016-05-01

    A substantial proportion of patients with chronic spontaneous urticaria (CSU) are refractory to antihistamines. However, identifying the subpopulation whose urticaria is not completely controlled by antihistamines remains difficult. The response of autologous serum skin test (ASST), a clinical test for the detection of basophil histamine-releasing activity upon autoantibodies or autoreactive stimulation, has been suggested as a potential predictor in the control of urticaria. We sought to identify proteins that were differentially expressed in the sera of patients with positive and negative ASST results and to investigate their association with urticaria control.Proteomics analysis was performed using sera from 3 CSU patients with positive ASST results compared with those showing negative ASST results. Seven upregulated and 5 downregulated proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in the ASST-positive group compared with the ASST-negative group.Proteins that were differentially expressed according to the ASST results in CSU patients were classified into 6 groups: apolipoproteins, glycoproteins, modified albumin, haptoglobulin, plectin, and others. Among these, apolipoprotein J or clusterin was validated using an enzyme-linked immunosorbent assay. Clusterin levels in 69 ASST-positive patients were significantly higher than those in 69 ASST-negative patients and in 86 healthy controls (231.2 ± 44.0 vs 210.2 ± 36.1 vs 118.7 ± 71.9 μg/mL, P urticaria would be refractory to antihistamines. Serum clusterin can be a prognostic marker to determine the responsiveness to antihistamine treatment in patients with CSU.

  3. Research progress in prognostic markers of acute-on-chronic liver failure

    Directory of Open Access Journals (Sweden)

    ZHANG Yuling

    2014-10-01

    Full Text Available Acute-on-chronic liver failure (ACLF is a clinical entity encompassing an acute deterioration of liver function and failure of one or more organs, which results in high short-term mortality rate. In recent years, a number of novel prognostic markers of ACLF have emerged and provided a basis for the treatment and prognostic evaluation of ACLF. Researches on both commonly used and novel makers for prognosis of ACLF are reviewed in order to improve the existing prognostic evaluation system and to provide a basis for the treatment and prognostic evaluation of ACLF.

  4. Socioeconomic inequalities in prognostic markers of non-Hodgkin lymphoma: analysis of a national clinical database

    DEFF Research Database (Denmark)

    Frederiksen, Birgitte Lidegaard; Brown, Peter de Nully; Dalton, Susanne Oksbjerg

    2011-01-01

    in histological subgroups reflecting aggressiveness of disease among the social groups. One of the most likely mechanisms of the social difference is longer delay in those with low socioeconomic position. The findings of social inequality in prognostic markers in non-Hodgkin lymphoma (NHL) patients could already......The survival of non-Hodgkin lymphoma patients strongly depends on a range of prognostic factors. This registry-based clinical cohort study investigates the relation between socioeconomic position and prognostic markers in 6234 persons included in a national clinical database in 2000-2008, Denmark....... Several measures of individual socioeconomic position were achieved from Statistics Denmark. The risk of being diagnosed with advanced disease, as expressed by the six prognostic markers (Ann Arbor stage III or IV, more than one extranodal lesion, elevated serum lactate dehydrogenase (LDH), performance...

  5. Qualitative and Quantitative Requirements for Assessing Prognostic Markers in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Christoph Burdelski

    2014-04-01

    Full Text Available Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC data from 39 prognosis markers in subsets of 50 – >10,000 tumors. We found a strong association between the “prognostic power” of individual markers and the number of tissues that should be minimally included in such studies. The prognostic relevance of more than 90% of the 39 IHC markers could be detected if ≥6400 tissue samples were analyzed. Studying markers of tissue quality, including immunohistochemistry of ets-related gene (ERG and vimentin, and fluorescence in-situ hybridization analysis of human epidermal growth factor receptor 2 (HER2, we found that 18% of tissues in our tissue microarray (TMA showed signs of reduced tissue preservation and limited immunoreactivity. Comparing the results of Kaplan-Meier survival analyses or associations to ERG immunohistochemistry in subsets of tumors with and without exclusion of these defective tissues did not reveal statistically relevant differences. In summary, our study demonstrates that TMA-based marker validation studies using biochemical recurrence as an endpoint require at least 6400 individual tissue samples for establishing statistically relevant associations between the expression of molecular markers and patient outcome if weak to moderate prognosticators should also be reliably identified.

  6. Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer

    OpenAIRE

    Gr?nberg, Malin; Ahlin, Cecilia; Naeser, Ylva; Janson, Eva Tiensuu; Holmberg, Lars; Fj?llskog, Marie-Louise

    2017-01-01

    Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer...

  7. Microarray-based analysis and clinical validation identify ubiquitin-conjugating enzyme E2E1 (UBE2E1 as a prognostic factor in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hongmei Luo

    2016-11-01

    Full Text Available Abstract Background Previous research suggested that single gene expression might be correlated with acute myeloid leukemia (AML survival. Therefore, we conducted a systematical analysis for AML prognostic gene expressions. Methods We performed a microarray-based analysis for correlations between gene expression and adult AML overall survival (OS using datasets GSE12417 and GSE8970. Positive findings were validated in an independent cohort of 50 newly diagnosed, non-acute promyelocytic leukemia (APL AML patients by quantitative RT-PCR and survival analysis. Results Microarray-based analysis suggested that expression of eight genes was each associated with 1-year and 3-year AML OS in both GSE12417 and GSE8970 datasets (p < 0.05. Next, we validated our findings in an independent cohort of AML samples collected in our hospital. We found that ubiquitin-conjugating enzyme E2E1 (UBE2E1 expression was adversely correlated with AML survival (p = 0.04. Multivariable analysis showed that UBE2E1 high patients had a significant shorter OS and shorter progression-free survival after adjusting other known prognostic factors (p = 0.03. At last, we found that UBE2E1 expression was negatively correlated with patients’ response to induction chemotherapy (p < 0.05. Conclusions In summary, we demonstrated that UBE2E1 expression was a novel prognostic factor in adult, non-APL AML patients.

  8. [Primary small-cell bronchial cancer: value of serum tumor markers in the prognostic evaluation].

    Science.gov (United States)

    Watine, J; Charet, J C

    1999-09-25

    TUMOR MARKERS: We reviewed the biomedical literature searching for the most well-documented serum markers with prognostic value independent of the usual radioclinical and histological parameters of small cell lung cancer. Neuron specific enolase (NSE) would have a pretherapeutic prognostic value better than LDH (lacto-dehydrogenase) and perhaps better than serum sodium, biocarbonates, and uric acid. The superiority of NSE over serum albumin remains to be proven. Although there are only a few reports, TK (thymine kinase), TPA (tissue polypeptide antigen), Cyfra 21-1 and/or IL-2 (interleukin-2) secretion might have better pretherapeutic prognostic value than NSE. We also found that iterative blood assays to follow therapeutic effects in patients with small-cell lung cancer have not been proven to provide independent prognostic information. As medical laboratory resources must be concentrated on priority exploitable assays, the currently available data would suggest that it is not necessary to routinely measure serum tumor markers, and in particular NSE, for the prognostic evaluation of small-cell lung cancer patients.

  9. Ubiquitin: an immunohistochemical marker of Mallory bodies and alcoholic liver disease

    DEFF Research Database (Denmark)

    Vyberg, Mogens; Leth, Peter Mygind

    1991-01-01

    One hundred forty eight liver needle biopsies, comprising 88 consecutive biopsies from patients with clinically diagnosed or suspected alcoholic liver disease and 60 selected biopsies from non-alcoholics, were immunostained for the cell stress protein ubiquitin (Ub). Ub + cells were detected in all...... biopsies from non-alcoholic patients with liver diseases in which hepatocyte ballooning and occasionally MBs are seen, a few Ub + cells were revealed in two out of ten with primary biliary cirrhosis (one of which also showed MBs) but none in biopsies with primary sclerosing cholangitis, long-standing large...... of 33 biopsies with alcoholic hepatitis (AH). Practically all Mallory bodies (MBs) showed intense Ub-staining. In addition, many cells revealed Ub + granules lying aggregated (pre-MBs) or dispersed in the cytoplasm of ballooned cells. The mean number of Ub + cells in 10 biopsies with AH was more than 30...

  10. Fatigue as prognostic risk marker of mental sickness absence in white collar employees.

    Science.gov (United States)

    Roelen, C A M; Heymans, M W; van Rhenen, W; Groothoff, J W; Twisk, J W R; Bültmann, U

    2014-06-01

    To investigate fatigue as prognostic risk marker for identifying working employees at risk of long-term sickness absence (SA). At baseline, fatigue was measured in 633 white collar employees with the checklist individual strength (CIS) including scales for fatigue severity, reduced concentration, reduced motivation, and reduced physical activity. SA was medically certified by an occupational physician in the 3rd or 4th SA week with diagnostic codes according to the 10th version of the International Classification of Diseases. Medically certified SA was retrieved at the individual level from an occupational health register after 1-year follow-up. CIS scores were investigated as prognostic risk markers predicting medically certified SA and particularly SA certified as mental SA. 614 employees (N = 378 men and N = 236 women) had complete data and were eligible for analysis; 63 (10 %) had medically certified SA of whom 39 (6 %) had mental SA. Fatigue severity and total CIS scores were associated with medically certified SA in men, but poorly discriminated between men with and without medically certified SA. Fatigue severity, reduced concentration, reduced motivation, and total CIS scores were also associated with mental SA in men. CIS and its reduced concentration scale were valid prognostic risk markers of mental SA. CONCLUSION Fatigue was a prognostic risk marker of mental SA in white collar men. The CIS should be further validated as a screening tool for the risk of mental SA in white collar working populations.

  11. The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer

    DEFF Research Database (Denmark)

    Baranyai, Zsolt; Krzystanek, Marcin; Josa, Valeria

    2014-01-01

    The aim of the present study was to analyse the preoperative platelet count and the platelet-lymphocyte ratio (PLR) in patients with colorectal cancer (CRC) of different stages and with hepatic metastasis of CRC (mCRC) and to compare these factors as potential prognostic markers. Clinicopathologi...

  12. Fatigue as Prognostic Risk Marker of Mental Sickness Absence in White Collar Employees

    NARCIS (Netherlands)

    Roelen, C.A.M.; Heymans, M.W.; van Rhenen, W.; Groothoff, J.W.; Twisk, J.W.R.; Bultmann, U.

    2014-01-01

    Purpose: To investigate fatigue as prognostic risk marker for identifying working employees at risk of long-term sickness absence (SA). Methods: At baseline, fatigue was measured in 633 white collar employees with the checklist individual strength (CIS) including scales for fatigue severity, reduced

  13. Fatigue as prognostic risk marker of mental sickness absence in white collar employees

    NARCIS (Netherlands)

    Roelen, C. A. M.; Heymans, M. W.; van Rhenen, W.; Groothoff, J. W.; Twisk, J. W. R.; Bültmann, U.

    2014-01-01

    To investigate fatigue as prognostic risk marker for identifying working employees at risk of long-term sickness absence (SA). At baseline, fatigue was measured in 633 white collar employees with the checklist individual strength (CIS) including scales for fatigue severity, reduced concentration,

  14. Serum cathepsin H as a potential prognostic marker in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Schweiger, A; Christensen, Ib Jarle; Nielsen, Hans Jørgen

    2005-01-01

    Cathepsin H is a lysosomal cysteine protease that may participate in tumor progression. In order to evaluate its potential as a prognostic marker, its protein levels were measured by ELISA in preoperative sera from 324 patients with colorectal cancer. The level of cathepsin H was significantly...

  15. Fatigue as Prognostic Risk Marker of Mental Sickness Absence in White Collar Employees

    NARCIS (Netherlands)

    Roelen, C. A. M.; Heymans, M. W.; van Rhenen, W.; Groothoff, J. W.; Twisk, J. W. R.; Bultmann, U.

    Purpose To investigate fatigue as prognostic risk marker for identifying working employees at risk of long-term sickness absence (SA). Methods At baseline, fatigue was measured in 633 white collar employees with the checklist individual strength (CIS) including scales for fatigue severity, reduced

  16. CXCL12 genetic variants as prognostic markers in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Chen RW

    2015-10-01

    Full Text Available Ruiwan Chen,1,* Yafei Xu,2,* Xiaojing Du,2,* Na Liu,2 Yingqin Li,2 Qingmei He,2 Linglong Tang,2 Yanping Mao,2 Ying Sun,2 Lei Chen,2,* Jun Ma2,* 1Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, 2Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: The chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12 axis plays an important role in tumorigenesis, metastasis, and recurrence of tumors. Its single nucleotide polymorphisms (SNPs are associated with patient survival in several types of cancer. However, the prognostic value of SNPs in nasopharyngeal carcinoma (NPC has not been fully investigated. This retrospective study assessed the relationships between CXCR4 rs2228014 and CXCL12 rs1801157 polymorphisms and patient outcome in 222 patients newly diagnosed with NPC. The analysis found no significant correlation between the presence of both SNPs and clinicopathological factors. However, univariate analysis showed that N classification, clinical stage, and the CXCL12 rs1801157 polymorphism were significantly associated with distant metastasis-free survival (P=0.018, 0.028, and 0.013, respectively and progression-free survival (P=0.007, 0.046, and 0.021, respectively. After adjusting clinicopathological factors, multivariate analysis identified CXCL12 rs1801157 as an independent prognostic factor for distant metastasis-free survival and progression-free survival (hazard ratio: 3.332; 95% confidence interval: 1.597–6.949; P=0.001 and hazard ratio: 2.665 95% confidence interval: 1.387–5.119; P=0.003, respectively. Our results suggest that CXCL12 rs1801157 AA genotype might serve as a potential prognostic factor in patients with NPC. Keywords: nasopharyngeal carcinoma, CXCR4, CXCL12, polymorphism

  17. Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target?

    KAUST Repository

    Vasaikar, Suhas

    2018-02-06

    BackgroundGlioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment.MethodsData from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells.ResultsBy bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer.ConclusionsETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients.

  18. Fragmented QRS: A simple electrocardiographic prognostic marker in cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Sita Ram Mittal

    2016-01-01

    Full Text Available Fragmented QRS is defined as the presence of R′ wave or notching of R or S wave in the presence of narrow QRS. It indicates heterogeneous depolarization of the ventricular myocardium that can occur due to ischemia, fibrosis, or scar. It may also be a marker of coronary microvascular dysfunction. In the context of epicardial coronary artery disease, it is associated with multivessel disease and greater incidence of cardiac events. It has been shown to be an indicator of higher incidence of arrhythmias and sudden death in arrhythmic right ventricular dysplasia, Brugada syndrome, and acquired long QT syndrome. Its regression following cardiac resynchronization therapy suggests electrical reverse remodeling. It has also been shown to be a marker of myocardial involvement in congenital heart diseases and is helpful in diagnosing subclinical cardiac involvement in various systemic diseases.

  19. Notch-1 and notch-4 receptors as prognostic markers in breast cancer.

    Science.gov (United States)

    Yao, Katharine; Rizzo, Paola; Rajan, Prabha; Albain, Kathy; Rychlik, Karen; Shah, Sneha; Miele, Lucio

    2011-10-01

    Studies looking at immunohistochemical (IHC) staining of Notch receptors in breast cancer and correlation with known prognostic factors are sparse. IHC staining for nuclear, cytoplasmic, and membrane Notch-1 (N1), Notch-4 (N4), and Jagged-1 (JAG1) was performed and correlated with known prognostic factors. Of 48 breast cancers, 36 (67%) were invasive, mean age was 50 years (range 43-86 years), 37 (77%) were estrogen receptor (ERα) positive, and 13 (27%) node positive. There was significantly more marked N1 membranous staining in ERα-positive tumors (P membranous N4 significantly correlated with Ki67 (P membranous JAG1 significantly correlated with Ki67 (P markers is feasible and correlates with known prognostic factors consistent with a biological role of Notch signaling in breast cancer progression.

  20. Copy-number analysis identified new prognostic marker in acute myeloid leukemia.

    Science.gov (United States)

    Nibourel, O; Guihard, S; Roumier, C; Pottier, N; Terre, C; Paquet, A; Peyrouze, P; Geffroy, S; Quentin, S; Alberdi, A; Abdelali, R B; Renneville, A; Demay, C; Celli-Lebras, K; Barbry, P; Quesnel, B; Castaigne, S; Dombret, H; Soulier, J; Preudhomme, C; Cheok, M H

    2017-03-01

    Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

  1. Calprotectin is a potential prognostic marker for polycystic ovary syndrome.

    Science.gov (United States)

    Chen, Shouzhen; Jiang, Mei; Ding, Tao; Wang, Junmei; Long, Ping

    2017-03-01

    Background Calprotectin is an antimicrobial, calcium and zinc-binding heterocomplex protein and has been proposed as a marker to rule out inflammatory conditions. The aim of this study was to evaluate the role of calprotectin in the diagnosis of polycystic ovary syndrome and to investigate the association between calprotectin and insulin resistance. Methods A total of 41 females with polycystic ovary syndrome and 54 age-matched without polycystic ovary syndrome were eligible for the study. Serum concentration of calprotectin was determined using enzyme-linked immunosorbent assay. Clinical characteristics, hormone and metabolic parameters were evaluated in each subject. The predictive value of serum calprotectin was assessed using receiver operating characteristic curves. Correlations between the serum calprotectin concentrations and insulin resistance were examined using Spearman's correlation. Results We found that the serum calprotectin concentrations were significantly higher in polycystic ovary syndrome compared with the non-polycystic ovary syndrome group ( P polycystic ovary syndrome diagnosis. A significant positive correlation was found between the serum calprotectin and insulin resistance. Conclusions These results suggest that calprotectin might be a useful adjunct in the diagnosis of polycystic ovary syndrome, especially those with insulin resistance.

  2. Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer.

    Science.gov (United States)

    Santoiemma, Phillip P; Reyes, Carolina; Wang, Li-Ping; McLane, Mike W; Feldman, Michael D; Tanyi, Janos L; Powell, Daniel J

    2016-10-01

    Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Several factors prognostic for survival have been identified including the presence of certain lymphocyte markers. Tumor-infiltrating lymphocytes (TILs), particularly cytotoxic CD8+ TILs, have been shown to be most favorable for prognosis in ovarian cancer, although other immune cells including CD3+ T-cells, CD4+ T-cells, and B-cells have also demonstrated survival benefits. Although data for these markers exists, results are not uniform in the literature. Furthermore, other immunomodulatory protein markers that have been targeted in effective immunotherapies for other malignancies may prove to be favorable in ovarian cancer. Here, extensive immunohistochemical analysis was performed on a tissue microarray, containing 135 ovarian cancer cases obtained during tumor debulking detecting 15 key lymphocyte markers such as CD3, CD4, and CD20, as well as activation and immunomodulatory molecules such as TIA-1 and PD-L1. Samples were analyzed for expression of markers in tumor islets or stroma and expression was correlated with overall survival, histotype, stage, age, debulking grade, and response to chemotherapy. Our results confirm the presence of CD8+ and CD20+ TILs is positively correlated with overall survival, with further multivariate modeling replicating that prognostic benefit. Additional markers of significant prognostic importance, including TIA-1, CD103 and HLA Class-II were also revealed. Our results further support the vital role of cytotoxic T-cells in defense against ovarian cancer and reveals new questions as to the role of B-cells in tumor control as well as the potential benefits of immunotherapy involving other immune modulating molecules. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Generalised convulsive status epilepticus in Singapore: clinical outcomes and potential prognostic markers.

    Science.gov (United States)

    Rathakrishnan, Rahul; Sidik, Novalia Purnama; Huak, Chan Yiong; Wilder-Smith, Einar P

    2009-04-01

    To study the characteristics, outcomes and prognostic markers of convulsive status epilepticus (SE) in Singapore. 62 adult admissions to the National University Hospital Singapore from 2002 to 2005 were studied. Ethnicity, history of epilepsy, educational subnormality, neuroimaging, seizure duration, length of stay, Modified Rankin Scale (MRS) pre and post discharge, blood glucose, creatine kinase, potassium, white cell and platelet count were recorded. An MRS> or =3 at discharge was defined as a poor outcome. ROCs of significant variables were plotted to identify the best test cut-offs. Mean age was 59.2 years (range 20-94). 75.9% patients had epilepsy. Mean length of stay was 14 days (range 1-75). Univariate analyses revealed age (p=0.01, OR 1.075, 95% CI 1.030-1.122), length of stay in ICU (p=0.03, OR 1.299, 95% CI 1.014-1.665) and hospital (p=0.014, OR 1.203, 95% CI 1.038-1.393) and hyperglycemia (p=0.045, OR 1.327, 95% CI 1.007-1.750) associated with poor outcome. Test cut-off values for prognostic markers were established: age> or =55 years (ROC 0.790, sensitivity 72.3, specificity 85.7, PPV9 4.4%, NPV 48.8%) and serum glucose> or =7 mmol/L (ROC 0.737, sensitivity 72.3, specificity 80.0, PPV 93.5%, NPV 36.4%). A discriminant model using these variables was then constructed with probability scores for poor outcome. Age, hyperglycemia and length of stay in hospital influenced outcome from convulsive SE in the local population with hyperglycemia being a novel prognostic marker. Some prognostic markers cited in the literature differed, highlighting the possibility that these indicators may vary across population groups.

  4. Skeletal Muscle Depletion and Markers for Cancer Cachexia Are Strong Prognostic Factors in Epithelial Ovarian Cancer.

    Directory of Open Access Journals (Sweden)

    Stefanie Aust

    Full Text Available Tumor cachexia is an important prognostic parameter in epithelial ovarian cancer (EOC. Tumor cachexia is characterized by metabolic and inflammatory disturbances. These conditions might be reflected by body composition measurements (BCMs ascertained by pre-operative computed tomography (CT. Thus, we aimed to identify the prognostically most relevant BCMs assessed by pre-operative CT in EOC patients.We evaluated muscle BCMs and well established markers of nutritional and inflammatory status, as well as clinical-pathological parameters in 140 consecutive patients with EOC. Furthermore, a multiplexed inflammatory marker panel of 25 cytokines was used to determine the relationship of BCMs with inflammatory markers and patient's outcome. All relevant parameters were evaluated in uni- and multivariate survival analysis.Muscle attenuation (MA-a well established BCM parameter-is an independent prognostic factor for survival in multivariate analysis (HR 2.25; p = 0.028. Low MA-reflecting a state of cachexia-is also associated with residual tumor after cytoreductive surgery (p = 0.046 and with an unfavorable performance status (p = 0.015. Moreover, MA is associated with Eotaxin and IL-10 out of the 25 cytokine multiplex marker panel in multivariate linear regression analysis (p = 0.021 and p = 0.047, respectively.MA-ascertained by routine pre-operative CT-is an independent prognostic parameter in EOC patients. Low MA is associated with the inflammatory, as well as the nutritional component of cachexia. Therefore, the clinical value of pre-operative CT could be enhanced by the assessment of MA.

  5. Diffuse Large B-cell lymphoma: Prognostic markers and their impact on therapy.

    Science.gov (United States)

    Jamil, Muhammad O; Mehta, Amitkumar

    2016-05-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma (NHL). DLBCL is clinically, pathologically and molecularly heterogeneous disease. Various clinical, pathological and molecular markers have been developed to characterize the disease. Based on these characterizations, new targeted agents are being investigated to optimize the treatment and improve the outcomes of DLBCL. Enhanced molecular understanding, invention of targeted agents and immunotherapy has opened the doors for improvement in the treatment of DLBCL. In this review, we will discuss various prognostic markers of DLBCL and their potential therapeutic implications.

  6. Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690.

    Science.gov (United States)

    Kashani-Sabet, Mohammed; Nosrati, Mehdi; Miller, James R; Sagebiel, Richard W; Leong, Stanley P L; Lesniak, Andrew; Tong, Schuyler; Lee, Sandra J; Kirkwood, John M

    2017-11-15

    Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose IFNα-2b versus observation.Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multimarker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multimarker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier analysis, and both univariate and multivariate Cox regression analyses.Results: By Kaplan-Meier analysis, high multimarker expression scores were significantly predictive of RFS (P melanoma in a prospectively collected cohort. Clin Cancer Res; 23(22); 6888-92. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer.

    Science.gov (United States)

    Collina, Francesca; Di Bonito, Maurizio; Li Bergolis, Valeria; De Laurentiis, Michelino; Vitagliano, Carlo; Cerrone, Margherita; Nuzzo, Francesco; Cantile, Monica; Botti, Gerardo

    2015-01-01

    Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.

  8. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Francesca Collina

    2015-01-01

    Full Text Available Triple-negative breast cancer (TNBC has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.

  9. Early postoperative tumor marker responses provide a robust prognostic indicator for N3 stage gastric cancer.

    Science.gov (United States)

    Zhang, Qingrui; Qu, Hui; Sun, Guorui; Li, Zhiqiang; Ma, Shuzhen; Shi, Zhenxing; Zhao, Ensheng; Zhang, Hao; He, Qingsi

    2017-08-01

    The clinical significance of tumor markers after radical gastrectomy has not been well characterized. The purpose of this study is to evaluate the prognostic value of early postoperative tumor marker normalization in N3 stage gastric cancer (GC) patients. A total of 259 N3 stage GC patients with preoperatively elevated carcinoembryonic antigen (CEA, >5 ng/mL) or carbohydrate antigen 19-9 (CA19-9, >37 U/mL) levels underwent radical gastrectomy were analyzed retrospectively. Early postoperative tumor marker response was considered as a normalization of CEA or CA19-9 levels 4 weeks after surgery. The disease-free survival (DFS) and overall survival (OS) were analyzed. N3 stage GC patients were divided into N3a (n = 157) and N3b (n = 102) groups according to the 8th TNM stage system. Early tumor marker response was identified in 96 of 157 N3a patients (61.15%) and 57 of 102 N3b patients (55.88%). In N3 stage GC patients with a tumor marker response, significant increase was observed in both DFS (25.2 months vs 12.5 months, P early tumor marker response was an independent factor for DFS and OS in N3 stage GC, as well as for depth of invasion and metastatic lymph node rate (P Early postoperative CEA or CA19-9 normalization serves as a strong prognostic indicator in N3 stage GC. Both N3a and N3b patients with increased early postoperative tumor marker levels showed poor outcomes.

  10. Expression of EMT markers and mode of surgery are prognostic in phyllodes tumors of the breast.

    Science.gov (United States)

    Feng, Xiaolong; Zhao, Lin; Shen, Honghong; Liu, Xiaozhen; Yang, Yang; Lv, Shuhua; Niu, Yun

    2017-05-16

    Phyllodes tumors of the breast are rare neoplasms that account for tumors and 2-3% of fibro-epithelial neoplasms of the breast. We evaluated the clinicopathological characteristics of a cohort of 246 Chinese patients in relation to the expression of epithelial-to-mesenchymal (EMT) markers in benign, borderline and malignant tumors and the prognostic value of different surgical regimens. We observed that survival outcomes correlated with the mode of surgical management in the three patient groups. Expression of E-cadherin, Snail, Slug and Twist were higher in epithelial cells from borderline and malignant tumors than those in benign tumors, whereas the expression of N-cadherin was opposite. Levels of the EMT markers Snail and Slug in the stromal compartment increased with the advancing tumor grade. Expression of mesenchymal stem cell markers contributed to the inherent heterogeneity in the malignant tumors. Based on Cox models, surgical management emerged as an independent predictor for disease-free survival, whereas a history of recent growth and tumor grade were independent predictors for overall survival. These findings show that expression of EMT markers, the mode of surgical management, and a history of recent tumor growth had prognostic potential for patients with phyllodes tumors of the breast.

  11. Expression of EMT markers and mode of surgery are prognostic in phyllodes tumors of the breast

    Science.gov (United States)

    Feng, Xiaolong; Zhao, Lin; Shen, Honghong; Liu, Xiaozhen; Yang, Yang; Lv, Shuhua; Niu, Yun

    2017-01-01

    Phyllodes tumors of the breast are rare neoplasms that account for tumors and 2-3% of fibro-epithelial neoplasms of the breast. We evaluated the clinicopathological characteristics of a cohort of 246 Chinese patients in relation to the expression of epithelial-to-mesenchymal (EMT) markers in benign, borderline and malignant tumors and the prognostic value of different surgical regimens. We observed that survival outcomes correlated with the mode of surgical management in the three patient groups. Expression of E-cadherin, Snail, Slug and Twist were higher in epithelial cells from borderline and malignant tumors than those in benign tumors, whereas the expression of N-cadherin was opposite. Levels of the EMT markers Snail and Slug in the stromal compartment increased with the advancing tumor grade. Expression of mesenchymal stem cell markers contributed to the inherent heterogeneity in the malignant tumors. Based on Cox models, surgical management emerged as an independent predictor for disease-free survival, whereas a history of recent growth and tumor grade were independent predictors for overall survival. These findings show that expression of EMT markers, the mode of surgical management, and a history of recent tumor growth had prognostic potential for patients with phyllodes tumors of the breast. PMID:28380418

  12. Treatment Outcome and Prognostic Molecular Markers of Supratentorial Primitive Neuroectodermal Tumors.

    Directory of Open Access Journals (Sweden)

    Seo Hee Choi

    Full Text Available To identify prognostic factors and define the optimal management of patients with supratentorial primitive neuroectodermal tumors (sPNETs, we investigated treatment outcomes and explored the prognostic value of specific molecular markers.A total of 47 consecutive patients with pathologically confirmed sPNETs between May 1985 and June 2012 were included. Immunohistochemical analysis of LIN28, OLIG2, and Rad51 expression was performed and correlated with clinical outcome.With a median follow-up of 70 months, 5-year overall survival (OS and progression-free survival (PFS was 55.5% and 40%, respectively, for all patients. Age, surgical extent, and radiotherapy were significant prognostic factors for OS and PFS. Patients who received initially planned multimodal treatment without interruption (i.e., radiotherapy and surgery (≥subtotal resection, with or without chemotherapy showed significantly higher 5-year OS (71.2% and PFS (63.1%. In 29 patients with available tumor specimens, tumors with high expression of either LIN28 or OLIG2 or elevated level of Rad51 were significantly associated with poorer prognosis.We found that multimodal treatment improved outcomes for sPNET patients, especially when radiotherapy and ≥subtotal resection were part of the treatment regimen. Furthermore, we confirmed the prognostic significance of LIN28 and OLIG2 and revealed the potential role of Rad51 in sPNETs.

  13. New prognostic markers in acute myeloid leukemia: perspective from the clinic.

    Science.gov (United States)

    Foran, James M

    2010-01-01

    Acute myeloid leukemia (AML) is a disease with marked heterogeneity in both response to therapy and survival. Cytogenetics, age, and performance status have long determined prognosis and therapy. The advent of molecular diagnostics has heralded an explosion in new prognostic factors, including gene mutations in KIT, FLT3 (Fms-like tyrosine kinase 3), NPM1 (nucleophosmin 1), and CEBPA (CCAAT enhancer-binding protein-α). Microarray technology can now identify unique gene expression signatures associated with prognosis. Similarly microRNA expression, single nucleotide polymorphism arrays, and DNA methylation signatures have recently described important new prognostic subgroups of AML, and are contributing to our understanding of AML disease biology. Combined with proteomic profiling, these technologies have helped identify new targets and signaling pathways, and may soon help to identify individual patients likely to benefit from specific therapies, including allogeneic hematopoietic cell transplantation. In summary, new clinical and molecular prognostic markers have begun to significantly improve our understanding of AML biology. We are now close to a time when we will be able to use these prognostic factors and technologies to identify new targets for therapy and to determine who may benefit from that therapy, and ultimately change how we treat individual patients with AML.

  14. Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Nøjgaard, Camilla; Johansen, Julia S; Christensen, Erik

    2003-01-01

    patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS: Serum YKL-40 and PIIINP were elevated......BACKGROUND/AIMS: YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS: Three hundred and seventy...... in alcoholic patients, related to the presence of liver fibrosis and may provide prognostic information....

  15. Glucose transporter-1 as an independent prognostic marker for cancer: a meta-analysis

    Science.gov (United States)

    Zhao, Zheng-Xiao; Lu, Lin-Wei; Qiu, Jian; Li, Qiu-Ping; Xu, Fei; Liu, Bao-Jun; Dong, Jing-Cheng; Gong, Wei-Yi

    2018-01-01

    Objective Glucose transporter-1 (GLUT-1) as the major glucose transporter present in human cells is found overexpressed in a proportion of human malignancies. This meta-analysis is attempted to assess the prognostic significance of GLUT-1 for survival in various cancers. Materials and Methods We conducted an electronic search using the databases PubMed, Embase and Web of Science, from inception to Oct 20th, 2016. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Results Fourty-one studies with a total of 4794 patients were included. High GLUT-1 expression was significantly associated with poorer prognosis [overall survival: HR = 1.833 (95% CI: 1.597–2.069, P GLUT-1 expression may be an independent prognostic marker to predict poor survival in various types of cancers. Further clinical trials with high quality need to be conducted to confirm our conclusion. PMID:29416806

  16. Prognostic significance of new immunohistochemical markers in refractory classical Hodgkin lymphoma: a study of 59 cases.

    Directory of Open Access Journals (Sweden)

    Danielle Canioni

    Full Text Available Although most classical Hodgkin lymphoma patients are cured, a significant minority fail after primary therapy and may die as result of their disease. To date, there is no consensus on biological markers that add value to usual parameters (which comprise the International Prognostic Score used at diagnosis to predict outcome. We evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders for bcl2, Ki67, CD20, TiA1 and c-kit expression by semi-quantitative immunohistochemical study and correlated the results with the response to treatment.The results showed that expression of bcl2 and CD20 in Hodgkin and Reed Sternberg cells, and expression of TiA1 in micro-environmental lymphocytes, and c-kit positive mast cells in microenvironment, were independent prognostic markers. These novel cHL markers could be used in association with clinical parameters to identify newly diagnosed patients with favorable or unfavorable prognosis and to better tailor treatment for different risk groups.

  17. EGFR mutations as a prognostic and predictive marker in non-small-cell lung cancer

    Science.gov (United States)

    Fang, Shu; Wang, Zhehai

    2014-01-01

    Non-small-cell lung cancer (NSCLC) has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. At present, there is a consensus among clinicians that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown favorable efficacy in NSCLC patients with EGFR mutation, and some relevant research has suggested that the presence of EGFR mutations is a favorable prognostic marker. However, the association of EGFR mutation status with the responsiveness to conventional chemotherapy agents and survival in NSCLC patients is still unclear. This review provides an overview of and assesses the role of EGFR as a prognostic marker for postoperative patients and as a predictive marker for response to cytotoxic chemotherapy. In addition, we review the comparison of response to chemotherapy between EGFR mutations in exon 19 and in exon 21 and the predictive role of p.T790M mutation. PMID:25302015

  18. Prognostics

    Data.gov (United States)

    National Aeronautics and Space Administration — Prognostics has received considerable attention recently as an emerging sub-discipline within SHM. Prognosis is here strictly defined as “predicting the time at...

  19. Associations of persistent organic pollutants in serum and adipose tissue with breast cancer prognostic markers

    Energy Technology Data Exchange (ETDEWEB)

    Arrebola, J.P., E-mail: jparrebola@ugr.es [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); Virgen de las Nieves University Hospital, Radiation Oncology Department, Oncology Unit, Granada (Spain); CIBER en Epidemiología y Salud Pública (CIBERESP) (Spain); Fernández-Rodríguez, M.; Artacho-Cordón, F. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); University of Granada, Radiology and Physical Medicine Department (Spain); Garde, C. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); Perez-Carrascosa, F.; Linares, I.; Tovar, I. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); Virgen de las Nieves University Hospital, Radiation Oncology Department, Oncology Unit, Granada (Spain); González-Alzaga, B. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); Escuela Andaluza de Salud Pública, Granada (Spain); Expósito, J. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); Virgen de las Nieves University Hospital, Radiation Oncology Department, Oncology Unit, Granada (Spain); Torne, P. [Instituto de Investigación Biosanitaria (ibs. GRANADA), Hospitales Universitarios de Granada (Spain); and others

    2016-10-01

    This study aimed to evaluate associations between exposure to a group of persistent organic pollutants, measured in both adipose tissue and serum samples from breast cancer patients, and a set of tumor prognostic markers. The study population comprised 103 breast cancer patients recruited in Granada, Southern Spain. Data for tumor prognostic markers were retrieved from hospital clinical records and socio-demographic information was gathered by questionnaire. Persistent organic pollutants were quantified by gas chromatography with electron capture detection. Exposure levels were categorized in quartiles, and associations were evaluated using unconditional logistic regression. Adipose tissue HCB concentrations were associated positively with ER and PR expression (p-trends = 0.044 and 0.005, respectively) and negatively with E-Cadherin and p53 expression (p-trends = 0.012 and 0.027, respectively). PCB-180 adipose tissue concentrations were positively associated with HER2 expression (p-trend = 0.036). Serum PCB-138 concentrations were positively associated with ER and PR expression (p-trends = 0.052 and 0.042, respectively). The risk of p53 expression was higher among women in the lowest quartile of serum PCB-138 concentrations, but no significant trend was observed (p-trend = 0.161). These findings indicate that human exposure to certain persistent organic pollutants might be related to breast cancer aggressiveness. We also highlight the influence on exposure assessment of the biological matrix selected, given that both serum and adipose tissue might yield relevant information on breast cancer prognosis. - Highlights: • The role of POP exposure on the pathogenesis breast cancer is still controversial. • POPs were analyzed in serum and adipose tissue from breast cancer patients. • POP concentrations were associated with breast cancer prognostic markers. • POPs in serum and adipose tissue of breast cancer patients may provide different clues.

  20. Analyzing proteasomal subunit expression reveals Rpt4 as a prognostic marker in stage II colorectal cancer.

    LENUS (Irish Health Repository)

    2012-02-01

    Colorectal cancer is a leading cause of cancer-related deaths worldwide. Early diagnosis and treatment of colorectal cancer is the key to improving survival rates and as such a need exists to identify patients who may benefit from adjuvant chemotherapy. The dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in oncogenesis and cancer cell survival, and proteasome inhibitors are in clinical use for a number of malignancies including multiple myeloma. In our study, we examined the protein expression of several key components of the UPS in colorectal cancer using immunohistochemistry to determine expression levels of ubiquitinylated proteins and the proteasomal subunits, 20S core and Rpt4 in a cohort of 228 patients with colon cancer. Multivariate Cox analysis revealed that neither the intensity of either ubiquitinylated proteins or the 20S core was predictive in either Stage II or III colon cancer for disease free survival or overall survival. In contrast, in Stage II patients increased Rpt4 staining was significantly associated with disease free survival (Cox proportional hazard ratio 0.605; p = 0.0217). Our data suggest that Rpt4 is an independent prognostic variable for Stage II colorectal cancer and may aid in the decision of which patients undergo adjuvant chemotherapy.

  1. Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer.

    Science.gov (United States)

    Grönberg, Malin; Ahlin, Cecilia; Naeser, Ylva; Janson, Eva Tiensuu; Holmberg, Lars; Fjällskog, Marie-Louise

    2017-01-01

    Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84) and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89). Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46). Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.

  2. Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer.

    Directory of Open Access Journals (Sweden)

    Malin Grönberg

    Full Text Available Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84 and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89. Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46. Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.

  3. [Serum neuron-specific enolase as a prognostic marker after a cardiac arrest].

    Science.gov (United States)

    Rech, Tatiana H; Vieira, Silvia Regina Rios; Brauner, Janete Salles

    2006-12-01

    Cardiac arrest is a state of severe cerebral perfusion deficit. Patients recovering from a cardiopulmonary resuscitation are at great risk of subsequent death or incapacitating neurologic injury, including persistent vegetative state. The early definition of prognosis for these patients has ethical and economic implications. The main purpose of this manuscript was to review the prognostic value of serum Neuron-Specific Enolase (NSE) in predicting outcomes in patients early after a cardiac arrest. Severe neurologic disability is the most feared complication after a cardiac arrest. Many studies are trying to find prognostic markers that can be associated with outcomes in patients surviving a cardiac arrest. Biochemical markers of neuronal injury seem to be promising in this scenario. Therefore, NSE levels have been studied in patients after a cardiac arrest and high enzyme levels suggest more extensive brain damage and are associated with unfavorable clinical outcomes. Outcome after a cardiac arrest is mostly determined by the degree of hypoxic brain damage and early determinations of serum NSE level can be a valuable ancillary method for assessing outcome in these patients.

  4. Thioredoxin is a novel diagnostic and prognostic marker in patients with ischemic stroke.

    Science.gov (United States)

    Qi, Ai-qin; Li, Yan; Liu, Qiang; Si, Jun-Zeng; Tang, Xiao-Mei; Zhang, Zhi-Qiang; Qi, Qin-De; Chen, Wei-Bi

    2015-03-01

    Serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity, was recognized as an oxidative-stress marker. The purpose of this study was to investigate the potential diagnostic and prognostic role of TRX in Chinese patients with acute ischemic stroke (AIS). From January 1, 2012, to December 31, 2013, all patients with first-ever acute ischemic stroke were recruited to participate in the study. Serum levels of TRX were assayed with solid-phase sandwich ELISA, and severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission. Short-term functional outcome was measured by a modified Rankin scale (mRS) 3 months after admission. Multivariate analyses were performed using logistic regression models. We found the serum TRX reflected the disease severity of AIS. There was a significant positive association between serum TRX levels and NIHSS scores (r= 0.476, Pmarker of short-term functional outcome [odds ratio (OR) 9.482 (95% CI, 3.11-8.15) Pdiagnostic and prognostic marker in patients with acute ischemic stroke. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Ceruloplasmin as a prognostic marker in patients with bile duct cancer.

    Science.gov (United States)

    Han, In Woong; Jang, Jin-Young; Kwon, Wooil; Park, Taesung; Kim, Yongkang; Lee, Kyoung Bun; Kim, Sun-Whe

    2017-04-25

    Bile duct cancer is one of the lethal cancers, presenting difficulties in early diagnosis and limited treatment modalities. Despite current advances in biomarker research, most studies have been performed in Western populations. Therefore, the purpose of this study was to determine a prognostic marker for bile duct cancer, especially in Korean patients, whose incidence of bile duct cancer is high. Comparing cancer and normal bile duct tissue, we identified 29091 differentially expressed genes. CP, SCEL, and MUC16 had positive coefficients with a log2 ratio >1 for advanced T, N stage and perineural invasion cancer tissue. Strong immunohistochemical expression of ceruloplasmin was dominant in tumors with advanced T stage (p>0.999) and perineural invasion (p=0.316). We performed tissue microarray experiment with 79 bile duct cancer tissue samples and 21 normal bile duct tissue samples. Candidate genes that has positive correlation with T, N stage and perineural invasion were drawn with multivariate analysis. Tissue expression of the genes was evaluated with an immunohistochemical study. Ceruloplasmin is supposed to be related with advanced T stage and perineural invasion, having a possibility as a candidate prognostic marker for bile duct cancer.

  6. Prostate-specific membrane antigen expression is a potential prognostic marker in endometrial adenocarcinoma.

    Science.gov (United States)

    Mhawech-Fauceglia, Paulette; Smiraglia, Dominic J; Bshara, Wiam; Andrews, Christopher; Schwaller, Juerg; South, Stacey; Higgs, Donald; Lele, Shashikant; Herrmann, Francois; Odunsi, Kunle

    2008-03-01

    The aim of this study was to determine the role of prostate-specific membrane antigen (PSMA) as a prognostic marker in endometrial adenocarcinoma (EAC) and to explore whether its down-regulation could be due to epigenetic mechanism. First, we examined the expression and the prognostic value of PSMA by semiquantitative reverse transcription-PCR and immunohistochemistry in EAC tissue samples. Second, to explore the role of CpG methylation in down-regulation PSMA in EAC, we evaluated PSMA CpG island methylation using methylation-specific PCR in cells lines and in a subset of patients' samples. Furthermore, association of the status of tumor methylation to the clinical and histologic variables was also evaluated. Higher PSMA mRNA levels were associated with stage I (P = 0.046) and PSMA protein intensity by immunohistochemistry (P = 0.032). In multivariate analysis, loss of PSMA expression was associated with a worse disease-free survival (P = 0.02). PSMA was methylated in prostate cell lines (DU145 and PC3) and endometrial cell lines. In addition, PSMA was methylated in 5 of 18 samples (all 5 had low PSMA mRNA value). There was a significant association between PSMA methylation and loss of protein expression by immunohistochemistry and PSMA-RNA level with P value of 0.036 and 0.011, respectively. In addition, there was an association between PSMA methylation and tumor size (P = 0.025). In summary, (a) PSMA is underexpressed in advanced stage EAC, (b) loss of PSMA expression can be considered as a prognostic marker in patients with EAC, and (c) loss of PSMA expression in a subset of EAC cases could be due to epigenetic silencing.

  7. The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma.

    Science.gov (United States)

    Montes de Oca, Rocío; Gurard-Levin, Zachary A; Berger, Frédérique; Rehman, Haniya; Martel, Elise; Corpet, Armelle; de Koning, Leanne; Vassias, Isabelle; Wilson, Laurence O W; Meseure, Didier; Reyal, Fabien; Savignoni, Alexia; Asselain, Bernard; Sastre-Garau, Xavier; Almouzni, Geneviève

    2015-03-01

    Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, where robust diagnostic tools to aid clinical treatment decisions are lacking. Recent data implicating chromatin regulators in cancer initiation and progression offers a promising avenue to develop new tools to help guide clinical decisions. Here we exploit a published transcriptome dataset and an independent validation cohort to correlate the mRNA expression of selected chromatin regulators with respect to the four intrinsic breast cancer molecular subtypes. We then perform univariate and multivariate analyses to compare the prognostic value of a panel of chromatin regulators to Ki67, a currently utilized proliferation marker. Unsupervised hierarchical clustering revealed a gene cluster containing several histone chaperones and histone variants highly-expressed in the proliferative subtypes (basal-like, HER2-positive, luminal B) but not in the luminal A subtype. Several chromatin regulators, including the histone chaperones CAF-1 (subunits p150 and p60), ASF1b, and HJURP, and the centromeric histone variant CENP-A, associated with local and metastatic relapse and poor patient outcome. Importantly, we find that HJURP can discriminate favorable and unfavorable outcome within the luminal A subtype, outperforming the currently utilized proliferation marker Ki67, as an independent prognostic marker for luminal A patients. The integration of chromatin regulators as clinical biomarkers, in particular the histone chaperone HJURP, will help guide patient substratification and treatment options for low-risk luminal A breast carcinoma patients. Copyright © 2014. Published by Elsevier B.V.

  8. Hypoxia inducible BHLHB2 is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Weibin; Reiser-Erkan, Carolin; Michalski, Christoph W.; Raggi, Matthias C. [Department of Surgery, Technische Universitaet Muenchen, Munich (Germany); Quan, Liao; Yupei, Zhao [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Peking (China); Friess, Helmut [Department of Surgery, Technische Universitaet Muenchen, Munich (Germany); Erkan, Mert, E-mail: erkan@chir.med.tu-muenchen.de [Department of Surgery, Technische Universitaet Muenchen, Munich (Germany); Kleeff, Joerg [Department of Surgery, Technische Universitaet Muenchen, Munich (Germany)

    2010-10-22

    cells. Patients with weak/absent nuclear BHLHB2 staining had significantly worse median survival compared to those with strong staining (13 months vs. 27 months, p = 0.03). In a multivariable analysis, BHLHB2 staining was an independent prognostic factor (Hazard-Ratio = 2.348, 95% CI = 1.250-4.411, p = 0.008). Conclusions: Hypoxia-inducible BHLHB2 expression is a novel independent prognostic marker in pancreatic cancer patients and indicates increased chemosensitivity towards gemcitabine.

  9. Effect of Hydrochloric Acid Decalcification on Expression Pattern of Prognostic Markers in Invasive Breast Carcinomas.

    Science.gov (United States)

    Maclary, Shawn C; Mohanty, Sambit K; Bose, Shikha; Chung, Fai; Balzer, Bonnie L

    2017-02-01

    In the United States, it is estimated that 100,000 people are living with metastatic breast cancer (BC) with bone representing the most common site of involvement. However, patients with isolated bone metastasis at presentation may have a longer survival. Therapeutic options for BC bone metastases often include systemic anticancer therapy (endocrine, chemotherapy, monoclonal antibodies, and/or other targeted therapies), which is largely dependent on the immunohistochemical (IHC) repertoire of the cancer for the prognostic markers [estrogen (ER) and progesterone receptors (PR), Ki-67, p53, and Her-2/neu] at its osseous metastatic site. Traditionally, specimens obtained from the bone metastasis require decalcification, which may affect the immunoreactivity of these prognostic markers. To the best of our knowledge, limited studies describe the effect of decalcification on immunoexpression of the above-mentioned markers. A detailed illustration of the effect of decalcification on BC specimens in a real-time manner is lacking in the literature. Herein, we sought to determine the impact of decalcification on the IHC expression pattern of the above listed markers on BC tissue following decalcification. After Institutional Review Board approval, sections from the residual tumor specimens were collected prospectively from 15 BC excision specimens and 1 curetting from a BC bone metastasis. The sections (3 to 6 sections/case) for decalcification were collected following routine submission for pathologic evaluation. The sections were subjected to hydrochloric acid (HCl)-based Decal Stat decalcifying solution for 2, 12, 18, and 24 hours in each case. IHC studies for ER, PR, Ki-67, p53, and Her-2/neu were performed on 1 representative section of the regularly processed tumor block and 1 decalcified tumor block from each time point. Scoring of ER and PR were performed according to the Allred scoring system. Scoring of Her-2/neu was performed according to CAP/ASCO guidelines. The

  10. Bax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Bose Pinaki

    2012-08-01

    Full Text Available Abstract Background Resistance to apoptosis is a hallmark of cancer and proteins regulating apoptosis have been proposed as prognostic markers in several malignancies. However, the prognostic impact of apoptotic markers has not been consistently demonstrated in oral squamous cell carcinoma (OSCC. This inconsistency in reported associations between apoptotic proteins and prognosis can be partly attributed to the intrinsic low resolution and misclassification associated with manual, semi-quantitative methods of biomarker expression measurement. The aim of this study was to examine the association between apoptosis-regulating proteins and clinical outcomes in oral squamous cell carcinoma (OSCC using the quantitative fluorescence immunohistochemistry (IHC based AQUAnalysis technique. Methods Sixty-nine OSCC patients diagnosed between 1998–2005 in Calgary, Alberta, Canada were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs were assembled from triplicate cores of formalin-fixed paraffin embedded pre-treatment tumour tissue. Bax, Bcl-2 and Bcl-XL protein expression was quantified using fluorescent IHC and AQUA technology in normal oral cavity squamous epithelium (OCSE and OSCC tumour samples. Survival was analyzed using Kaplan-Meier plots and the Cox proportional hazard model. Results Bax expression was predominantly nuclear in OCSE and almost exclusively cytoplasmic in OSCC. No similar differences in localization were observed for Bcl-2 or Bcl-XL. Only Bax expression associated with disease-specific survival (DSS, with 5-year survival estimates of 85.7% for high Bax versus 50.3% for low Bax (p = 0.006, in univariate analysis. High Bax expression was also significantly associated with elevated Ki67 expression, indicating that increased proliferation might lead to an improved response to radiotherapy in patients with elevated Bax expression. In multivariate analyses

  11. Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression.

    Science.gov (United States)

    Saraon, Punit; Trudel, Dominique; Kron, Ken; Dmitromanolakis, Apostolos; Trachtenberg, John; Bapat, Bharati; van der Kwast, Theodorus; Jarvi, Keith A; Diamandis, Eleftherios P

    2014-04-01

    Prostate cancer is the second leading cause of cancer-related death among men in North America. While a majority of prostate cancer cases remain indolent, subsets of patients develop aggressive cancers, which may lead to death. The current methods of detection include digital rectal examination and the serum PSA test. However, due to lack of specificity, neither of these approaches is able to accurately discriminate between indolent and aggressive cancer, which is why there is a need for additional prognostic factors. Previously, we identified enzymes of the ketogenic pathway, particularly ACAT1, to be elevated in aggressive prostate cancer. In the current study, we assessed the diagnostic and prognostic potential of ACAT1 by analyzing its expression using immunohistochemistry on a tissue microarray consisting of 251 clinically localized prostate cancer patients who have undergone radical prostatectomy. Using quantitative digital imaging software, we found that ACAT1 expression was significantly greater in cancerous cores compared to adjacent benign cores (P cancers versus GS≤6 cancers (P cancers versus GS7 cancers (P = 0.001), as well as pT3/pT4 versus pT2 cancers (P = 0.001). In addition, ACAT1 predicted biochemical recurrence in univariate (HR, 1.81, CI = 1.13-2.9, P = 0.0128), and multivariate models (HR, 1.69, CI = 1.01-2.81, P = 0.0431) including pre-operative PSA level, Gleason score and pathological stage. In univariate time-to-recurrence analysis, ACAT1 expression predicted recurrence in ERG negative cases (P = 0.0025), whereas ERG positive cases did not display any differences. Taken together, these findings indicate that ACAT1 expression could serve as a potential prognostic marker in prostate cancer, specifically in differentiating indolent and aggressive forms of cancer. © 2013 Wiley Periodicals, Inc.

  12. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer.

    LENUS (Irish Health Repository)

    Wang, Lai Mun

    2012-02-01

    BACKGROUND: Tumor budding along the advancing front of colorectal adenocarcinoma is an early event in the metastatic process. A reproducible, prognostic budding scoring system based on outcomes in early stage colorectal cancer has not been established. DESIGN: One hundred twenty-eight T3N0M0 colorectal carcinoma patients with known outcome were identified. Tumor budding was defined as isolated tumor cells or clusters of <5 cells at the invasive tumor front. Tumor bud counts were generated in 5 regions at 200x by 2 pathologists (conventional bud count method). The median bud count per case was used to divide cases into low (median=0) and high budding (median > or =1) groups. Forty cases were reevaluated to assess reproducibility using the conventional and a novel rapid bud count method. RESULTS: Fifty-seven (45%) carcinomas had high and 71 (55%) had low budding scores. High budding was associated with an infiltrative growth pattern (P<0.0001) and lymphovascular invasion (P=0.005). Five-year cancer-specific survival was significantly poorer in high compared with low budding groups: 63% versus 91%, respectively, P<0.0001. Multivariate analysis demonstrated tumor budding to be independently prognostic (hazard ratio=4.76, P<0.001). Interobserver agreement was at least equivalent comparing the conventional to the rapid bud count methods: 87.5% agreement (kappa=0.75) versus 92.5% agreement (kappa=0.85), respectively. CONCLUSIONS: Tumor budding is a strong, reproducible, and independent prognostic marker of outcome that is easily assessed on hematoxylin and eosin slides. This may be useful for identifying the subset of T3N0M0 patients at high risk of recurrence who may benefit from adjuvant therapy.

  13. Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma.

    Science.gov (United States)

    Wouters, Jasper; Vizoso, Miguel; Martinez-Cardus, Anna; Carmona, F Javier; Govaere, Olivier; Laguna, Teresa; Joseph, Jesuchristopher; Dynoodt, Peter; Aura, Claudia; Foth, Mona; Cloots, Roy; van den Hurk, Karin; Balint, Balazs; Murphy, Ian G; McDermott, Enda W; Sheahan, Kieran; Jirström, Karin; Nodin, Bjorn; Mallya-Udupi, Girish; van den Oord, Joost J; Gallagher, William M; Esteller, Manel

    2017-06-05

    Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.

  14. Interleukin-6 as a prognostic marker in dogs in an intensive care unit.

    Science.gov (United States)

    Schüttler, Julia; Neumann, Stephan

    2015-06-01

    Interleukin-6 (IL-6) is involved in the acute phase reaction during inflammatory disease, including septicemia and the inflammatory response syndrome (SIRS). In people, IL-6 has been studied as a prognostic marker in intensive care medicine, where nonsurvivors had significantly higher IL-6 concentrations than survivors. The objective of the study was to investigate the prognostic value of IL-6 in dogs admitted to the intensive care unit based on sensitivity and specificity. Dogs suffering from different severe diseases treated in the intensive care unit were divided into 2 groups of survivors and nonsurvivors. Serum IL-6 concentrations were measured with a canine-specific ELISA (enzyme-linked immunosorbent assay) kit. Sixty-nine dogs were included in the study, including 20 survivors, 9 nonsurvivors, and 40 control dogs. In the control group, IL-6 serum concentrations were below the detection level (0 pg/mL). In the group of nonsurviving dogs, IL-6 ranged from 45-4656 pg/mL (median 1398 pg/mL). The surviving dogs had a range of 0-405 pg/mL (median 84.5 pg/mL). The mean IL-6 concentration was significantly higher (P care patients with acute internal disease. © 2015 American Society for Veterinary Clinical Pathology.

  15. FBXW7 Acts as an Independent Prognostic Marker and Inhibits Tumor Growth in Human Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Zhanchun Li

    2015-01-01

    Full Text Available F-box and WD repeat domain-containing 7 (FBXW7 is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS.

  16. ADENOSINE DEAMINASE ACTIVITY AND SERUM C-REACTIVE PROTEIN AS PROGNOSTIC MARKERS OF CHAGAS DISEASE SEVERITY

    Directory of Open Access Journals (Sweden)

    Iván Darío BRAVO-TOBAR

    2015-10-01

    Full Text Available SUMMARY Chagas disease is a public health problem worldwide. The availability of diagnostic tools to predict the development of chronic Chagas cardiomyopathy is crucial to reduce morbidity and mortality. Here we analyze the prognostic value of adenosine deaminase serum activity (ADA and C-reactive protein serum levels (CRP in chagasic individuals. One hundred and ten individuals, 28 healthy and 82 chagasic patients were divided according to disease severity in phase I (n = 35, II (n = 29, and III (n = 18. A complete medical history, 12-lead electrocardiogram, chest X-ray, and M-mode echocardiogram were performed on each individual. Diagnosis of Chagas disease was confirmed by ELISA and MABA using recombinant antigens; ADA was determined spectrophotometrically and CRP by ELISA. The results have shown that CRP and ADA increased linearly in relation to disease phase, CRP being significantly higher in phase III and ADA at all phases. Also, CRP and ADA were positively correlated with echocardiographic parameters of cardiac remodeling and with electrocardiographic abnormalities, and negatively with ejection fraction. CRP and ADA were higher in patients with cardiothoracic index ≥ 50%, while ADA was higher in patients with ventricular repolarization disturbances. Finally, CRP was positively correlated with ADA. In conclusion, ADA and CRP are prognostic markers of cardiac dysfunction and remodeling in Chagas disease.

  17. Serum interleukin-6 as a prognostic marker in neonatal calf diarrhea.

    Science.gov (United States)

    Fischer, Stephani; Bauerfeind, Rolf; Czerny, Claus-Peter; Neumann, Stephan

    2016-08-01

    Neonatal calf diarrhea is still one of the most important diseases in calf rearing, and severe diarrhea has a marked effect on animal welfare. Furthermore, significant economic losses can result from this disease due to high mortality rates, high medical costs, and low weight gain. To avoid a fatal outcome of the disease, it is crucial that vulnerable calves are identified as early as possible. Interleukin-6 is described as an early and reliable prognostic marker in several diseases. In this study, 20 scouring calves were tested by ELISA for their IL-6 serum concentrations. Samples were collected twice, at the beginning of diarrhea and 7 to 10d later. Regarding the clinical outcome after 7 to 10d, calves were classified as recovered or nonrecovered. A receiver operating characteristic analysis was conducted to determine the prognostic value of IL-6 for the progress of clinical symptoms. At the beginning of diarrhea, the IL-6 concentration was significantly higher in nonrecovering calves compared with those that recover 7 to 10d after the onset of diarrhea. Interleukin-6 proved to be a useful additional parameter in the clinical examination. High initial IL-6 values can support the decision for closer monitoring and an adapted therapeutic strategy for the respective calves. This may help to prevent unnecessary animal suffering and reduce economic losses. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  18. FGFR Family Members Protein Expression as Prognostic Markers in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma.

    Science.gov (United States)

    Koole, Koos; Clausen, Martijn J A M; van Es, Robert J J; van Kempen, Pauline M W; Melchers, Lieuwe J; Koole, Ron; Langendijk, Johannes A; van Diest, Paul J; Roodenburg, Jan L N; Schuuring, Ed; Willems, Stefan M

    2016-08-01

    Fibroblast growth factor receptor family member proteins (FGFR1-4) have been identified as promising novel therapeutic targets and prognostic markers in a wide spectrum of solid tumors. The present study investigates the expression and prognostic value of four FGFR family member proteins in a large multicenter oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) cohort. Protein expression of FGFR1-4 was determined by immunohistochemistry on tissue microarrays containing 951 formalin-fixed paraffin embedded OCSCC and OPSCC tissues from the University Medical Center Utrecht and University Medical Center Groningen. Protein expression was correlated to overall survival using Cox regression models, and bootstrapping was performed as internal validation. FGFR proteins were highly expressed in 39-64 % of OCSCC and 63-79 % of OPSCC. Seventy-three percent (299/412) of OCSCC and 85 % (305/357) of OPSCC highly co-expressed two or more FGFR family member proteins. FGFR1 protein was more frequently highly expressed in human papillomavirus (HPV)-negative OPSCC than HPV-positive OPSCC (82 vs. 65 %; p = 0.008). Furthermore, protein expression of FGFR family members was not related to overall survival in OCSCC or OPSCC (p > 0.05). FGFR family members are frequently highly expressed in OCSCC and OPSCC. These FGFR family member proteins are therefore potential targets for novel therapies that are urgently required to improve survival of OCSCC and OPSCC patients.

  19. Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Nøjgaard, Camilla; Johansen, Julia S; Christensen, Erik

    2003-01-01

    patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS: Serum YKL-40 and PIIINP were elevated...... with the different grades of fibrosis. Patients with elevated serum YKL-40 or PIIINP had shorter survival than patients with normal serum levels of YKL-40 (Plevels of YKL-40 and PIIINP are elevated......BACKGROUND/AIMS: YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS: Three hundred and seventy...

  20. Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease

    DEFF Research Database (Denmark)

    Nøjgaard, Camilla; Johansen, Julia S; Christensen, Erik

    2003-01-01

    BACKGROUND/AIMS: YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS: Three hundred and seventy...... patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS: Serum YKL-40 and PIIINP were elevated...... in the patients compared to controls. Patients with steatosis or no fibrosis had the lowest serum levels of YKL-40 and PIIINP, whereas patients with alcoholic hepatitis and/or cirrhosis had the highest levels. Serum YKL-40 was associated with the presence of fibrosis, and serum PIIINP was also associated...

  1. Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection.

    Science.gov (United States)

    Kuroda, Daisuke; Sawayama, Hiroshi; Kurashige, Junji; Iwatsuki, Masaaki; Eto, Tsugio; Tokunaga, Ryuma; Kitano, Yuki; Yamamura, Kensuke; Ouchi, Mayuko; Nakamura, Kenichi; Baba, Yoshifumi; Sakamoto, Yasuo; Yamashita, Yoichi; Yoshida, Naoya; Chikamoto, Akira; Baba, Hideo

    2017-06-27

    Controlling Nutritional Status (CONUT), as calculated from serum albumin, total cholesterol concentration, and total lymphocyte count, was previously shown to be useful for nutritional assessment. The current study investigated the potential use of CONUT as a prognostic marker in gastric cancer patients after curative resection. Preoperative CONUT was retrospectively calculated in 416 gastric cancer patients who underwent curative resection at Kumamoto University Hospital from 2005 to 2014. The patients were divided into two groups: CONUT-high (≥4) and CONUT-low (≤3), according to time-dependent receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated. CONUT-high patients were significantly older (p nutritional status but also for predicting long-term OS in gastric cancer patients after curative resection.

  2. Beta blocker dose and markers of sympathetic activation in heart failure patients: interrelationships and prognostic significance.

    Science.gov (United States)

    Cohen-Solal, Alain; Jacobson, Arnold F; Piña, Ileana L

    2017-11-01

    Extent of cardiac sympathetic activation can be estimated from physiological parameters, blood biomarkers, and imaging findings. This study examined the prognostic value of three markers of sympathetic activity and their relationship to beta blocker dose in heart failure patients. A post hoc analysis of 858 heart failure subjects in the ADMIRE-HF trial was performed. Variables related to sympathetic activity were plasma norepinephrine, baseline heart rate, the heart to mediastinum (H/M) ratio of 123 I-mIBG uptake, and beta blocker dose. Univariate and multivariate analyses for occurrence of mortality (all-cause and cardiac) and arrhythmic events were performed. Beta blocker dose was significantly related to age, heart rate, b-type natriuretic peptide (negatively), body mass index, body weight and plasma norepinephrine. Univariate predictors of all-cause and cardiac mortality were baseline heart rate (χ2  = 4.5, P = 0.029 and χ2  = 5 .2, P = 0.022, respectively), plasma norepinephrine level (χ2  = 8.9, P = 0.0006 and χ2  = 8.6, P = 0.003, respectively), and H/M (χ = 22.4, P 67 b.p.m. was associated with significantly higher cardiac mortality. Higher beta blocker dose was associated with lower mortality, but of the variables associated with sympathetic activity examined, cardiac 123 I-mIBG uptake was the most powerful prognostic marker in heart failure patients. Elevated heart rate was associated with greater risk for cardiac death. © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

  3. Study of nonstandard auto-antibodies as prognostic markers in auto immune hepatitis in children

    Directory of Open Access Journals (Sweden)

    Mahmoud Nermine H

    2009-07-01

    Full Text Available Abstract Background Antibodies to chromatin and soluble liver antigen have been associated with severe form of autoimmune hepatitis and/or poor treatment response and may provide guidance in defining subsets of patients with different disease behaviors. The major clinical limitation of these antibodies is their lower individual occurrence in patients with autoimmune hepatitis. Aim To estimate the value of detection of these non-standard antibodies in autoimmune hepatitis as prognostic markers. Methods Both antibodies were tested by enzyme immunoassay in 20 patients with autoimmune hepatitis. Results Antibodies to soluble liver antigen were not detected in any of our patients. On the other hand anti chromatin antibodies were present in 50% (10/20. Antibodies to chromatin occurred more commonly in females than males (8/14 versus 2/6. Of the 14 patients who relapsed 8(57% had antichromatin antibodies while they were present in only 2 out of 6(33.3% non relapsers. Antichromatin antibodies were found more in patients with antinuclear (3/4 and anti smooth muscle antibodies (9/13 more than in those with liver kidney microsomal antibodies (1/4 and those seronegative (1/4 i.e. they were +ve in patients with type I (8/12(66.6% more than those with type II (1/4(25% and those seronegative (1/4(25%. Antibodies to chromatin are associated with high levels of γ globulin but yet with no statistical difference between seropositive and seronegative counterparts (p = 0.65. Conclusion Antibodies to chromatin may be superior than those to soluble liver antigen in predicting relapse and may be useful as prognostic marker. Further studies with larger number of patients and combined testing of more than one antibody will improve the performance parameters of these antibodies and define optimal testing conditions for them before they can be incorporated into management algorithms that project prognosis.

  4. C-terminal tensin-like protein is a novel prognostic marker for primary melanoma patients.

    Directory of Open Access Journals (Sweden)

    Cecilia Sjoestroem

    Full Text Available C-terminal tensin-like protein (Cten is a focal adhesion protein originally identified as a tumor suppressor in prostate cancer. It has since been found to be overexpressed and function as an oncogene in numerous other cancers, but the expression status of Cten in melanoma is still unknown.Using tissue microarrays containing 562 melanocytic lesions, we evaluated Cten protein expression by immunohistochemistry. The association between Cten expression and patient survival was examined using Kaplan-Meier survival analysis, and univariate and multivariate Cox regression analyses were used to estimate the crude and adjusted hazard ratios.Strong Cten expression was detected in 7%, 24%, 41%, and 46% of normal nevi, dysplastic nevi, primary melanoma, and metastatic melanoma samples, respectively, and Cten expression was found to be significantly higher in dysplastic nevi compared to normal nevi (P = 0.046, and in primary melanoma compared to dysplastic nevi (P = 0.003, but no difference was observed between metastatic and primary melanoma. Cten staining also correlated with AJCC stages (P = 0.015 and primary tumor thickness (P = 0.002, with Cten expression being induced in the transition from thin (<1 mm to thick (≥1 mm melanomas. Strong Cten expression was significantly associated with a worse 5-year overall (P = 0.008 and disease-specific survival (P = 0.004 for primary melanoma patients, and multivariate Cox regression analysis revealed that Cten expression was an independent prognostic marker for these patients (P = 0.038 for overall survival; P = 0.021 for disease-specific survival.Our findings indicate that induction of Cten protein expression is a relatively early event in melanoma progression, and that Cten has the potential to serve as a prognostic marker for primary melanoma patients.

  5. Mental health symptoms as prognostic risk markers of all-cause and psychiatric sickness absence in office workers

    NARCIS (Netherlands)

    Roelen, C.A.M.; Rhenen, van W.; Hoedeman, R.; Groothoff, J.W.; Klink, van der J.J.L.; Bültmann, U.

    2013-01-01

    To investigate mental health symptoms as prognostic risk markers of all-cause and psychiatric sickness absence (SA). Methods: Mental health symptoms were measured in 1137 office workers with the Four-Dimensional Symptom Questionnaire (4DSQ), including scales for distress, depression, anxiety and

  6. Mental health symptoms as prognostic risk markers of all-cause and psychiatric sickness absence in office workers

    NARCIS (Netherlands)

    Roelen, Corne A. M.; Hoedeman, Rob; van Rhenen, Willem; Groothoff, Johan W.; van der Klink, Jac J. L.; Bultmann, Ute

    Background: To investigate mental health symptoms as prognostic risk markers of all-cause and psychiatric sickness absence (SA). Methods: Mental health symptoms were measured in 1137 office workers with the Four-Dimensional Symptom Questionnaire (4DSQ), including scales for distress, depression,

  7. Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Werther, Kim; Sørensen, Steen; Christensen, Ib Jarle

    2003-01-01

    analyses, the combination of high serum CEA and high serum VEGF was significantly (hazard ratio 3.0, p = 0.02) associated with poor survival compared to high serum CEA and low serum VEGF. It is concluded that 6 months postoperatively serum CEA is a better prognostic marker than corresponding serum...

  8. Individualized Cutoff Value of the Preoperative Carcinoembryonic Antigen Level is Necessary for Optimal Use as a Prognostic Marker.

    Science.gov (United States)

    Jeon, Byeong Geon; Shin, Rumi; Chung, Jung Kee; Jung, In Mok; Heo, Seung Chul

    2013-06-01

    Carcinoembryonic antigen (CEA) is an important prognostic marker in colorectal cancer (CRC). However, in some stages, it does not work. We performed this study to find a way in which preoperative CEA could be used as a constant prognostic marker in harmony with the TNM staging system. Preoperative CEA levels and recurrences in CRC were surveyed. The distribution of CEA levels and the recurrences in each TNM stage of CRC were analyzed. An optimal cutoff value for each TNM stage was calculated and tested for validity as a prognostic marker within the TNM staging system. The conventional cutoff value of CEA (5 ng/mL) was an independent prognostic factor on the whole. However, when evaluated in subgroups, it was not a prognostic factor in stage I or stage III of N2. A subgroup analysis according to TNM stage revealed different CEA distributions and recurrence rates corresponding to different CEA ranges. The mean CEA levels were higher in advanced stages. In addition, the recurrence rates of corresponding CEA ranges were higher in advanced stages. Optimal cutoff values from the receiver operating characteristic curves were 7.4, 5.5, and 4.5 ng/mL for TNM stage I, II, and III, respectively. Those for N0, N1, and N2 stages were 5.5, 4.8, and 3.5 ng/mL, respectively. The 5-year disease-free survivals were significantly different according to these cutoff values for each TNM and N stage. The multivariate analysis confirmed the new cutoff values to be more efficient in discriminating the prognosis in the subgroups of the TNM stages. Individualized cutoff values of the preoperative CEA level are a more practical prognostic marker following and in harmony with the TNM staging system.

  9. Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer.

    Science.gov (United States)

    Todenhöfer, Tilman; Hennenlotter, Jörg; Guttenberg, Philipp; Mohrhardt, Sarah; Kuehs, Ursula; Esser, Michael; Aufderklamm, Stefan; Bier, Simone; Harland, Niklas; Rausch, Steffen; Gakis, Georgios; Stenzl, Arnulf; Schwentner, Christian

    2015-03-19

    The role of urine markers in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC) is discussed extensively. In case of negative cystoscopy the additional prognostic value of these markers has not been clearly defined yet. The present study is the first systematic approach to directly compare the ability of a urine marker panel to predict the risk of recurrence and progression in bladder cancer (BC) patients with no evidence of relapse during surveillance for NMIBC. One hundred fourteen patients who underwent urine marker testing during surveillance for NMIBC and who had no evidence of BC recurrence were included. For all patients cytology, Fluorescence-in-situ-hybridization (FISH), immunocytology (uCyt+) and Nuclear matrix protein 22 enzyme-linked immunosorbent assay (NMP22) were performed. All patients completed at least 24 months of endoscopic and clinical follow-up of after inclusion. Within 24 months of follow-up, 38 (33.0%) patients experienced disease recurrence and 11 (9.8%) progression. Recurrence rates in patients with positive vs. negative cytology, FISH, uCyt+ and NMP22 were 52.6% vs. 21.9% (HR = 3.9; 95% CI 1.75-9.2; p < 0.001), 47.6% vs. 25.0% (HR 2.7; 1.2-6.2; p = 0.01), 43.8% vs. 22.4% (HR 3.3; 1.5-7.6; p = 0.003) and 43.8% vs. 16.7% (HR 4.2; 1.7-10.8; p = 0.001). In patients with negative cytology, a positive NMP22 test was associated with a shorter time to recurrence (p = 0.01), whereas FISH or uCyt+ were not predictive of recurrence in these patients. In the group of patients with negative cytology and negative NMP22, only 13.5% and 5.4% developed recurrence and progression after 24 months. Patients with positive urine markers at time of negative cystoscopy are at increased risk of recurrence and progression. In patients with negative cytology, only NMP22 is predictive for recurrence. Patients with negative marker combinations including NMP22 harbour a low risk of recurrence. Therefore, the

  10. The Search for Molecular Prognostic Markers of Diabetic Nephropathy in Patients with Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    V. M. Ibragimov

    2016-03-01

    Full Text Available The purpose of this study was to search for molecular prognostic markers of diabetic nephropathy (DN in patients with type 2 diabetes mellitus (T2DM. The study included 205 patients with T2DM and DN (stages 1 to 4. All patients were stratified by the MDRD equation. The control group included 30 healthy individuals. All T2DM patients were divided into 4 groups depending on the DN stages. Group 1 included 42 patients with DN-Stage 1 (prenephropathy, Group 2 included 48 patients with DN-Stage 2 (incipient nephropathy; Group 3 included 65 patients with DN-Stage 3 (overt nephropathy, and Group 4 included 50 patients with DN-Stage 4 (kidney failure. Molecular phenotyping of urine was processed with methods of proteomics: the prefractionation, the separation of proteins with standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA, matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA. The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database. Potentially new molecular markers of DN development were identified. The research into signaling pathways and the molecules that are involved in ECM formation may help in developing strategies to prevent DN.

  11. Circulating Tumor Cells in Metastatic Breast Cancer: A Prognostic and Predictive Marker

    Directory of Open Access Journals (Sweden)

    Sayyed Farshid Moussavi-Harami

    2014-05-01

    Full Text Available The role of circulating tumor cells (CTCs as a marker for disease progression in metastatic cancer is controversial. The current review will serve to summarize the evidence on CTCs as a marker of disease progression in patients with metastatic breast cancer. The immunohistochemistry (IHC-based CellSearch® is the only FDA-approved isolation technique for quantifying CTCs in patients with metastatic breast cancer. We searched PubMed and Web of Knowledge for clinical studies that assessed the prognostic and predictive value of CTCs using IHC-based isolation. The patient outcomes reported include median and Cox-proportional hazard ratios for overall survival (OS and progression-free survival (PFS. All studies reported shorter OS for CTC-positive patients versus CTC-negative. A subset of the selected trials reported significant lower median PFS for CTC-positive patients. The reported trials support the utility of CTC enumeration for patient prognosis. But further studies are required to determine the utility of CTC enumeration for guiding patient therapy. There are three clinical trials ongoing to test this hypothesis. These studies, and others, will further establish the role of CTCs in clinical practice.

  12. EphA8 is a prognostic marker for epithelial ovarian cancer.

    Science.gov (United States)

    Liu, Xiaoqin; Xu, Yunzhao; Jin, Qin; Wang, Wei; Zhang, Shu; Wang, Xudong; Zhang, Yuquan; Xu, Xujuan; Huang, Jianfei

    2016-04-12

    EphA8 is one of the Eph receptors in the Eph/ephrin receptor tyrosine kinase (RTK) subfamily. During tumorigenesis, EphA8 is involved in angiogenesis, cell adhesion and migration. In this study, we determined the mRNA and protein expression levels of EphA8 in cancerous and normal ovarian tissue samples by quantitative reverse transcription PCR (qRT-PCR) (N = 60) and tissue microarray immunohistochemistry analysis (TMA-IHC) (N = 223) respectively. EphA8 protein levels in cancer tissues were correlated with epithelial ovarian cancer (EOC) patients' clinical characteristics and overall survival. Both EphA8 mRNA and protein levels were significantly higher in EOC tissues than in normal or benign ovarian tissues (all P < 0.05). High EphA8 protein level was associated older age at diagnosis, higher FIGO stage, positive lymph nodes, presence of metastasis, positive ascitic fluid, and higher serum CA-125 level. High EphA8 protein level is an independent prognostic marker in EOC. We conclude that EphA8 acts as an oncogene in EOC development and progression. Detection of EphA8 expression could be a useful prognosis marker and targeting EphA8 represents a novel strategy for EOC treatment.

  13. Combination of meta-analysis and graph clustering to identify prognostic markers of ESCC

    Directory of Open Access Journals (Sweden)

    Hongyun Gao

    2012-01-01

    Full Text Available Esophageal squamous cell carcinoma (ESCC is one of the most malignant gastrointestinal cancers and occurs at a high frequency rate in China and other Asian countries. Recently, several molecular markers were identified for predicting ESCC. Notwithstanding, additional prognostic markers, with a clear understanding of their underlying roles, are still required. Through bioinformatics, a graph-clustering method by DPClus was used to detect co-expressed modules. The aim was to identify a set of discriminating genes that could be used for predicting ESCC through graph-clustering and GO-term analysis. The results showed that CXCL12, CYP2C9, TGM3, MAL, S100A9, EMP-1 and SPRR3 were highly associated with ESCC development. In our study, all their predicted roles were in line with previous reports, whereby the assumption that a combination of meta-analysis, graph-clustering and GO-term analysis is effective for both identifying differentially expressed genes, and reflecting on their functions in ESCC.

  14. Weibull regression with Bayesian variable selection to identify prognostic tumour markers of breast cancer survival.

    Science.gov (United States)

    Newcombe, P J; Raza Ali, H; Blows, F M; Provenzano, E; Pharoah, P D; Caldas, C; Richardson, S

    2017-02-01

    As data-rich medical datasets are becoming routinely collected, there is a growing demand for regression methodology that facilitates variable selection over a large number of predictors. Bayesian variable selection algorithms offer an attractive solution, whereby a sparsity inducing prior allows inclusion of sets of predictors simultaneously, leading to adjusted effect estimates and inference of which covariates are most important. We present a new implementation of Bayesian variable selection, based on a Reversible Jump MCMC algorithm, for survival analysis under the Weibull regression model. A realistic simulation study is presented comparing against an alternative LASSO-based variable selection strategy in datasets of up to 20,000 covariates. Across half the scenarios, our new method achieved identical sensitivity and specificity to the LASSO strategy, and a marginal improvement otherwise. Runtimes were comparable for both approaches, taking approximately a day for 20,000 covariates. Subsequently, we present a real data application in which 119 protein-based markers are explored for association with breast cancer survival in a case cohort of 2287 patients with oestrogen receptor-positive disease. Evidence was found for three independent prognostic tumour markers of survival, one of which is novel. Our new approach demonstrated the best specificity.

  15. Serum cardiac troponin T as a prognostic marker in early sepsis.

    Science.gov (United States)

    Spies, C; Haude, V; Fitzner, R; Schröder, K; Overbeck, M; Runkel, N; Schaffartzik, W

    1998-04-01

    Sepsis is the leading cause of death in the noncardiologic ICU. Maldistributed nutritive blood flow and altered convective and diffusive oxygen transport during sepsis can lead to organ dysfunction and multiple organ failure. One of the causes of myocardial dysfunction is thought to be myocardial ischemia in sepsis; however, conventional biochemical parameters to detect myocardial ischemia lack sensitivity and specificity. Serum cardiac troponin T (S-TnT) was reported to have higher sensitivity and specificity in diagnosing minor myocardial injury. The aim of this study was to investigate if and how often S-TnT is pathologically elevated in patients with sepsis and to evaluate whether S-TnT might be a prognostic marker in early sepsis. Prospective study. Surgical ICU. Twenty-six patients with sepsis were included in this study within 24 h of the onset of sepsis. The patients were allocated a priori to a high S-TnT group (S-TnT > or = 0.2 microg/L) and a low S-TnT group (S-TnT<0.2 microg/L). Blood samples for the determination of S-TnT and conventional myocardial ischemia markers as well as for adhesion molecules were drawn. Hemodynamic measurements were performed every 4 h during the first 24 h and then once per day over 7 days. S-TnT was determined by enzyme-linked immunosorbent sandwich assay. Eighteen patients had pathologically high S-TnT values. High S-TnT values were associated with an increased mortality rate (15/18 in the high S-TnT group vs 3/8 in the low S-TnT group; p=0.02). Significant differences between the two groups were found in the norepinephrine dosages at maximum values of S-TnT. Soluble intercellular adhesion molecule-1 was significantly elevated in the high S-TnT group. As high S-TnT values were associated with an increased mortality rate, it seems reasonable to further evaluate S-TnT as a prognostic marker of myocardial ischemia in patients with sepsis under different therapeutic regimens.

  16. Characterization of novel markers of senescence and their prognostic potential in cancer.

    Science.gov (United States)

    Althubiti, M; Lezina, L; Carrera, S; Jukes-Jones, R; Giblett, S M; Antonov, A; Barlev, N; Saldanha, G S; Pritchard, C A; Cain, K; Macip, S

    2014-11-20

    Cellular senescence is a terminal differentiation state that has been proposed to have a role in both tumour suppression and ageing. This view is supported by the fact that accumulation of senescent cells can be observed in response to oncogenic stress as well as a result of normal organismal ageing. Thus, identifying senescent cells in in vivo and in vitro has an important diagnostic and therapeutic potential. The molecular pathways involved in triggering and/or maintaining the senescent phenotype are not fully understood. As a consequence, the markers currently utilized to detect senescent cells are limited and lack specificity. In order to address this issue, we screened for plasma membrane-associated proteins that are preferentially expressed in senescent cells. We identified 107 proteins that could be potential markers of senescence and validated 10 of them (DEP1, NTAL, EBP50, STX4, VAMP3, ARMX3, B2MG, LANCL1, VPS26A and PLD3). We demonstrated that a combination of these proteins can be used to specifically recognize senescent cells in culture and in tissue samples and we developed a straightforward fluorescence-activated cell sorting-based detection approach using two of them (DEP1 and B2MG). Of note, we found that expression of several of these markers correlated with increased survival in different tumours, especially in breast cancer. Thus, our results could facilitate the study of senescence, define potential new effectors and modulators of this cellular mechanism and provide potential diagnostic and prognostic tools to be used clinically.

  17. Serum tetranectin is an independent prognostic marker in colorectal cancer and weakly correlated with plasma suPAR, plasma PAI-1 and serum CEA

    DEFF Research Database (Denmark)

    Høgdall, Claus K; Christensen, Ib J; Stephens, Ross W

    2002-01-01

    PAR and CEA had a 2.43 increased risk as compared to a patient with median levels of these biochemical markers. Significant correlations were found with Dukes' stages for all the biochemical markers and between the respective biochemical markers. The findings confirm that TN is a strong prognostic factor...... in patients with colorectal cancer. TN may be valuable as a prognostic variable in future studies evaluating new treatment strategies for colorectal cancer....

  18. Alpha-1 antitrypsin, a diagnostic and prognostic marker of vernal keratoconjunctivitis.

    Science.gov (United States)

    Ahsan, Akif; Salman, Khushtar A; Alam, Sana; Siddiqui, Anwar H; Naeem, Syed Shariq; Ahmad, Aquil; Khan, Iqbal M

    2014-05-01

    A major chunk of ocular allergies in humans involve the conjunctiva, of which Vernal Keratoconjunctivitis (VKC) appears to be more common. VKC, a chronic allergic conjunctivitis, frequently affects young males and is characterized by intense inflammation of the limbal and/or tarsal conjunctiva. The etiology and immuno-pathogenesis of VKC still remain unclear. Alpha-1 antitrypsin (AAT), a member of serine proteinase inhibitor (SERPIN) superfamily, is an acute phase protein whose concentration in blood increases in response to inflammation. AAT deficiency is one of the many factors that may be involved in several abnormalities such as liver disease, emphysema, inflammatory joint diseases and inflammatory eye diseases. In the present study, the role played by this protein in VKC was analyzed in a selective case/control study to assess its diagnostic and prognostic value. The case control study included 50 patients of VKC reporting to Ophthalmology out patient department (OPD). Age and sex matched 40 healthy subjects served as control. Serum AAT level of both the cases and controls were evaluated and compared. Moreover the serum AAT levels of the patients at presentation were compared with their serum AAT level after three weeks post treatment. Levels of AAT in the serum of VKC patients at presentation (2.80 ± 0.42 mg/ml) were significantly higher as compared to controls (2.31 ± 0.21 mg/ml) whereas no significant difference was observed between the serum level of post treatment VKC patients (2.48 ± 0.26 mg/ml) and controls. AAT is a potent acute phase protein whose concentration rises significantly in VKC, irrespective of the age and sex of the patient. Moreover, the serum level of AAT declined significantly post treatment; therefore it might be used as a prognostic marker.

  19. Sleep-Time Ambulatory BP Is an Independent Prognostic Marker of CKD.

    Science.gov (United States)

    Hermida, Ramón C; Ayala, Diana E; Mojón, Artemio; Fernández, José R

    2017-09-01

    The prognostic value of clinic and ambulatory BP in predicting incident CKD and whether CKD risk reduction associates with progressive treatment-induced decrease of clinic, awake, or asleep BP are unknown. We prospectively evaluated 2763 individuals without CKD, 1343 men and 1420 women (mean±SD age: 51.5±14.3 years old), with baseline ambulatory BP ranging from normotension to hypertension. On recruitment and annually thereafter (more frequently if hypertension treatment was adjusted on the basis of ambulatory BP), we simultaneously monitored BP and physical activity (wrist actigraphy) for 48 hours to accurately derive individualized mean awake and asleep BP. During a median 5.9-year follow-up, 404 participants developed CKD. Mean asleep systolic BP was the most significant predictor of CKD in a Cox proportional hazard model adjusted for age, diabetes, serum creatinine concentration, urinary albumin concentration, previous cardiovascular event, and hypertension treatment time (on awakening versus at bedtime; per 1-SD elevation: hazard ratio, 1.44; 95% confidence interval, 1.31 to 1.56; Pambulatory BP was not significant when corrected by mean asleep BP. Analyses of BP changes during follow-up revealed 27% reduction in the risk of CKD per 1-SD decrease in mean asleep systolic BP, independent of changes in mean clinic BP or awake ambulatory BP. In conclusion, sleep-time BP is a highly significant independent prognostic marker for CKD. Furthermore, progressive treatment-induced decrease of asleep BP, a potential therapeutic target requiring ambulatory BP evaluation, might be a significant method for reducing CKD risk. Copyright © 2017 by the American Society of Nephrology.

  20. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.

    Science.gov (United States)

    Tarawneh, Rawan; D'Angelo, Gina; Crimmins, Dan; Herries, Elizabeth; Griest, Terry; Fagan, Anne M; Zipfel, Gregory J; Ladenson, Jack H; Morris, John C; Holtzman, David M

    2016-05-01

    Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1

  1. Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease

    Science.gov (United States)

    Tarawneh, Rawan; D’Angelo, Gina; Crimmins, Dan; Herries, Elizabeth; Griest, Terry; Fagan, Anne M.; Zipfel, Gregory J.; Ladenson, Jack H.; Morris, John C.; Holtzman, David M.

    2016-01-01

    IMPORTANCE Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. OBJECTIVE To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. MAIN OUTCOMES AND MEASURES Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls overtime. RESULTS A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64–0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = −0.38, P = .02; hippocampal volumes: adjusted r = −0.36, P = .03; entorhinal volumes: adjusted r = −0.46, P = .006; and parahippocampal volumes: adjusted r = −0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical

  2. Early blood lactate area as a prognostic marker in pediatric septic shock.

    Science.gov (United States)

    Kim, Young A; Ha, Eun-Ju; Jhang, Won Kyoung; Park, Seong Jong

    2013-10-01

    We attempted to evaluate whether the early lactate area is useful as an early prognostic marker of mortality in pediatric septic shock patients. We performed a retrospective study of pediatric patients with septic shock who were admitted to the pediatric intensive care unit of Asan Medical Center, Seoul, Korea. Serial arterial lactate levels were obtained immediately and then every 6 h after admission for a total of 24 h. The lactate area (mmol/lh) was defined as the sum of the area under the curve (AUC) of serial lactate levels measured during the 24 h following admission. We compared the lactate-associated parameters as a predictor of mortality. A total of 65 patients were included in this study, and the overall 28-day mortality of these patients was 26.2%. Survivors compared with non-survivors had an initial lactate level of 3.13 ± 2.79 vs. 6.16 ± 4.87 mmol/l, a lactate clearance of 32.8 ± 63.4 vs. -30.8 ± 75.6%, and a lactate area of 59.7 ± 56.0 vs. 168.0 ± 107.0 mmol/lh (p pediatric septic shock patients.

  3. FGFR4 Profile as a Prognostic Marker in Squamous Cell Carcinoma of the Mouth and Oropharynx

    Science.gov (United States)

    Dutra, Roberta Lelis; de Carvalho, Marcos Brasilino; dos Santos, Marcelo; Mercante, Ana Maria da Cunha; Gazito, Diana; de Cicco, Rafael; Group, GENCAPO; Tajara, Eloiza Helena; Louro, Iúri Drumond; da Silva, Adriana Madeira Álvares

    2012-01-01

    Background Fibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis. Patients and Methods DNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays. Results Presence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death. Conclusion Our results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx. PMID:23226373

  4. STROMAL EXPRESSION OF CD10 IN INVASIVE BREAST CARCINOMA AND ITS CORRELATION WITH KNOWN PROGNOSTIC MARKERS

    Directory of Open Access Journals (Sweden)

    Swayamprava Pradhan

    2017-09-01

    Full Text Available BACKGROUND Breast carcinoma is the most common non-skin malignancy in women. More recently, it has been suggested that extracellular proteinase regulates growth factors and cytokines that might contribute to tumour progression. Since CD10 is a cell surface metalloproteinase which inactivates various biologically active peptides, it might facilitate cancer cell invasion and/or metastasis. MATERIALS AND METHODS 48 cases of Invasive Breast Carcinomas were taken up for the study along with 5 cases of benign tumour as a control group (fibro adenoma and phyllodes. Statistical Analysis: For all statistical data chi-square test was applied using IBM SPSS Statistics 20. RESULTS CD10 was found to be positive in 89% (n=43 cases of which 30.3% (n=13 cases showed weak immunoreactivity whereas strong immunoreactivity was observed in 69.7% (n=30 cases. Stromal CD10 expression correlated with well-established prognostic markers, i.e. higher tumour grade (P<0.001, lymph node metastasis (P=0.003, high mitotic rate (P=0.002, increasing NPI (P=0.003, ER negativity (P=0.032, PR negativity (P=0.041 and HER2/neu positivity (P=0.849. CONCLUSION Stromal CD10 expression in Invasive breast carcinomas is closely correlated with invasion and metastasis and it might play an important role in the pathogenesis.

  5. The Eag potassium channel as a new prognostic marker in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Schalkwyk Gerhard V

    2010-12-01

    Full Text Available Abstract Background Ovarian cancer is the second most common cancer of the female genital tract in the United Kingdom (UK, accounting for 6% of female deaths due to cancer. This cancer is associated with poor survival and there is a need for new treatments in addition to existing chemotherapy to improve survival. Potassium (K+ channels have been shown to be overexpressed in various cancers where they appear to play a role in cell proliferation and progression. Objectives To determine the expression of the potassium channels Eag and HERG in ovarian cancer tissue and to assess their role in cell proliferation. Methods The expression of Eag and HERG potassium channels was examined in an ovarian cancer tissue microarray. Their role in cell proliferation was investigated by blocking voltage-gated potassium channels in an ovarian cancer cell line (SK-OV-3. Results We show for the first time that high expression of Eag channels in ovarian cancer patients is significantly associated with poor survival (P = 0.016 unlike HERG channel expression where there was no correlation with survival. There was also a significant association of Eag staining with high tumour grade (P = 0.014 and presence of residual disease (P = 0.011. Proliferation of SK-OV-3 cells was significantly (P + channel blockers. Conclusion This novel finding demonstrates a role for Eag as a prognostic marker for survival in patients with ovarian cancer.

  6. Serum Uric Acid Level as a Prognostic Marker in Patients With Acute Respiratory Distress Syndrome.

    Science.gov (United States)

    Lee, Hyun Woo; Choi, Sun Mi; Lee, Jinwoo; Park, Young Sik; Lee, Chang-Hoon; Yim, Jae-Joon; Yoo, Chul-Gyu; Kim, Young Whan; Han, Sung Koo; Lee, Sang-Min

    2017-01-01

    Uric acid acts as both a pathogenic inflammatory mediator and an antioxidative agent. Several studies have shown that uric acid level correlates with the incidence, severity, and prognosis of pulmonary diseases. However, the association between uric acid level and acute respiratory distress syndrome (ARDS) has not been studied. This study was conducted to elucidate how serum uric acid level is related with clinical prognosis of ARDS. A retrospective cohort study with propensity score matching was conducted at a medical intensive care unit of a tertiary teaching hospital. The medical records of patients diagnosed with ARDS admitted from 2005 through 2011 were reviewed. Two hundred thirty-seven patients with ARDS met the inclusion criteria. Patients with a serum uric acid level uric acid group, and those with a level ≥3 mg/dL were classified into the normal to high uric acid group. We selected 40 patients in each group using propensity score matching. A higher percentage of patients in the low uric acid group experienced clinical improvement in ARDS. More patients died from sepsis in the normal to high uric acid group. Kaplan-Meier analysis showed that a low serum uric acid level was significantly associated with better survival rate. In patients with ARDS, a low serum uric acid level may be a prognostic marker of a low risk of in-hospital mortality.

  7. TGF-β1 of no avail as prognostic marker in lyme disease

    Directory of Open Access Journals (Sweden)

    Julia Schumann

    2014-05-01

    Full Text Available Background. Within the present in vivo study using the wild type mouse strains C3H/HeN and FVB/N it was intended to (1 measure TGF-β1 expression in the course of lyme disease, (2 examine the potential correlation of TGF-β1 expression with the clinical outcome of a Borrelia infection (with a focus on lyme arthritis, (3 develop a diagnostic tool based on the endogenous factor TGF-β1 to predict the progressivity of lyme disease.Findings. In the course of lyme disease there was an increase in the serum content of active TGF-β1, which became significant 56 days post infection (p < 0.001. The serum concentration of total TGF-β1 in the course of infection initially decreased then rebounded and subsequently dropped again. Despite considerable individual variations in active TGF-β1 serum concentrations there were no identifiable dissimilarities in the clinical appearance of the mice. Likewise, no correlation could be seen between the serum content of active TGF-β1 and the severity of lyme arthritis of tibiotarsal joints of infected mice.Conclusions. The present study clearly shows that TGF-β1 is of no avail as prognostic marker in lyme disease. Hence, the search for an endogenous predictive factor, which can be determined in an easy and reliable manner, remains open.

  8. K-ras gene mutation as an early prognostic marker of colon cancer.

    Science.gov (United States)

    Szpon, Łukasz; Stal, Aleksander; Zawadzki, Marcin; Lis-Nawara, Anna; Kielan, Wojciech; Grzebieniak, Zygmunt

    2016-01-01

    Due to increased colorectal cancer incidence there is a necessity of seeking new both prognostic and prediction factors that will allow to evolve new diagnostic tests. K-ras gene seems to be such a factor and its mutations are considered to be an early marker of progression of colorectal cancer. The aim of the study was to find a correlation between K-ras gene mutation in patients with diagnosed colorectal cancer and selected clinical parameters. A total of 104 patients (41 women and 63 men) with diagnosed colorectal cancer were included in this study. The average age of male group was 68.3 and in female group - 65.9. Samples were taken from paraffine blocks with tissue from diagnosed patients and K-ras gene mutation were identified. Afterwards the statistical analysis was made seeking the correlation between K-ras gene mutation incidence and clinical TNM staging system, tumour localisation, histological type, sex, age. K-ras gene mutations were detected in 20.1% of all colorectal cancers. Significantly higher rate of K-ras gene mutations were diagnosed among patients classified at stage I (40%), stage IIC (50%) and stage IV (50%) according to the TNM classification. The results of our study are compatible with other studies and indicate the correlation between K-ras gene mutation and colorectal cancer incidence. Identification of K-ras gene mutation may complement other diagnostic methods at early stage of colorectal cancer.

  9. Prognostic value of cancer stem cell marker aldehyde dehydrogenase in ovarian cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Shuyan Liu

    Full Text Available OBJECTIVE: Aldehyde dehydrogenase (ALDH has recently been reported as a marker of cancer stem-like cells in ovarian cancer. However, the prognostic role of ALDH in ovarian cancer still remains controversial. In this study, we aimed to evaluate the association between the expression of ALDH and the outcome of ovarian cancer patients by performing a meta-analysis. METHODS: We systematically searched for studies investigating the relationships between ALDH expression and outcome of ovarian cancer patients. Only articles in which ALDH expression was detected by immunohistochemical staining were included. A meta-analysis was performed to generate combined hazard ratios (HRs with 95% confidence intervals (CIs for overall survival (OS and disease-free survival (DFS. RESULTS: A total of 1,258 patients from 7 studies (6 articles were included in the analysis. Our results showed that high ALDH expression in patients with ovarian cancer was associated with poor prognosis in terms of Os (HR, 1.25; 95% CI, 1.07-1.47; P = 0.005 and DFS (HR, 1.58; 95% CI, 1.00-2.49; P = 0.052, though the difference for DFS was not statistically significant. In addition, there was no evidence of publication bias as suggested by Begg's and Egger's tests (Begg's test, P = 0.707; Egger's test, P = 0.355. CONCLUSION: The present meta-analysis indicated that elevated ALDH expression was associated with poor prognosis in patients with ovarian cancer.

  10. Pericarditis as a Marker of Occult Cancer and a Prognostic Factor for Cancer Mortality.

    Science.gov (United States)

    Søgaard, Kirstine Kobberøe; Farkas, Dóra Körmendiné; Ehrenstein, Vera; Bhaskaran, Krishnan; Bøtker, Hans Erik; Sørensen, Henrik Toft

    2017-09-12

    Pericarditis may be a serious complication of malignancy. Its significance as a first symptom of occult cancer and as a prognostic factor for cancer survival is unknown. Using Danish medical databases, we conducted a nationwide cohort study of all patients with a first-time diagnosis of pericarditis during 1994 to 2013. We excluded patients with previous cancer and followed up the remaining patients for subsequent cancer diagnosis until November 30, 2013. We calculated risks and standardized incidence ratios of cancer for patients with pericarditis compared with the general population. We assessed whether pericarditis predicts cancer survival by the Kaplan-Meier method and Cox regression using a matched comparison cohort of cancer patients without pericarditis. Among 13 759 patients with acute pericarditis, 1550 subsequently were diagnosed with cancer during follow-up. The overall cancer standardized incidence ratio was 1.5 (95% confidence interval [CI], 1.4-1.5), driven predominantly by increased rates of lung, kidney, and bladder cancer, lymphoma, leukemia, and unspecified metastatic cancer. The pericarditis was 2.7%, and the standardized incidence ratio was 12.4 (95% CI, 11.2-13.7). The 3- to pericarditis, respectively, and the hazard ratio was 1.5 (95% CI, 1.3-1.8). One-year survival was 65% and 70%, respectively, corresponding to a 3- to Pericarditis may be a marker of occult cancer and augurs increased mortality after a cancer diagnosis. © 2017 American Heart Association, Inc.

  11. Long non-coding RNA expression profiles predict metastasis in lymph node-negative breast cancer independently of traditional prognostic markers

    DEFF Research Database (Denmark)

    Sørensen, Kristina P; Thomassen, Mads; Tan, Qihua

    2015-01-01

    of traditional prognostic markers and time to metastasis. CONCLUSIONS: To our knowledge, this is the first study investigating the prognostic potential of lncRNA profiles. Our study suggest that lncRNA profiles provide additional prognostic information and may contribute to the identification of early breast...... cancer patients eligible for adjuvant therapy, as well as early breast cancer patients that could avoid unnecessary systemic adjuvant therapy. This study emphasizes the potential role of lncRNAs in breast cancer prognosis....

  12. Should C-reactive protein concentration at ICU discharge be used as a prognostic marker?

    Directory of Open Access Journals (Sweden)

    Póvoa Pedro

    2010-09-01

    Full Text Available Abstract Background About one third of hospital mortality in critically ill patients occurs after Intensive Care Unit (ICU discharge. Some authors have recently hypothesized that unresolved or latent inflammation and sepsis may be an important factor that contributes to death following successful discharge from the ICU. Aim The aim of our study was to determine the ability of the clinical and inflammatory markers at ICU discharge to predict post-ICU mortality. Methods A prospective observational cohort study was conducted during a 14-month period in an 8 bed polyvalent ICU. Acute Physiology and Chronic Health Evaluation (APACHE II score, Simplified Acute Physiology Score (SAPS II, Sequential Organ Failure Assessment (SOFA score, Therapeutic Intervention Scoring System-28 (TISS-28, C-reactive protein (CRP, white cell count (WCC and body temperature of the day of ICU discharge were collected from patients who survived their first ICU admission. Results During this period 156 patients were discharged alive from the ICU. A total of 29 patients (18.6% died after ICU discharge. There were no differences in clinical and demographic characteristics between survivors and nonsurvivors. C-reactive protein levels at ICU discharge were not significantly different between survivors and nonsurvivors. The area under receiver operating characteristics curves of APACHE II, SAPS II, SOFA, TISS-28, CRP, WCC and body temperature at ICU discharge as prognostic markers of hospital death were 0.76 (95% confidence interval (CI 0.67-0.86; 0.75 (95% CI 0.66-0.85; 0.72 (95% CI 0.62-0.83; 0.64 (95% CI 0.52-0.77; 0.55 (95% CI 0.43-0.67; 0.55 (95% CI 0.42-0.66 and 0.54 (95% CI 0.44-0.67 respectively. The hospital mortality rate of the patients with CRP 10 mg/dL was 15.1%, 16.1% and 33.3% respectively (p = NS. Conclusions At ICU discharge serum CRP concentration was a poor marker of post-ICU prognosis. Post-ICU death appears to be unrelated to the persistent inflammatory

  13. Cystatin C: A prognostic marker after myocardial infarction in patients without chronic kidney disease.

    Science.gov (United States)

    Abid, Leila; Charfeddine, Salma; Kammoun, Samir; Turki, Mouna; Ayedi, Fatma

    2016-07-01

    Cystatin C is an endogenous marker of renal function. It is a well established better marker of glomerular filtration rate than serum creatinine. There is also evidence that cystatin C is associated with atherosclerotic disease. The present prospective study evaluated the prognostic value of cystatin C after myocardial infarction in patients without chronic kidney disease. A total of 127 patients who underwent coronary angiography after an acute coronary syndrome (ACS) were included. Cystatin C was associated with the severity of coronary artery disease (CAD). Cystatin C levels were significantly higher in patients with 3-vessels disease and severe CAD according to GENSINI score (p = 0.01 and p < 0.001 respectively). Among the patients admitted for ST elevation myocardial infarction, Cystatin C concentration was correlated with the initial TIMI flow in the culprit artery (p < 0.001). Mean duration of the follow-up period was 10.76 ± 2.1 months. High Cystatin C concentrations were associated to the occurrence of unfavourable outcomes and cardiovascular mortality during follow-up (1.19 ± 0.4 vs. 1.01 ± 0.35 mg/L, p = 0.01 and 1.21 ± 0.36 vs. 0.96 ± 0.27 mg/L, p = 0.03). Among different laboratory parameters, cystatin C was the best marker to predict the occurrence of major adverse cardiovascular events during the follow-up (Area under the receiveroperating characteristic curve = 0.743). High cystatin C levels are associated with the severity of coronary artery disease in patients presenting an acute coronary syndrome and a normal renal function. Cystatin C is also associated to unfavourable cardiovascular outcomes during follow-up and appears as a strong predictor for risk of cardiovascular events and death.

  14. Perioperative NT-proBNP level: Potential prognostic markers in children undergoing congenital heart disease surgery.

    Science.gov (United States)

    Qu, Jiangbo; Liang, Huiying; Zhou, Na; Li, Lijuan; Wang, Yanfei; Li, Jianbin; Cui, Yanqin

    2017-08-01

    To assess the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at different time points and early outcome, and to evaluate the reliability of NT-proBNP level as a predictor of early outcome after surgery in a large series of children with congenital heart disease (CHD). A retrospective observational study involving 363 consecutive children with CHD was used. Plasma NT-proBNP records were obtained for each patient before and 1, 12, and 36 hours after surgery. The specificity, sensitivity, and prediction value of NT-proBNP in predicting early postoperative outcomes were determined. Analyses confirmed that time-varying NT-proBNP level, particularly 1-hour postoperative levels, had prognostic value on the prediction of prolonged duration of mechanical ventilation, intensive care unit (ICU) stay, and inotropic therapy. Joint modeling analyses of a linear mixed effects model for NT-proBNP from before to 36 hours after surgery and generalized linear models for the duration of the mechanical ventilation, ICU stay, and inotropic therapy showed that a 1% increase in NT-proBNP was associated with 5.5%, 3.9%, and 3.5% relative increases in expected duration of mechanical ventilation, ICU stay, and inotropic therapy, respectively; related P values were .001, .001, and .01, respectively. After CHD surgery, the perioperative NT-proBNP levels might be powerful markers to identify subjects at higher risk for worse outcome. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  15. HLA Class II Antigen Expression in Colorectal Carcinoma Tumors as a Favorable Prognostic Marker

    Directory of Open Access Journals (Sweden)

    Giuseppe Sconocchia

    2014-01-01

    Full Text Available The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC tumors, its association with the clinical course of the disease, and the underlying mechanism(s. Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1α (IL-1α production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1α production by monocytes.

  16. Prognostic Value of Right Ventricular Dysfunction Markers for Serious Adverse Events in Acute Normotensive Pulmonary Embolism.

    Science.gov (United States)

    Weekes, Anthony J; Johnson, Angela K; Troha, Daniel; Thacker, Gregory; Chanler-Berat, Jordan; Runyon, Michael

    2017-02-01

    Right ventricular dysfunction (RVD) in pulmonary embolism (PE) has been associated with increased morbidity. Tools for RVD identification are not well defined. The prognostic value of RVD markers to predict serious adverse events (SAE) during hospitalization is unclear. Prospectively compare the incidence of SAE in normotensive emergency department patients with PE based upon RVD by goal-directed echocardiography (GDE), cardiac biomarkers, and right-to-left ventricle ratio by computed tomography (CT). Simplified Pulmonary Embolism Severity Index (sPESI) was calculated. Deaths and readmissions within 30 days were recorded. Consecutive normotensive PE patients underwent GDE focused on RVD (RV enlargement, hypokinesis, or septal bowing), serum troponin, and brain natriuretic peptide (BNP), and evaluation of the CT ventricle ratio. In-hospital SAE and complications within 30 days were recorded. We enrolled 123 normotensive PE patients (median age 59 years, 49% female). Twenty-six of 123 (26%) patients had one or more SAE. RVD was detected in 26% by GDE, in 39% by biomarkers, and in 38% with CT. In-hospital SAE included one death, six respiratory interventions, six dysrhythmias, three major bleeding episodes, and 21 hypotension episodes. Forty-one percent of patients RVD positive by GDE had SAE, compared to the 18% RVD negative by GDE. Odds ratios for GDE, CT, BNP, troponin, and sPESI for SAE were 3.2 (95% confidence interval [CI] 1.2-8.5), 2.0 (95% CI 0.8-5.1), 3.3 (95% CI 1.3-8.6), 4.2 (95% CI 1.4-13.5), and 2.9 (95% CI 1.1-8.3), respectively. Five patients had non-PE-related deaths within 30 days. The incidence of SAE within days of PE was significant in our cohort. Those with RVD had an increased risk of nonmortality SAE. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. High expression of SLC34A2 is a favorable prognostic marker in lung adenocarcinoma patients.

    Science.gov (United States)

    Zhang, Zhaoxuan; Ye, Shan; Zhang, Min; Wu, Jing; Yan, Hong; Li, Xiaojie; He, Jie

    2017-07-01

    Dysregulation of SLC34A2 (NaPi2b) in tumors has attracted wide attention, but its expression and function in non-small cell lung cancer remains unclear. By examining its expression in lung adenocarcinoma and correlation to patient outcome, we aimed to explore its prognostic and therapeutic values in this deadly disease. Overall, 175 cases of lung adenocarcinoma sample were included in this study. Histological subtyping of them was diagnosed according to standards of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011. Protein expression of SLC34A2 and anaplastic lymphoma kinase in these samples was determined by immunohistochemistry. Epidermal growth factor receptor mutations were examined using amplification refractory mutation system. Statistical analysis was performed using software of Pearson's correlation coefficient. High expression of SLC34A2 was identified in about 2/3 patients and correlated with significantly better patient's overall survival. Epidermal growth factor receptor mutations were detected in about 53% of patients with no statistically significant difference to patient's overall survival. Anaplastic lymphoma kinase rearrangement was found in 8 out of 175 patients, harboring this abnormality leads to shorter overall survival. No correlation has been found between SLC34A2 expression and epidermal growth factor receptor mutation or anaplastic lymphoma kinase rearrangements in lung adenocarcinoma. High expression of SLC34A2 is present in about 3/4 lung adenocarcinoma samples and predicts better outcome. Since it is a membrane protein, antibody-based drugs targeting this marker might bring new resolution to this deadly disease.

  18. Steroid hormone receptor expression in ovarian cancer: progesterone receptor B as prognostic marker for patient survival

    Directory of Open Access Journals (Sweden)

    Lenhard Miriam

    2012-11-01

    Full Text Available Abstract Background There is partially conflicting evidence on the influence of the steroid hormones estrogen (E and progesterone (P on the development of ovarian cancer (OC. The aim of this study was to assess the expression of the receptor isoforms ER-α/-β and PR-A/-B in OC tissue and to analyze its impact on clinical and pathological features and patient outcome. Methods 155 OC patients were included who had been diagnosed and treated between 1990 and 2002. Patient characteristics, histology and follow-up data were available. ER-α/-β and PR-A/-B expression were determined by immunohistochemistry. Results OC tissue was positive for ER-α/-β in 31.4% and 60.1% and PR-A/-B in 36.2% and 33.8%, respectively. We identified significant differences in ER-β expression related to the histological subtype (p=0.041, stage (p=0.002 and grade (p=0.011 as well as PR-A and tumor stage (p=0.03. Interestingly, median receptor expression for ER-α and PR-A/-B was significantly higher in G1 vs. G2 OC. Kaplan Meier analysis revealed a good prognosis for ER-α positive (p=0.039 and PR-B positive (p Conclusion ER-α/-β and PR-A/-B are frequently expressed in OC with a certain variability relating to histological subtype, grade and stage. Univariate analysis indicated a favorable outcome for ER-α positive and PR-B positive OC, while multivariate analysis showed PR-B to be the only independent prognostic marker for patient survival. In conclusion, ER and PR receptors may be useful targets for a more individualized OC therapy.

  19. Tumor expression of Nectin-4 as a prognostic marker in breast cancer

    Directory of Open Access Journals (Sweden)

    Hisham Al-Torky

    2015-12-01

    Full Text Available Background: Identification of new molecular tumor associated biomarkers is the most important current challenge in cancer research. Nectin-4 is one of the Nectin glycoproteins, which are cell adhesion molecules have been involved in tumor biology. Objectives: The objective was to evaluate Nectin-4 expression by immunohistochemistry (IHC as a prognostic tumor marker in breast cancer (BC. Patients and Methods: This study was carried out on 100 female patients with BC. Their ages ranged between 29 and 67 years, with a mean of 41.3 years. Fifty other age-matched patients, subjected to reduction mammoplasty, served as controls. Data collected prospectively included patient demographics and tumor characteristics, including histopathological type and grade, IHC for Nectin-4 expression, estrogen receptors (ER, progesterone receptors (PR, and human epidermal growth factor receptor 2 (HER2-Neu. Patients were regularly followed-up for 2 years, recording loco-regional recurrence, distant metastasis, and mortality. Results: Nectin-4 expression by IHC was detected in 62% of BC patients, but in none of the tumor-free controls (P = 0.0001. Nectin-4 expression showed a statistically significant positive correlation with higher tumor grade (P = 0.003 and axillary lymph node involvement (P = 0.0001, but not with increasing tumor size (P = 0.273. It had a significant inverse correlation with ER and PR, and a significant positive correlation with HER2-Neu (P = 0.0001. Furthermore, there was a significant correlation between Nectin-4 expression and the development of distant metastases (P = 0.014, local recurrence (P = 0.046, and mortality (P = 0.049. Conclusions: Nectin-4 is a highly recommended biomarker for predicting progression and prognosis of BC. [Arch Clin Exp Surg 2015; 4(4.000: 178-184

  20. Long non-coding RNA expression profiles predict metastasis in lymph node-negative breast cancer independently of traditional prognostic markers

    DEFF Research Database (Denmark)

    Sørensen, Kristina P; Thomassen, Mads; Tan, Qihua

    2015-01-01

    INTRODUCTION: Patients with clinically and pathologically similar breast tumors often have very different outcomes and treatment responses. Current prognostic markers allocate the majority of breast cancer patients to the high-risk group, yielding high sensitivities in expense of specificities...... primary breast tumors from adjuvant naïve patients with a mean follow-up of 18 years. Eighty two patients who developed detectable distant metastasis were compared to 82 patients where no metastases were diagnosed. For validation, we determined the prognostic value of the lncRNA profiles by comparing...... of traditional prognostic markers and time to metastasis. CONCLUSIONS: To our knowledge, this is the first study investigating the prognostic potential of lncRNA profiles. Our study suggest that lncRNA profiles provide additional prognostic information and may contribute to the identification of early breast...

  1. [Leuko-glycemic index as an in-hospital prognostic marker in patients with ST-segment elevation myocardial infarction].

    Science.gov (United States)

    León-Aliz, Ebrey; Moreno-Martínez, Francisco L; Pérez-Fernández, Guillermo A; Vega-Fleites, Luis F; Rabassa-López-Calleja, Magda A

    2014-01-01

    Blood glucose and white blood cell count on admission have demonstrated prognostic significance in patients with myocardial infarction; leuko-glycemic index, a recently proposed marker, still lacks enough knowledge about its value. To evaluate the leuko-glycemic index as a prognostic marker in patients with ST-segment elevation myocardial infarction. A retrospective study was carried out in 128 patients with ST-segment elevation myocardial infarction, who were admitted between January 2009 and October 2010 in the Intensive Care Unit of the Hospital Dr. Celestino Hernández Robau. Clinical and laboratory data were collected, including glucose and white blood cell count on admission, from which we calculated the leuko-glycemic index and we evaluated its prognostic value. Patients who had a poor outcome such as death, major cardiac complications and failed-thrombolysis, showed higher values of leuko-glycemic index (Pglycemic index was an independent predictor after multivariate analysis. The leuko-glycemic index was associated with an increased occurrence of hospital complications, death and failed-thrombolysis; its pathological value was an independent predictor of in-hospital death and complications in the studied sample. Copyright © 2013 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  2. Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

    Directory of Open Access Journals (Sweden)

    Roy DM

    2014-07-01

    Full Text Available David M Roy,1 Logan A Walsh21Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY, USA; 2Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: The extracellular matrix (ECM is the complex network of proteins that surrounds cells in multicellular organisms. Due to its diverse nature and composition, the ECM has a multifaceted role in both normal tissue homeostasis and pathophysiology. It provides structural support, segregates tissues from one another, and regulates intercellular communication. Furthermore, the ECM sequesters a wide range of growth factors and cytokines that may be released upon specific and well-coordinated cues. Regulation of the ECM is performed by the extracellular proteases, which are tasked with cleaving and remodeling this intricate and diverse protein matrix. Accordingly, extracellular proteases are differentially expressed in various tissue types and in many diseases such as cancer. In fact, metastatic dissemination of tumor cells requires degradation of extracellular matrices by several families of proteases, including metalloproteinases and serine proteases, among others. Extracellular proteases are emerging as strong candidate cancer biomarkers for aiding and predicting patient outcome. Not surprisingly, inhibition of these protumorigenic enzymes in animal models of metastasis has shown impressive therapeutic effects. As such, many of these proteolytic inhibitors are currently in various phases of clinical investigation. In addition to direct approaches, aberrant expression of extracellular proteases in disease states may also facilitate the selective delivery of other therapeutic or imaging agents. Herein, we outline extracellular proteases that are either bona fide or probable prognostic markers in breast cancer. Furthermore, using existing patient data and multiple robust statistical analyses, we highlight several

  3. Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients

    Directory of Open Access Journals (Sweden)

    Schachner Melitta

    2011-05-01

    Full Text Available Abstract Background L1 cell adhesion molecule (CD171 is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. Methods Using a sensitive enzyme-linked immunosorbent assay (ELISA, soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. Results Median levels of soluble L1 were significantly higher (p p Conclusion These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.

  4. FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients

    Directory of Open Access Journals (Sweden)

    Hagedorn Martin

    2007-02-01

    Full Text Available Abstract Background In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10, its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW7 loss. Results We tested the expression of FBXW7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV with those of grade II tumors (G-II. In more than 80% G-IV, expression of FBXW7 was significantly reduced. In addition, levels of FBXW7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma. Conclusion Our results show that FBXW7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW7 plays an important role in glioma

  5. Visit-to-visit blood pressure variability as a prognostic marker in patients with cardiovascular and cerebrovascular diseases--relationships and comparisons with vascular markers of atherosclerosis.

    Science.gov (United States)

    Lau, Kui Kai; Wong, Yuen Kwun; Chan, Yap Hang; Teo, Kay Cheong; Chan, Koon Ho; Wai Li, Leonard Sheung; Cheung, Raymond Tak Fai; Siu, Chung Wah; Ho, Shu Leong; Tse, Hung Fat

    2014-07-01

    Visit-to-visit blood pressure variability (BPV) is a simple surrogate marker for the development of atherosclerotic diseases, cardiovascular and all-cause mortality. Nevertheless, the relative prognostic value of BPV in comparison with other established vascular assessments remain uncertain. We prospectively followed-up 656 high-risk patients with diabetes or established cardiovascular or cerebrovascular diseases for the occurrence of major adverse cardiovascular events (MACEs). Baseline brachial endothelial function, carotid intima-media thickness (IMT) and plaque burden, ankle-brachial index and arterial stiffness were determined. Visit-to-visit BPV were recorded during a mean 18 ± 9 outpatient clinic visits. After a mean 81 ± 12 month's follow-up, 123 patients (19%) developed MACEs. Patients who developed a MACE had significantly higher systolic BPV, more severe endothelial function, arterial stiffness and systemic atherosclerotic burden compared to patients who did not develop a MACE (all Patherosclerosis, visit-to-visit BPV provides similar prognostic information and may represent a new and simple marker for adverse outcomes in patients with vascular diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Galectins-1, -3, and -7 Are Prognostic Markers for Survival of Ovarian Cancer Patients

    Directory of Open Access Journals (Sweden)

    Heiko Schulz

    2017-06-01

    Full Text Available There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, and -7 was investigated in 156 ovarian cancer specimens by immunochemical staining. Staining was evaluated in the cytoplasm and nucleus of cancer cells as well as the peritumoral stroma using a semi quantitative score (Remmele (IR score. Patients’ overall survival was compared between different groups of Galectin expression. Galectin (Gal-1 and -3 staining was observed in the peritumoral stroma as well as the nucleus and cytoplasm of tumor cells, while Gal-7 was only present in the cytoplasm of tumor cells. Patients with Gal-1 expression in the cytoplasm or high Gal-1 expression in the peritumoral stroma showed reduced overall survival. Nuclear Gal-3 staining correlated with a better outcome. We observed a significantly reduced overall survival for cases with high Gal-7 expression and a better survival for Gal-7 negative cases, when compared to cases with low expression of Gal-7. We were able to show that both tumor and stroma staining of Gal-1 could serve as negative prognostic factors for ovarian cancer. We were able to confirm cytoplasmic Gal-7 as a negative prognostic factor. Gal-3 staining in the nucleus could be a new positive prognosticator for ovarian cancer.

  7. Galectins-1, -3, and -7 Are Prognostic Markers for Survival of Ovarian Cancer Patients.

    Science.gov (United States)

    Schulz, Heiko; Schmoeckel, Elisa; Kuhn, Christina; Hofmann, Simone; Mayr, Doris; Mahner, Sven; Jeschke, Udo

    2017-06-08

    There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, and -7 was investigated in 156 ovarian cancer specimens by immunochemical staining. Staining was evaluated in the cytoplasm and nucleus of cancer cells as well as the peritumoral stroma using a semi quantitative score (Remmele (IR) score). Patients' overall survival was compared between different groups of Galectin expression. Galectin (Gal)-1 and -3 staining was observed in the peritumoral stroma as well as the nucleus and cytoplasm of tumor cells, while Gal-7 was only present in the cytoplasm of tumor cells. Patients with Gal-1 expression in the cytoplasm or high Gal-1 expression in the peritumoral stroma showed reduced overall survival. Nuclear Gal-3 staining correlated with a better outcome. We observed a significantly reduced overall survival for cases with high Gal-7 expression and a better survival for Gal-7 negative cases, when compared to cases with low expression of Gal-7. We were able to show that both tumor and stroma staining of Gal-1 could serve as negative prognostic factors for ovarian cancer. We were able to confirm cytoplasmic Gal-7 as a negative prognostic factor. Gal-3 staining in the nucleus could be a new positive prognosticator for ovarian cancer.

  8. The prognostic value of clinical factors and cancer stem cell-related markers in gliomas

    DEFF Research Database (Denmark)

    Dahlrot, Rikke Hedegaard

    2014-01-01

    fluorescence-based automated quantitative image acquisition. The prognostic significance was subsequently investigated in relation to the observed clinical prognostic variables. We found that Musashi-1 was not prognostic in WHO grade II tumours, but in WHO grade III high levels of Musashi-1 were associated...... on experiences from clinical trials, with the risk that the results obtained are restricted to highly selected patients only. Moreover, these studies provided only little knowledge of the clinical behaviour of the tumours. For some time, it has been believed that somatic stem cells are responsible for self...... tumours. Moreover, CSCs have been suggested as the cause of resistance towards radiotherapy and chemotherapy. In gliomas, CSCs were originally identified by means of the expression of CD133, but other proteins have subsequently been suggested as CSC related. To improve patients' survival, further...

  9. The need for additional genetic markers for MDS stratification: what does the future hold for prognostication?

    Science.gov (United States)

    Otrock, Zaher K.; Tiu, Ramon V.; Maciejewski, Jaroslaw P.; Sekeres, Mikkael A.

    2013-01-01

    Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic disorders. Metaphase cytogenetics (MC) has been the gold standard for genetic testing in MDS, but it can detect clonal cytogenetic abnormalities in only 50% of cases. New karyotyping tests include fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization (aCGH), and single nucleotide polymorphism arrays (SNP-A). These techniques have increased the detected genetic abnormalities in MDS, many of which confer prognostic significance to overall and leukemia-free survival. This has eventually increased our understanding of MDS genetics. With the help of new technologies, we anticipate that the existing prognostic scoring systems will incorporate mutational data into their parameters. This review discusses the progress in MDS diagnosis through the use of array-based technologies. We also discuss the recently investigated genetic mutation in MDS, and revisit the MDS classification and prognostic scoring systems. PMID:23373781

  10. MAGE-A gene expression in peripheral blood serves as a poor prognostic marker for patients with lung cancer.

    Science.gov (United States)

    Gu, Lina; Sang, Meixiang; Yin, Danjing; Liu, Fei; Wu, Yunyan; Liu, Shina; Huang, Weina; Shan, Baoen

    2018-02-12

    MAGE-A genes belong to the cancer/testis antigens family. The prognostic significance of MAGE-A expression in the peripheral blood of patients with lung cancer is unknown. Therefore, this study evaluated the expression and possible prognostic significance of MAGE-A in the peripheral blood of patients with lung cancer. In this study, we detected MAGE-A gene expression in the peripheral blood of 150 patients with lung cancer and 30 healthy donors using multiplex semi-nested PCR and analyzed their correlation with clinicopathological risk factors. MAGE-A expression was associated with factors indicating poor prognosis. The expression of MAGE-A and each individual MAGE-A gene were also associated with low overall survival in patients with lung cancer. The expression of MAGE-A genes in peripheral blood may act as a poor prognostic marker in patients with lung cancer. © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  11. E-cadherin as a prognostic marker in human serous carcinomas of the ovary: an immunohistochemical analysis.

    Science.gov (United States)

    Dian, Darius; Brüning, Ansgar; Mylonas, Ioannis

    2011-08-01

    Ovarian cancer is a gynecologic cancer with a high mortality rate, demonstrating the need for effective and reliable tumor markers during the staging and treatment processes. Expression of E-cadherin was immunohistochemically analyzed in 100 ovarian cancer tissue samples. A significant association of E-cadherin expression with histological grading (p = 0.001) and surgical stage (p = 0.020) could be demonstrated. However, the staining intensity of E-cadherin was not significantly associated with progression-free, cause-specific survival or overall survival in serous ovarian carcinomas. The E-cadherin expression was associated with FIGO surgical staging and histological differentiation in serious ovarian carcinomas, suggesting a substantial role in the carcinogenesis of serous ovarian carcinomas. However, although patients with a strong E-cadherin staining intensity had a better prognosis, no statistical significant differences could be observed. Therefore, E-cadherin might not be a useful prognostic tumor marker in serous ovarian carcinomas.

  12. Clinicopathological and molecular significance of Sumolyation marker (ubiquitin conjugating enzyme 9 (UBC9)) expression in breast cancer of black women.

    Science.gov (United States)

    Agboola, A O J; Musa, A A; Ayoade, B A; Banjo, A A; Anunobi, C C; Deji-Agboola, A M; Rakha, E A; Nolan, C; Ellis, I O; Green, A R

    2014-01-01

    The majority of breast cancers (BC) in Nigerian women are triple negative and show breast cancer-associated gene 1 (BRCA1) deficiency as well as the basal like phenotype, with a high mortality rate. In contrast to the well-defined predictive factors for the hormonal therapy, there is a paucity of information on the BRCA1 deficiency breast tumor biology, particularly among African women. BRCA1 Sumoylation (UBC9) has been speculated to be involved in the ER transcription activity, BRCA1 deficiency and triple negative BC. We therefore hypothesized that UBC9, a SUMOylation marker, may have contributed to the aggressive nature of BRCA1 tumor phenotype observed in Nigerian women. This study investigated the immunoprofiles of UBC9 in tissue microarray (TMA) of 199 Nigerian women and correlated their protein expression with clinical outcome, pathological responses and the expression of other biomarkers to demonstrate the functional significance in Nigerian women. The protein expression of UBC9, as compared with other biomarkers, showed an inverse correlation with steroid hormones (ER, progesterone (PgR)), BRCA1, p27, p21 and MDM4, and a positive correlation with triple negative, basal cytokeratins (CK14 and CK5/6), epidermal growth factor receptor (EGFR), basal-like breast cancer phenotype, p53, phosphoinositide-3-kinases (PI3KCA), placental cadherin, (P-cadherin) and BRCA1 regulators (metastasis tumor antigen-1 (MTA1). Survival analysis showed that those tumors positive for UBC9 expression had a significantly poorer breast cancer-specific survival (BCSS) as compared with those showing negative expression. UBC9 remained an independent predictor of outcome for BCSS. This study demonstrates that UBC9 appears to play an important role in the tumor biology of Nigerian women. Therefore, a novel UBC9 targeted therapy in black women with BC could enhance a better patient outcome. Copyright © 2013 Elsevier GmbH. All rights reserved.

  13. Prognostic role of histological necrosis for nonmetastatic clear cell renal cell carcinoma: correlation with pathological features and molecular markers.

    Science.gov (United States)

    Minervini, Andrea; Di Cristofano, Claudio; Gacci, Mauro; Serni, Sergio; Menicagli, Michele; Lanciotti, Michele; Salinitri, Giuseppe; Rocca, Carlo Della; Lapini, Alberto; Nesi, Gabriella; Bevilacqua, Generoso; Minervini, Riccardo; Carini, Marco

    2008-10-01

    We defined the prognostic role of tumor necrosis and its extent in nonmetastatic clear cell renal cell carcinoma. Also, we further investigated its pathogenesis by correlating this tumor feature with other pathological characteristics and molecular markers related to the von Hippel Lindau-hypoxia inducible factor pathway and to tumor proliferation. A total of 213 patients with nonmetastatic clear cell renal cell carcinoma were evaluated. Mean followup was 66 months. The presence and extent of histological necrosis were correlated with clinicopathological factors, Ki-67 antigen expression calculated by the MIB-1 (Ki-67 antibody) index, pVHL, HIF-1alpha, the tumor infiltrating lymphocyte subset and cancer specific survival. Histological necrosis was present in 63.8% of clear cell renal cell carcinoma cases. Necrosis was significantly associated with grade and the degree of tumor infiltrating lymphocytes, while its extent correlated significantly with grade, the degree of tumor infiltrating lymphocytes and stage. Tumor necrosis was a significant prognostic factor, which was confirmed even when limiting analysis to patients with intracapsular renal cell carcinoma. On multivariate analysis histological necrosis was not an independent predictor of cancer specific survival. The extent of tumor necrosis was not a significant prognostic factor. The presence and extent of histological necrosis was not associated with high Ki-67 expression and it did not correlate with pVHL expression or with nuclear and cytoplasmic HIF-1alpha expression. Based on our results we cannot support histological necrosis and its extent as prognostic factors for clear cell renal cell carcinoma. Efforts should be made to develop nomograms that use routinely available and objective predictor variables. The precise mechanism that causes tumor necrosis remains unknown but the host immune response might significantly contribute to its development.

  14. Upregulation of microRNA-21 is a poor prognostic marker in patients with childhood B cell acute lymphoblastic leukemia.

    Science.gov (United States)

    Labib, Hany Abedelmalik; Elantouny, Neveen G; Ibrahim, Nevin F; Alnagar, Ahmed A

    2017-08-01

    Many studies have demonstrated that microRNA-21 (miR-21) is an oncogene and is upregulated in tumor tissue. However, its association with B-cell acute lymphoblastic leukemia (B-ALL) remains poorly understood. The expression of miR-21 was detected by real-time quantitative PCR in 75 children with de novo B-ALL as well as in 50 healthy controls. This study was conducted to evaluate the miR-21 as a biomarker for risk assessment, diagnosis and prognosis. Compared with normal controls, miR-21 expression was significantly upregulated in childhood B-ALL patients. Using the receiver operating characteristic curve 3.23 was selected as the cut-off value of miR-21 expression in distinguishing patients from controls. Patients group with High miR-21 expression was significantly associated with those aged 10 years, lower platelets count, more incidence of CNS infiltration and poorer treatment outcome also, they showed a significantly poorer disease-free survival (DFS) and overall survival (OS) compared to those with low miR-21 expression group. Its expression was an independent prognostic marker according to multivariate analysis. This is the first report demonstrating the upregulation of miR-21 in childhood B-ALL, and its association with poor response to induction therapy, shorter DFS and OS. These results suggest that miR-21 upregulation represent an unfavorable prognostic marker in Childhood B-ALL.

  15. YKL-40 protein expression is not a prognostic marker in patients with primary breast cancer

    DEFF Research Database (Denmark)

    Roslind, Anne; Knoop, Ann; Jensen, Maj-Britt

    2007-01-01

    YKL-40 is a new biomarker in serum with a prognostic value in several localized and metastatic malignancies. The current knowledge regarding the biological functions of YKL-40 in cancer links YKL-40 to increased aggressiveness of the tumor. Utilizing tissue microarrays, YKL-40 protein expression...

  16. YKL-40 protein expression is not a prognostic marker in patients with primary breast cancer

    DEFF Research Database (Denmark)

    Roslind, A.; Knoop, A.S.; Jensen, Maiken Brit

    2008-01-01

    YKL-40 is a new biomarker in serum with a prognostic value in several localized and metastatic malignancies. The current knowledge regarding the biological functions of YKL-40 in cancer links YKL-40 to increased aggressiveness of the tumor. Utilizing tissue microarrays, YKL-40 protein expression...

  17. Pretransplant C-reactive protein as a prognostic marker in allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Jordan, Karina Kwi Im; Christensen, Ib Jarle; Heilmann, Carsten

    2014-01-01

    We evaluated the prognostic role of baseline levels of C-reactive Protein (CRP) as well as CRP levels during conditioning in patients undergoing myeloablative allogeneic stem cell transplantation (SCT). Furthermore, we studied the impact of baseline clinical factors and conditioning regimens on CRP...

  18. Telomere length is an independent prognostic marker in MDS but not in de novo AML.

    Science.gov (United States)

    Williams, Jenna; Heppel, Nicole H; Britt-Compton, Bethan; Grimstead, Julia W; Jones, Rhiannon E; Tauro, Sudhir; Bowen, David T; Knapper, Steven; Groves, Michael; Hills, Robert K; Pepper, Chris; Baird, Duncan M; Fegan, Chris

    2017-07-01

    Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P AML patients (age AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS. © 2017 John Wiley & Sons Ltd.

  19. Prognostic nutritional index serves as a predicative marker of survival and associates with systemic inflammatory response in metastatic intrahepatic cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Zhang C

    2016-10-01

    Full Text Available Chenyue Zhang,1,2 Haiyong Wang,1,3 Zhouyu Ning,1,2 Litao Xu,1,2 Liping Zhuang,1,2 Peng Wang,1,2 Zhiqiang Meng1,2 1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 3Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, People’s Republic of China Objective: The significance of the prognostic nutritional index (PNI has been widely reported and confirmed in many types of cancers. However, few studies are available indicating its prognostic power in patients with intrahepatic cholangiocarcinoma (ICC. Thus, we investigated its relationship with overall survival (OS to evaluate its role in predicting survival in patients with ICC. Patients and methods: Between October 2011 and October 2015, 173 consecutive patients with pathologically confirmed locally advanced or metastatic ICC were enrolled. First, the correlations between PNI and clinical factors were analyzed among these patients. Next, univariate and multivariate analyses were conducted to evaluate the association between PNI and OS among these patients with ICC. In addition, the relationships between PNI and three typical systemic inflammatory response (SIR markers – the neutrophil/lymphocyte ratio (NLR, the platelet/lymphocyte ratio (PLR, and the lymphocyte/monocyte ratio (LMR – were also assessed. Results: A lower PNI was linked with a shorter OS in patients with ICC, as reflected obviously in the Kaplan–Meier analyses. The patients with ICC were divided into the locally advanced group and the metastatic group. Further analyses revealed that PNI is not associated with OS in the locally advanced group. However, in the subgroup of patients with metastatic ICC, a lower PNI significantly correlated with a worsened OS. The OS for patients with a low PNI is 5 months, whereas the OS is 10.17 months for patients with a high PNI. Multivariate analyses revealed

  20. Ulex europeus agglutinin-I binding as a potential prognostic marker in ovarian cancer.

    Science.gov (United States)

    Blonski, Katharina; Milde-Langosch, Karin; Bamberger, Ana-Maria; Osterholz, Tina; Utler, Christian; Berger, Jürgen; Löning, Thomas; Schumacher, Udo

    2007-01-01

    Ovarian cancer represents the malignant tumour of the female genital tract with the worst prognosis, mainly caused by early intraperitoneal spread. Cell-to-cell and cell-to-matrix interactions play a functionally important role in this spread and are both mediated by the cell membrane. Changes in the glycosylation of the cell membrane, as detected by lectin histochemistry, are sometimes associated with a poor prognosis. The expression of lectin binding of 164 ovarian cancer patients was analysed and the staining results were correlated with the clinical data of the patients. The univariate and multivariate statistical analysis revealed an independent prognostic significance for Ulex europeus agglutinin-I (UEA-I) binding. These findings indicate that UEA-I binding can serve as a prognostic factor in ovarian cancer.

  1. Gene expression profiles as prognostic markers in women with ovarian cancer

    DEFF Research Database (Denmark)

    Jochumsen, Kirsten M; Tan, Qihua; Høgdall, Estrid V

    2009-01-01

    disease. Furthermore, its ability to classify in an external validation set was demonstrated. The identified 14-gene prognostic profile was able to predict survival (short- vs long-term survival) with a strength that is better than any other prognostic factor in epithelial ovarian cancer including FIGO......The purpose was to find a gene expression profile that could distinguish short-term from long-term survivors in our collection of serous epithelial ovarian carcinomas. Furthermore, it should be able to stratify in an external validation set. Such a classifier profile will take us a step forward...... toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III...

  2. Gene Expression Profiles as Prognostic Marker in Women with Ovarian Cancer

    DEFF Research Database (Denmark)

    Jochumsen, Kirsten Marie; Tan, Qihua; Høgdall, EV

    2009-01-01

    disease. Furthermore, its ability to classify in an external validation set was demonstrated. The identified 14-gene prognostic profile was able to predict survival (short- vs long-term survival) with a strength that is better than any other prognostic factor in epithelial ovarian cancer including FIGO......The purpose was to find a gene expression profile that could distinguish short-term from long-term survivors in our collection of serous epithelial ovarian carcinomas. Furthermore, it should be able to stratify in an external validation set. Such a classifier profile will take us a step forward...... toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III...

  3. Circulating cell-free DNA and its integrity as a prognostic marker for breast cancer

    OpenAIRE

    Iqbal, Sobuhi; Vishnubhatla, Sreenivas; Raina, Vinod; Sharma, Surabhi; Gogia, Ajay; Deo, Suryanarayana S V; Mathur, Sandeep; Shukla, Nutan Kumar

    2015-01-01

    The aim of our study was to look for alternative predictive biomarkers for breast cancer management in limited resource setup. A comprehensive analysis of circulating cell-free DNA (CCFD) in serum at baseline was performed to assess its prognostic potential. Quantitative polymerase chain reaction (qPCR) of ALU sequences using ALU115 and ALU247 primers was carried out in patients (N: baseline 148, postoperative 47) and 51 healthy controls. Mean serum DNA integrity, levels of ALU 247 and levels...

  4. 1C.05: MORNING SURGE AND SLEEP-TIME BLOOD PRESSURE AS PROGNOSTIC MARKERS OF CARDIOVASCULAR RISK: THE HYGIA PROJECT.

    Science.gov (United States)

    Ayala, D E; Dominguez-Sardiña, M; Otero, A; Rios, M T; Gomara, S M; Moya, A; Castiñeira, M C; Crespo, J J; Sineiro, E; Callejas, P A; Pousa, L; Mojon, A; Fernandez, J R; Hermida, R

    2015-06-01

    The extent of blood pressure (BP) surge upon waking has been associated with increased cardiovascular (CVD) risk in some, but not all, studies. Numerous studies, however, have consistently shown the association between elevated sleep-time BP mean and the rising BP pattern with increased CVD risk, leading to a paradox, as patients with sleep-time hypertension or non-dipper/riser BP pattern have attenuated morning BP surge. We evaluated the comparative prognostic value for CVD events of the morning BP surge and sleep-time BP among the participants in the ongoing Hygia Project. This study involved 11255 subjects, 6028 men/5227 women, 58.9 ± 14.5 years of age, prospectively evaluated throughout a 4.0-year median follow-up. BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. During monitoring, subjects maintained a diary listing the times of going to bed and awakening. We documented 1539 total events, including 400 deaths, 176 strokes, 144 myocardial infarctions, 147 coronary revascularizations, and 193 heart failures. A greater prewaking systolic BP surge was associated with significantly lower, not higher, CVD risk in a Cox proportional-hazard model adjusted for the significant influential characteristics of age, sex, diabetes, chronic kidney disease, cigarette smoking, waist perimeter, and history of previous CVD event (hazard ratio [HR] 0.83 [95%CI 0.78-0.88] per each 1-SD increment; P surge. The prognostic value of morning surge markedly decreased after correcting by the asleep BP mean, the single most significant prognostic marked of total CVD events (HR = 1.37 [1.29-1.44], P surge is associated with a significantly lower CVD risk, in line with the markedly greater risk associated with decreasing dipping of the BP pattern, and the most highly significant prognostic value of progressively elevated asleep BP, an independent prognostic marker of CVD risk that has also been prospectively validated as

  5. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course

    DEFF Research Database (Denmark)

    Khademi, Mohsen; Kockum, Ingrid; Andersson, Magnus L

    2011-01-01

    Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments.......Levels of CXCL13, a potent B-cell chemoattractant, are elevated in the cerebrospinal fluid (CSF) during multiple sclerosis (MS) and are associated with markers of MS activity. Levels decrease upon effective treatments....

  6. Ki67 expression in breast cancer. Correlation with prognostic markers and clinicopathological parameters in Saudi patients

    Directory of Open Access Journals (Sweden)

    Mohamed A. Elkablawy

    2016-02-01

    Full Text Available Objectives: To evaluate Ki67 immunoexpression pattern in Saudi breast cancer (BC patients and investigate any possible predictive or prognostic value for Ki67. Methods: This is a retrospective study designed to quantitatively assess the Ki67 proliferative index (PI in retrieved paraffin blocks of 115 Saudi BC patients diagnosed between January 2005 and March 2015 at the Department of Pathology, King Fahd Hospital, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. The Ki67 PI was correlated with individual and combined immunoprofile data of estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor 2 (HER2/neu with their clinicopathological parameters. Results: Ki67 immunoreactivity was highly expressed (greater than 25% of the tumor cells were positive in 85 (73.9% patients. The Ki67 PI was significantly associated with poor prognostic clinicopathological parameters including old age (p less than 0.02, high tumor grade (p less than 0.01, lymph node metastasis (p less than 0.001, and Her-2/neu positivity (p less than 0.009. However, the association with ER positivity, PR positivity, tumor size, and lymphovascular invasion were not statistically significant. The Ki67 PI was significantly associated with BC molecular subtypes that were Her2/neu positive (luminal B and HER-2 subtypes compared with the Her2/neu negative (luminal A subtype (p less than 0.04. Conclusion: The Ki67 PI is significantly higher in Saudi BC patients comparing with the reported literature. Ki67 PI was highest in the HER-2 and luminal-B molecular subtypes. Along with other prognostic indicators, Ki67 PI may be useful in predicting prognosis and management of Saudi BC patients.

  7. Limited Value of KAI1/CD82 Protein Expression as a Prognostic Marker in Human Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Maximilian Knoener

    2012-01-01

    Full Text Available The cell surface glycoprotein KAI1/CD82 suppresses tumor growth and metastasis in animal models. This study aimed to evaluate the prognostic relevance of KAI1/CD82 protein expression in human gastric cancer. Primary gastric carcinomas (n = 271 with amean clinical follow-up time of 48months were immunostained using the monoclonal anti-KAI1/CD82 antibody G2. Staining was evaluated as negative versus positive for statistical analysis. KAI1/CD82 immunoreactivity was absent in 103/271 (38% cases. There was a trend towards KAI1/CD82 negativity in poorly differentiated cases (p = 0.0679. Moreover, KAI1/CD82-negative carcinomas were associated with a higher pT status (p = 0.0222, metastatic lymph node involvement (p = 0.0018 and a higher clinical tumor stage (p = 0.0050. The median overall survival times of KAI1/CD82-negative and KAI1/CD82-positive gastric carcinomas were 20 and 37 months, respectively (p = 0.2305. These results are in line with the proposed function of KAI1/CD82 as a suppressor of tumor growth and metastasis. However, these data suggest that KAI1/CD82, as detected by immunohistochemistry, is of limited value as a prognostic marker for gastric cancer in routine histological workup.

  8. Prognostic Markers in Chondrosarcoma: Evaluation of Cell Proliferation and of Regulators of the Cell Cycle

    Directory of Open Access Journals (Sweden)

    John M. Harrelson

    1997-01-01

    Full Text Available Purpose. The prognosis, treatment principles and prediction of clinical outcome of patients with chondrosarcoma currently rest on histologic grading which is somewhat ambiguous due to difficulty in pathologic interpretation of this neoplasm. Immunohistochemistry, flow cytometry and oncogene/tumor suppressor gene expression have been examined as alternative indices to predict the biologic behavior of these tumors. Because of partial successes obtained with flow cytometry and because of the improvement in predicting recurrence offered by examining the S-phase fraction, we undertook the current study to determine if expression of specific regulators of the cell cycle would act as prognostic indicators for these patients.

  9. Therapeutic targeting of BCR-ABL: prognostic markers of response and resistance mechanism in chronic myeloid leukaemia.

    Science.gov (United States)

    Yeung, David T; Hughes, Timothy P

    2012-01-01

    Chronic myeloid leukemia (CML) is caused by the formation of the BCR-ABL fusion protein as a result of the t(9;22) chromosomal translocation. The elucidation of its molecular pathogenesis led to the identification of a therapeutic target and the subsequent synthesis and introduction of a small-molecule inhibitor for this target, imatinib. Because CML is the first disease successfully treated by targeted kinase inhibition, it served as a paradigm for discovery of disease mechanism and drug development in other diseases in which constitutive kinase expression plays a central role in pathogenesis. Despite the spectacular success of imatinib, not all CML patients derive great benefit from it. This review will cover some of the currently known prognostic markers of disease response and potential resistance mechanisms.

  10. The role of Cancer-Testis antigens as predictive and prognostic markers in non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Thomas John

    Full Text Available BACKGROUND: Cancer-Testis Antigens (CTAs are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC. We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. METHODS: We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94, post-operative observation (n = 49, adjuvant chemotherapy (n = 47 or unknown (n = 9. Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. RESULTS: NY-ESO-1 was expressed in 50/199 (25% samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03, but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008, whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046. Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. CONCLUSIONS: NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

  11. Computerized three-class classification of MRI-based prognostic markers for breast cancer

    Science.gov (United States)

    Bhooshan, Neha; Giger, Maryellen; Edwards, Darrin; Yuan, Yading; Jansen, Sanaz; Li, Hui; Lan, Li; Sattar, Husain; Newstead, Gillian

    2011-09-01

    The purpose of this study is to investigate whether computerized analysis using three-class Bayesian artificial neural network (BANN) feature selection and classification can characterize tumor grades (grade 1, grade 2 and grade 3) of breast lesions for prognostic classification on DCE-MRI. A database of 26 IDC grade 1 lesions, 86 IDC grade 2 lesions and 58 IDC grade 3 lesions was collected. The computer automatically segmented the lesions, and kinetic and morphological lesion features were automatically extracted. The discrimination tasks—grade 1 versus grade 3, grade 2 versus grade 3, and grade 1 versus grade 2 lesions—were investigated. Step-wise feature selection was conducted by three-class BANNs. Classification was performed with three-class BANNs using leave-one-lesion-out cross-validation to yield computer-estimated probabilities of being grade 3 lesion, grade 2 lesion and grade 1 lesion. Two-class ROC analysis was used to evaluate the performances. We achieved AUC values of 0.80 ± 0.05, 0.78 ± 0.05 and 0.62 ± 0.05 for grade 1 versus grade 3, grade 1 versus grade 2, and grade 2 versus grade 3, respectively. This study shows the potential for (1) applying three-class BANN feature selection and classification to CADx and (2) expanding the role of DCE-MRI CADx from diagnostic to prognostic classification in distinguishing tumor grades.

  12. Membrane connexin 43 acts as an independent prognostic marker in oral squamous cell carcinoma.

    Science.gov (United States)

    Brockmeyer, Phillipp; Jung, Klaus; Perske, Christina; Schliephake, Henning; Hemmerlein, Bernhard

    2014-07-01

    The aim of the present study was to evaluate the expression and localization of connexin (Cx) 26, -43 and -45 in a group of 35 patients with primary oral squamous cell carcinoma (OSCC) with the objective of making a more accurate disease prognosis. We analysed the expression of connexins in tissue samples of primary OSCC, matching oral mucosa free of dysplasia, and its associated lymph node metastases (LNM) by semi-quantitative immunohistochemistry of membrane, cytoplasmic and nuclear connexin expression. The levels of expression were correlated with the overall survival time (OS). Cx43 was overexpressed in tumour cells compared to epithelia in dysplasia-free mucosa. High membrane expression of Cx43 on tumour cells was the only statistically significant and independent prognostic factor of short OS (P=0.0088). Membrane expression of Cx43 in matching dysplasia-free mucosa acted similarly, but did not reach statistical significance (P=0.059). No correlation was found between the Cx26, Cx45 expression and OS. We conclude that Cx43 expression in dysplasia-free mucosa may indicate a very early stage of tumour promotion. Although overexpression of Cx43 is found in invasive tumours we only found membrane Cx43 expression to correlate with OS. This observation suggests that cytoplasmic Cx43 serves as storage and only membrane translocation may promote the formation of gap junctions and gap junctional intercellular communication (GJIC) with prognostic relevance.

  13. Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients

    Directory of Open Access Journals (Sweden)

    Mahmoud Moustafa

    2004-09-01

    Full Text Available Abstract Background Colorectal cancer is a common cancer all over the world. Aberrations in the cell cycle checkpoints have been shown to be of prognostic significance in colorectal cancer. Methods The expression of cyclin D1, cyclin A, histone H3 and Ki-67 was examined in 60 colorectal cancer cases for co-regulation and impact on overall survival using immunohistochemistry, southern blot and in situ hybridization techniques. Immunoreactivity was evaluated semi quantitatively by determining the staining index of the studied proteins. Results There was a significant correlation between cyclin D1 gene amplification and protein overexpression (concordance = 63.6% and between Ki-67 and the other studied proteins. The staining index for Ki-67, cyclin A and D1 was higher in large, poorly differentiated tumors. The staining index of cyclin D1 was significantly higher in cases with deeply invasive tumors and nodal metastasis. Overexpression of cyclin A and D1 and amplification of cyclin D1 were associated with reduced overall survival. Multivariate analysis shows that cyclin D1 and A are two independent prognostic factors in colorectal cancer patients. Conclusions Loss of cell cycle checkpoints control is common in colorectal cancer. Cyclin A and D1 are superior independent indicators of poor prognosis in colorectal cancer patients. Therefore, they may help in predicting the clinical outcome of those patients on an individual basis and could be considered important therapeutic targets.

  14. The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites.

    Science.gov (United States)

    Lutz, Philipp; Pfarr, Kenneth; Nischalke, Hans Dieter; Krämer, Benjamin; Goeser, Felix; Glässner, Andreas; Wolter, Franziska; Kokordelis, Pavlos; Nattermann, Jacob; Sauerbruch, Tilman; Hoerauf, Achim; Strassburg, Christian P; Spengler, Ulrich

    2015-11-01

    Diagnosis of spontaneous bacterial peritonitis (SBP) is based on a differential ascites leukocyte count which does not provide prognostic information. We performed a pilot study to assess calprotectin in ascites as an alternative diagnostic and prognostic marker. We collected ascites from patients with liver cirrhosis from March 2012 to July 2013. Routine clinical and laboratory data of the patients were recorded. Ascites calprotectin levels were determined by ELISA. Overall, we collected 120 ascites samples from 100 patients with liver cirrhosis and from eight patients with malignant peritoneal effusion as disease control. Samples without infection had significantly lower calprotectin levels (median 34 ng/mL, range 5-795) than SBP samples (median 928 ng/mL, range 21-110,480; pmarker for SBP than calprotectin alone (AUROC=0.93; pdiagnostic and prognostic marker in patients with liver cirrhosis and SBP and should be evaluated further.

  15. Pregnancy associated plasma protein-A as a marker for myocardial infarction and death in patients with stable coronary artery disease: A prognostic study within the CLARICOR Trial

    DEFF Research Database (Denmark)

    Iversen, Kasper K; Teisner, Børge; Winkel, Per

    2011-01-01

    OBJECTIVE: Pregnancy associated plasma protein-A (PAPP-A) is a potential new marker for vulnerable plaques in the coronary arteries only examined in stable coronary disease (CAD) in patients undergoing coronary angiography. Here we address the prognostic value of serum PAPP-A in unselected stable...

  16. C-terminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction : results from the OPTIMAAL study

    NARCIS (Netherlands)

    Voors, Adriaan A.; von Haehling, Stephan; Anker, Stefan D.; Hillege, Hans L.; Struck, Joachim; Hartmann, Oliver; Bergmann, Andreas; Squire, Iain; van Veldhuisen, Dirk J.; Dickstein, Kenneth

    The aim of the present study was to compare the prognostic value of a novel and promising marker, copeptin, with B-type natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP), on death or a composite cardiovascular endpoint in patients who developed heart failure after an acute myocardial

  17. Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma : Results of the Accelerated Radiotherapy with Carbogen Breathing and Nicotinamide phase III randomized trial

    NARCIS (Netherlands)

    Rademakers, Saskia E.; Hoogsteen, Ilse J.; Rijken, Paul F.; Terhaard, Chris H.; Doornaert, Patricia A.; Langendijk, Johannes A.; van den Ende, Piet; van der Kogel, Albert J.; Bussink, Johan; Kaanders, Johannes H.

    BackgroundThe prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. MethodsLabeling index of Ki-67 (Li Ki-67) in

  18. Microarray-based identification of CUB-domain containing protein 1 as a potential prognostic marker in conventional renal cell carcinoma.

    Science.gov (United States)

    Awakura, Yasuo; Nakamura, Eijiro; Takahashi, Takeshi; Kotani, Hirokazu; Mikami, Yoshiki; Kadowaki, Tadashi; Myoumoto, Akira; Akiyama, Hideo; Ito, Noriyuki; Kamoto, Toshiyuki; Manabe, Toshiaki; Nobumasa, Hitoshi; Tsujimoto, Gozoh; Ogawa, Osamu

    2008-12-01

    Renal cell carcinoma (RCC) is characterized by a variable and unpredictable clinical course. Thus, accurate prediction of the prognosis is important in clinical settings. We conducted microarray-based study to identify a novel prognostic marker in conventional RCC. The present study included the patients surgically treated at Kyoto University Hospital. Gene expression profiling of 39 samples was carried out to select candidate prognostic markers. Quantitative real-time PCR of 65 samples confirmed the microarray experiment results. Finally, we evaluated the significance of potential markers at their protein expression level by immunohistochemically analyzing 230 conventional RCC patients. Using expression profiling analysis, we identified 14 candidate genes whose expression levels predicted unfavorable disease-specific survival. Next, we examined the expression levels of nine candidate genes by quantitative real-time PCR and selected CUB-domain containing protein 1 (CDCP1) for further immunohistochemical analysis. Positive staining for CDCP1 inversely correlated with disease-specific and recurrence-free survivals. In multivariate analysis including clinical/pathological factors, CDCP1 staining was a significant predictor of disease-specific and recurrence-free survivals. We identified CDCP1 as a potential prognostic marker for conventional RCC. Further studies might be required to confirm the prognostic value of CDCP1 and to understand its function in RCC progression.

  19. [Osteoprotegerin as a marker of atherosclerosis and a prognostic factor in stroke].

    Science.gov (United States)

    Majerczyk, Marcin; Wajda, Jarosław; Holecki, Michał; Chudek, Jerzy

    2015-12-31

    Stroke is one of the most common causes of disability and lack of independence in activities of daily living in adults. One of the most important factors predisposing to stroke, besides hypertension and atrial fibrillation, is carotid atherosclerosis. Rupture of unstable plaque with formation of a platelet plug is the cause of about 20-25% of ischemic strokes. Osteoprotegerin (OPG) is an important regulator of bone remodeling under physiological and disease conditions, as well as the regulator of osteoclast differentiation. Elevated plasma OPG level is associated with increased risk of ischemic stroke and heart diseases, including atrial fibrillation, and is observed in patients with symptomatic carotid artery stenosis and atherosclerotic vulnerable plaques. Furthermore, the occurrence of certain genotypes of OPG is 10 times more common in people with unstable atherosclerotic plaque, making them an independent risk predictor of plaque instability. This article summarizes the current state of knowledge on the potential role of OPG as a biomarker and prognostic indicator of stroke.

  20. Association and prognostic value of serum inflammation markers in patients with leukoplakia and oral cavity cancer.

    Science.gov (United States)

    Chang, Pi-Yueh; Kuo, Yung-Bin; Wu, Tsu-Lan; Liao, Chun-Ta; Sun, Yu-Chen; Yen, Tzu-Chen; Chan, Err-Cheng

    2013-06-01

    Oral cavity cancer ranks as the fourth leading cancer in men in Taiwan. The development of a serum biomarker panel for early detection and disease monitoring is, therefore, warranted. Nine inflammation-associated markers were investigated in 46 patients with leukoplakia, 151 patients with untreated oral cavity squamous cell carcinoma (OSCC), and 111 age- and gender-matched healthy controls using enzyme-linked immunosorbent assay. During a subsequent 28-month surveillance of OSCC patients, serum samples were prospectively collected at predetermined intervals following the completion of therapy. Logistic regression analysis showed matrix metalloproteases (MMP)-2, MMP-9, C-reactive protein (CRP), transforming growth factor-β1 (TGF-β1), and E-selectin having the best discrimination power between groups and significant elevation trends of those five markers were noted from control to OSCC. By combining those five markers, a 0.888 and 0.938 area under curve by ROC curve analysis with 67.4% and 80% overall sensitivity and fixed 90% specificity for leukoplakia and OSCC groups were demonstrated. In the follow-up period, 25 OSCC patients developed recurring or secondary tumors. All examined markers had decreased in relapse-free patients following treatment. However, in patients with relapse, interleukin-6, CRP, and serum amyloid A remained at elevated levels. Statistical analysis showed that patients with CRP ≧2 mg/L and E-selectin ≧85 ng/mL at baseline had highest probability of relapse (odds ratio=3.029, p<0.05). The results indicate that inflammation plays a crucial role in the pathogenesis process of OSCC. By examining the inflammation markers, physicians could potentially identify patients at risk of cancer transformation or relapse.

  1. Angiotensin converting enzyme – a new prognostic marker of recurrence in the treatment of prostate cancer

    Directory of Open Access Journals (Sweden)

    M. I. Kogan

    2016-01-01

    Full Text Available Background. Introduction to the clinical practice of new criteria for the diagnosis and monitoring of neoplastic processes in the prostate based on the identification of informative predictors and markers of prostate cancer (PC, especially its aggressive forms, is one of the priority directions of scientific research in oncological urology. The goal – the search of new markers of aggressive forms of PC.Materials and methods. For identification associated with PC progression indicators – potential markers clinically aggressive forms of PC was determined activity kininase II (angiotensin-converting enzyme (ACE, EC 3.4.15.1 in serum of blood with using as substrate N-(3-(2-furyl acryloyl-L-phenylalanyl-glycyl-glycine (FAPGG. Retrospectively evaluated ACE activity in patients with the development of biochemical recurrence and without after hormone-radiation therapy.Results. It has been shown that the development of PC recurrence is associated with an increase in ACE activity, and the ACE activity starts to grow sooner than noted the development of biochemical recurrence. Joint determination of prostate-specific antigen and the activity of the enzyme after a month of treatment allows to select a group of patients with high risk of biochemical recurrence with sensitivity, specificity of 78.6 % (p < 0.001, respectively 94,6 % (p < 0.001.Conclusions. There is every reason to believe that ACE is a promising predictive marker of clinically aggressive forms of PC. The renin-angiotensin system in PC can be considered as a new therapeutic target for targeted therapy.

  2. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer

    OpenAIRE

    Collina, Francesca; Di Bonito, Maurizio; Li Bergolis, Valeria; De Laurentiis, Michelino; Vitagliano, Carlo; Cerrone, Margherita; Nuzzo, Francesco; Cantile, Monica; Botti, Gerardo

    2015-01-01

    Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as...

  3. Circulating cell-free DNA and its integrity as a prognostic marker for breast cancer.

    Science.gov (United States)

    Iqbal, Sobuhi; Vishnubhatla, Sreenivas; Raina, Vinod; Sharma, Surabhi; Gogia, Ajay; Deo, Suryanarayana S V; Mathur, Sandeep; Shukla, Nutan Kumar

    2015-01-01

    The aim of our study was to look for alternative predictive biomarkers for breast cancer management in limited resource setup. A comprehensive analysis of circulating cell-free DNA (CCFD) in serum at baseline was performed to assess its prognostic potential. Quantitative polymerase chain reaction (qPCR) of ALU sequences using ALU115 and ALU247 primers was carried out in patients (N: baseline 148, postoperative 47) and 51 healthy controls. Mean serum DNA integrity, levels of ALU 247 and levels of ALU 115 were significantly higher in patients than in healthy females. No significant differences were observed in the levels ALU 247 and ALU 115 between stage IV and earlier stages of the disease. The DNA integrity was significantly higher in stage IV than earlier stages. A significant decrease in DNA integrity was observed after surgery (pre: 0.55 ± 0.23 vs post: 0.43 ± 0.30; P = 0.002) while no such change could be observed for ALU 247 and ALU 115. Baseline DNA integrity was significantly higher in relapsed patients than in patients who were free of disease (P = 0.005). Higher baseline DNA integrity was also indicated, though statistically not significant, in patients who died (P = 0.14). In contrast, ALU 247 and ALU 115 levels were decreased in died patients as compared to survivors (24.8 ± 34.80 vs 73.5 ± 170.83, P = 0.02 for ALU 247 and 41.0 ± 47.99 vs 159.5 ± 299.54, P = 0.005 for ALU 115). Baseline levels of ALU 115 and ALU 247 were lower in relapsed patients, though statistically not significant. In univariate analysis, the only clinic-pathological parameter associated with disease prognosis was tumor size. The hazards of 5-year overall mortality was 3.60 (95 % CI: 1.03 12.53, P = 0.03) among patients with lower baseline serum levels of CCFD (ALU 247 integrity. Baseline serum levels of CCFD and its integrity were found to be potential prognostic biomarkers in patients of primary breast cancer at our centre.

  4. Glut1 and Glut3 as Potential Prognostic Markers for Oral Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Fernanda Rocha Rojas Ayala

    2010-04-01

    Full Text Available We associated clinical-pathological features of 142 OSCC with the expression pattern of GLUT1 and GLUT3 in order to estimate their prognostic value. Methods: Clinical-pathological features and overall survival data of 142 patients with Oral Squamous Cell Carcinoma (OSCC were retrospectively reviewed from A.C.Camargo hospital records. A tissue microarray (TMA was built for the immunohistochemical (IHC analysis of GLUT 1 and GLUT 3. IHC results were evaluated according to the staining pattern and number of positive cells. Results: GLUT 1 was over expressed in 50.3% of OSSC cases showing membrane staining pattern. However, nuclear expression was observed in 49.7% of the analyzed cases. GLUT 3 over expression was detected in 21.1% of OSCC cases. The pattern of GLUT 1 expression showed significant association with alcohol consumption (p = 0.004. Positive cell membrane GLUT 3 protein expression was associated with advanced clinic-staging of tumours (p = 0.005 as well as with vascular embolization (p = 0.005. Positive expression of GLUT 3 was associated with unfavorable free-disease survival (p = 0.021. Conclusion: GLUT1 and GLUT3 protein expression evaluated by immunohistochemistry are, significantly, indicators of poor prognosis outcome in oral squamous cell carcinoma, probably due to the enhanced glycolytic metabolism of more aggressive neoplastic cells.

  5. Osteoprotegerin as a marker of atherosclerosis and a prognostic factor in stroke

    Directory of Open Access Journals (Sweden)

    Marcin Majerczyk

    2015-12-01

    Full Text Available Stroke is one of the most common causes of disability and lack of independence in activities of daily living in adults.One of the most important factors predisposing to stroke, besides hypertension and atrial fibrillation, is carotid atherosclerosis. Rupture of unstable plaque with formation of a platelet plug is the cause of about 20-25% of ischemic strokes. Osteoprotegerin (OPG is an important regulator of bone remodeling under physiological and disease conditions, as well as the regulator of osteoclast differentiation. Elevated plasma OPG level is associated with increased risk of ischemic stroke and heart diseases, including atrial fibrillation, and is observed in patients with symptomatic carotid artery stenosis and atherosclerotic vulnerable plaques. Furthermore, the occurrence of certain genotypes of OPG is 10 times more common in people with unstable atherosclerotic plaque, making them an independent risk predictor of plaque instability. This article summarizes the current state of knowledge on the potential role of OPG as a biomarker and prognostic indicator of stroke.

  6. Dickkopf-1 Expression Is a Novel Prognostic Marker for Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Chengcheng Gao

    2012-01-01

    Full Text Available Aim. To investigate the involvement of Dickkopf-1 expression in gastric cancer. Methods. Dickkopf-1 mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR and immunohistochemistry in specimens of primary cancer and their adjacent noncancerous tissues in gastric cancer patients. Results. Dickkopf-1 mRNA and protein expression levels were both significantly upregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Its positive expression was correlated with depth of invasion, vessel invasion, lymph node and distant metastasis, and TNM stage of tumors. Additionally, in stages I, II, and III gastric cancers, the 5- year survival rate of patients with a high expression of Dickkopf-1 was significantly lower than that in patients with low expression. In stage IV, Dickkopf-1 expression did not correlate with the 5-year survival rate. Further multivariate analysis suggested that the up-regulation of Dickkopf-1 was an independent prognostic indicator for gastric cancer. Conclusion. A subset of cases with gastric cancer revealed the up-regulation of Dickkopf-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, Dickkopf-1 expression may be predictor for poor prognosis in patients with gastric cancer. This is the first report describing the involvement of Dickkopf-1 in gastric cancer.

  7. Expression of Bmi-1 is a prognostic marker in bladder cancer

    Directory of Open Access Journals (Sweden)

    Xu Li-Hua

    2009-02-01

    Full Text Available Abstract Background The molecular mechanisms of the development and progression of bladder cancer are poorly understood. The objective of this study was to analyze the expression of Bmi-1 protein and its clinical significance in human bladder cancer. Methods We examined the expression of Bmi-1 mRNA and Bmi-1 protein by RT-PCR and Western blot, respectively in 14 paired bladder cancers and the adjacent normal tissues. The expression of Bmi-1 protein in 137 specimens of bladder cancer and 30 specimens of adjacent normal bladder tissue was determined by immunohistochemistry. Statistical analyses were applied to test the relationship between expression of Bmi-1, and clinicopathologic features and prognosis. Results Expression of Bmi-1 mRNA and protein was higher in bladder cancers than in the adjacent normal tissues in 14 paired samples (P P P P P > 0.5. In superficial bladder cancers, the expression of Bmi-1 protein in recurrent cases was higher than in recurrence-free cases (62.5% versus 13.7%, P P P > 0.05. Five-year survival in the group with higher Bmi-1 expression was 50.8%, while it was 78.5% in the group with lower Bmi-1 expression (P P Conclusion Expression of Bmi-1 was greater in bladder cancers than in the adjacent normal tissues. The examination of Bmi-1 protein expression is potentially valuable in prognostic evaluation of bladder cancer.

  8. Hepatocyte growth factor is a prognostic marker in patients with colorectal cancer: a meta-analysis.

    Science.gov (United States)

    Huang, Chao-Yuan; Zhou, Qian-Yi; Hu, Yue; Wen, Yi; Qiu, Zhen-Wen; Liang, Man-Guang; Mo, Jun-Ling; Xu, Jian-Hua; Sun, Cong; Liu, Feng-Bin; Chen, Xin-Lin

    2017-04-04

    Hepatocyte growth factor (HGF) is a crucial factor associated with development, progression and metastasis of colorectal cancer (CRC). However, its prognostic value remains unclear. Thus studies referring to the correlation between HGF and CRC patients' prognosis were included to explore the role of HGF in CRC. At last nine articles were included. The results showed that the over-expression of HGF was associated with a poor prognosis, presented through overall survival (OS, Hazard ratio (HR) = 2.50, 95% confidence interval (CI): 2.12-2.96) and disease-free survival (DFS, HR = 1.99, 95% CI: 1.59-2.50). Subgroup analysis indicated that no significant difference was found between the Asian countries (OS: HR = 2.37; DFS: HR = 2.02) and the non-Asian countries (OS: HR = 3.15; DFS: HR = 1.87), between the studies that used univariate analyses (OS: HR = 2.51; DFS: HR = 2.07) and those that used multivariate analyses (OS: HR = 2.65; DFS: HR = 1.78), and between metastatic CRC (OS: HR = 2.26; DFS: HR = 2.06) and stage I-IV CRC (OS: HR = 3.08; DFS: HR = 0.70). Our meta-analysis has shown that the over-expression of HGF is valuable in CRC prognosis evaluation. This conclusion should be further confirmed by large-sample cohort studies.

  9. Plasma 8-iso-Prostaglandin F2α, a possible prognostic marker in aneurysmal subarachnoid hemorrhage.

    Science.gov (United States)

    Pan, De-Sheng; Yan, Min; Hassan, Muhammad; Fang, Ze-Bin; Chen, Man-Tao

    2017-06-01

    8-iso-Prostaglandin F2α (8-iso-PGF2α) is a potential biomarker of oxidative stress. This study clarified whether plasma 8-iso-PGF2α concentrations were affected and its underlying relevance to prognosis in aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational study, a total of 170 controls and 170 aSAH patients were enrolled. Plasma 8-iso-PGF2α concentrations were detected using an ELISA. Severity was assessed by World Federation of Neurological Surgeons (WFNS) scale and modified Fisher grading scale. Clinical outcomes included 6-month mortality and poor outcome referred to as Glasgow outcome scale score of 1-3. As compared to controls, admission plasma 8-iso-PGF2α concentrations were significantly enhanced. Increased concentrations of plasma 8-iso-PGF2α correlated with WFNS scores and modified Fisher scores. 8-iso-PGF2α in plasma was an independent predictor for clinical outcomes. Under ROC curve, the predictive values of 8-iso-PGF2α concentrations resembled those of WFNS scores and modified Fisher scores for clinical outcomes. An elevation in plasma 8-iso-PGF2α concentrations is associated with the severity and poor outcome after aSAH, substantializing 8-iso-PGF2α as a potential prognostic biomarker of aSAH. Copyright © 2017. Published by Elsevier B.V.

  10. Anemia and performance status as prognostic markers in acute hypercapnic respiratory failure due to chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Haja Mydin H

    2013-03-01

    Full Text Available Helmy Haja Mydin, Stephen Murphy, Howell Clague, Kishore Sridharan, Ian K TaylorDepartment of Respiratory Medicine, Sunderland Royal Infirmary, Sunderland, United KingdomBackground: In patients with acute hypercapnic respiratory failure (AHRF during exacerbations of COPD, mortality can be high despite noninvasive ventilation (NIV. For some, AHRF is terminal and NIV is inappropriate. However there is no definitive method of identifying patients who are unlikely to survive. The aim of this study was to identify factors associated with inpatient mortality from AHRF with respiratory acidosis due to COPD.Methods: COPD patients presenting with AHRF and who were treated with NIV were studied prospectively. The forced expiratory volume in 1 second (FEV1, World Health Organization performance status (WHO-PS, clinical observations, a composite physiological score (Early Warning Score, routine hematology and biochemistry, and arterial blood gases prior to commencing NIV, were recorded.Results: In total, 65 patients were included for study, 29 males and 36 females, with a mean age of 71 ± 10.5 years. Inpatient mortality in the group was 33.8%. Mortality at 30 days and 12 months after admission were 38.5% and 58.5%, respectively. On univariate analysis, the variables associated with inpatient death were: WHO-PS ≥ 3, long-term oxygen therapy, anemia, diastolic blood pressure < 70 mmHg, Early Warning Score ≥ 3, severe acidosis (pH < 7.20, and serum albumin < 35 g/L. On multivariate analysis, only anemia and WHO-PS ≥ 3 were significant. The presence of both predicted 68% of inpatient deaths, with a specificity of 98%.Conclusion: WHO-PS ≥ 3 and anemia are prognostic factors in AHRF with respiratory acidosis due to COPD. A combination of the two provides a simple method of identifying patients unlikely to benefit from NIV.Keywords: acute exacerbations of COPD, noninvasive ventilation, emphysema, prognostic markers

  11. Standardized and weighted time-dependent receiver operating characteristic curves to evaluate the intrinsic prognostic capacities of a marker by taking into account confounding factors.

    Science.gov (United States)

    Le Borgne, Florent; Combescure, Christophe; Gillaizeau, Florence; Giral, Magali; Chapal, Marion; Giraudeau, Bruno; Foucher, Yohann

    2017-01-01

    Time-dependent receiver operating characteristic curves allow to evaluate the capacity of a marker to discriminate between subjects who experience the event up to a given prognostic time from those who are free of this event. In this article, we propose an inverse probability weighting estimator of a standardized and weighted time-dependent receiver operating characteristic curve. This estimator provides a measure of the prognostic capacities by taking into account potential confounding factors. We illustrate the robustness of the estimator by a simulation-based study and its usefulness by two applications in kidney transplantation.

  12. PTEN as a prognostic and predictive marker in postoperative radiotherapy for squamous cell cancer of the head and neck.

    Directory of Open Access Journals (Sweden)

    Miroslaw Snietura

    Full Text Available BACKGROUND: Tumor suppressor PTEN is known to control a variety of processes related to cell survival, proliferation, and growth. PTEN expression is considered as a prognostic factor in some human neoplasms like breast, prostate, and thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: In this study we analyzed the influence of PTEN expression on the outcome of a randomized clinical trial of conventional versus 7-days-a-week postoperative radiotherapy for squamous cell cancer of the head and neck. The patients with cancer of the oral cavity, oropharynx, and larynx were randomized to receive 63 Gy in fractions of 1.8 Gy given 5 days a week (CF or 7 days a week (p-CAIR. Out of 279 patients enrolled in the study, 147 paraffin blocks were available for an immunohistochemical assessment of PTEN. To evaluate the prognostic value of PTEN expression and the effect of fractionation relative to PTEN, the data on the outcome of a randomized clinical trial were analyzed. Tumors with a high intensity of PTEN staining had significant gain in the loco-regional control (LRC from p-CAIR (5-year LRC 92.7% vs. 70.8%, for p-CAIR vs. CF, p = 0.016, RR = 0.26. By contrast, tumors with low intensity of PTEN did not gain from p-CAIR (5-year LRC 56.2% vs. 47.2%, p = 0.49, RR = 0.94. The intensity of PTEN highly affected the LRC in a whole group of 147 patients (5-year LRC 80.9% vs. 52.3% for high vs. low PTEN, p = 0.0007, RR = 0.32. In multivariate Cox analysis, including neck node involvement, EGFR, nm23, Ki-67, p53, cyclin D1, tumor site and margins, PTEN remained an independent predictor of LRC (RR = 2.8 p = 0.004. CONCLUSIONS/SIGNIFICANCE: These results suggest that PTEN may serve as a potent prognostic and predictive marker in postoperative radiotherapy for high-risk squamous cell cancer of the head and neck.

  13. Enhancer of zeste homolog 2 as an independent prognostic marker for cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Shuling Chen

    Full Text Available Novel biomarkers are of particular interest for predicting cancer prognosis. This study aimed to explore the associations between enhancer of zeste homolog 2 (EZH2 and patient survival in various cancers.Relevant literature was retrieved from PubMed and Web of Science databases. Pooled hazard ratios (HRs, odds ratios (ORs, and 95% confidence intervals (CIs were calculated.Forty-nine studies (8,050 patients were included. High EZH2 expression was significantly associated with shorter overall (hazard ratio [HR] 1.74, 95% CI: 1.46-2.07, disease-free (HR 1.59, 95% CI: 1.27-1.99, metastasis-free (HR 2.19, 95% CI: 1.38-3.47, progression-free (HR 2.53, 95% CI: 1.52-4.21, cancer-specific (HR 3.13, 95% CI: 1.70-5.74, and disease-specific (HR 2.29, 95% CI: 1.56-3.35 survival, but not recurrence-free survival (HR 1.38, 95% CI: 0.93-2.06. Moreover, EZH2 expression significantly correlated with distant metastasis (OR 3.25, 95% CI: 1.07-9.87 in esophageal carcinoma; differentiation (OR 3.00, 95% CI: 1.37-6.55 in non-small cell lung cancer; TNM stage (OR 3.18, 95% CI: 2.49-4.08 in renal cell carcinoma; and histological grade (OR 4.50, 95% CI: 3.33-6.09, estrogen receptor status (OR 0.15, 95% CI: 0.11-0.20 and progesterone receptor status (OR 0.30, 95% CI: 0.23-0.39 in breast cancer.Our results suggested that EZH2 might be an independent prognostic factor for multiple survival measures in different cancers.

  14. Predialysis hypernatremia is a prognostic marker in acute kidney injury in need of renal replacement therapy.

    Science.gov (United States)

    Mendes, Renata S; Soares, Márcio; Valente, Carla; Suassuna, José Hermógenes; Rocha, Eduardo; Maccariello, Elizabeth R

    2015-10-01

    The present study aimed to evaluate the prognostic impact of predialysis dysnatremia in patients with acute kidney injury requiring renal replacement therapy (RRT). A secondary analysis of a prospective multicenter cohort study was performed. Serum sodium (Na) concentrations were categorized immediately before the first RRT as normonatremia (135≤Na ≤145mEq/L), hyponatremia (mild [130≤Na ≤134mEq/L] or severe [Na ≤129mEq/L]), and hypernatremia (mild [146≤Na ≤155mEq/L] or severe [Na ≥156mEq/L]). Multivariable logistic regression was used to estimate the impact of sodium levels categories on hospital mortality. Dysnatremia occurred in 47.3% of 772 included patients. Hypernatremia was more frequent than hyponatremia (33.7% vs 13.6%, P=.001). Intensive care unit (ICU) and hospital mortality rates were 64.6% and 69%, respectively. Hospital mortality was higher in severe hypernatremia (89.1% [95% confidence interval {CI}, 78.7%-95.8%] vs 64.6% [CI, 59.8%-69.2%], Phypernatremia (odds ratio, 2.87; 95% CI, 1.2-6.9), poor chronic heath status, severity of illness, sepsis, and lactate were independently associated with outcome. Almost 50% of patients with acute kidney injury in need of RRT in the ICU had mild or severe dysnatremia before dialysis initiation. Hypernatremia was the main sodium disturbance and independently associated with poor outcome in the study population. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Cholesterol metabolism as a prognostic marker in patients with mildly symptomatic nonischemic dilated cardiomyopathy.

    Science.gov (United States)

    Sawamura, Akinori; Okumura, Takahiro; Hiraiwa, Hiroaki; Aoki, Soichiro; Kondo, Toru; Ichii, Takeo; Furusawa, Kenji; Watanabe, Naoki; Kano, Naoaki; Fukaya, Kenji; Morimoto, Ryota; Bando, Yasuko K; Murohara, Toyoaki

    2017-06-01

    Little is known about whether the alteration of cholesterol metabolism reflects abdominal organ impairments due to heart failure. Therefore, we investigated the prognostic value of cholesterol metabolism by evaluating serum campesterol and lathosterol levels in patients with early-stage nonischemic dilated cardiomyopathy (NIDCM). We enrolled 64 patients with NIDCM (median age 57.5 years, 31% female) with New York Heart Association functional class I/II. Serum campesterol and lathosterol levels were measured in all patients. The patients were then divided into four subsets based on the median non-cholesterol sterol levels (campesterol 3.6μg/mL, lathosterol 1.4μg/mL): reference (R-subset), high-campesterol/high-lathosterol; absorption-reduced (A-subset), low-campesterol/high-lathosterol; synthesis-reduced (S-subset), high-campesterol/low-lathosterol; double-reduced (D-subset), low-campesterol/low-lathosterol. Endpoint was a composite of cardiac events, including cardiac-related death, hospitalization for worsening heart failure, and lethal arrhythmia. Median brain natriuretic peptide (BNP) level was 114pg/mL. Mean left ventricular ejection fraction was 31.4%. D-subset had the lowest total cholesterol level and cardiac index and the highest BNP level and pulmonary capillary wedge pressure. D-subset also had the highest cardiac event rate during the mean 3.8 years of follow-up (log-rank p=0.001). Multivariate regression analysis showed that D-subset was an independent determinant of cardiac events. The receiver operating characteristic curve analysis revealed that total cholesterol cholesterol absorption and liver synthesis predicts future cardiac events in patients with mildly symptomatic NIDCM. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

  16. Proper ubiquitination effect on the fertilisation outcome post-ICSI.

    Science.gov (United States)

    Eskandari-Shahraki, M; Tavalaee, M; Deemeh, M R; Jelodar, Gh A; Nasr-Esfahani, M H

    2013-06-01

    Ubiquitin is an 8.5-kDa protein that tags outlived proteins for degradation by the proteasome. It also marks defective spermatozoa during epididymal passage and has been proposed as a biomarker of sperm quality. This study evaluates the relationship between sperm ubiquitination, protamine deficiency, semen parameters and fertilisation rate in infertile individuals undergoing the intracytoplasmic sperm insemination (ICSI) procedure. Semen samples from 73 ICSI candidates were collected and analysed according to World Health Organization criteria. A portion of each sample was evaluated for sperm ubiquitination using the sperm ubiquitin tag immunoassay (SUTI) with flow cytometry, and protamine deficiency by chromomycin A3 (CMA3) staining. In addition, the relationship between the fertilisation rate and sperm ubiquitination was calculated in ICSI candidates. The intensity of ubiquitination showed a significant negative correlation with sperm concentration (r = -0.255, P = 0.032) and a positive correlation with fertilisation rate (r = 0.384, P = 0.013) post-ICSI. No correlation was observed between protamine deficiency and the percentage of ubiquitination or ubiquitination intensity. The results of this study suggest that sperm ubiquitination prior to capacitation may be considered as a marker of defective spermatozoon. Spermatozoa that undergo proper ubiquitination may have a higher chance for fertilisation, because they are made redundant by the ubiquitin-proteasome pathway in the epididymis compared to hypo-ubiquitinated spermatozoa. © 2012 Blackwell Verlag GmbH.

  17. Diagnostic/prognostic molecular cytogenetic follow-up applied in satellited marker cases

    Energy Technology Data Exchange (ETDEWEB)

    Papenhausen, P.R.; Anderson, S.

    1994-09-01

    Special caution needs to be exercised in offering a good prognosis in Prader-Willi probe negative 15-derived marker cases, since it is clear that phenotypic effects can still be associated with the apparent presence of proximal sequences. We have had two postnatal cases in this category, one which was inherited from an unaffected paternal (non-mosaic) carrier, possibly demonstrating imprinting effects. Familial studies are continuing in this case. Although the D22/S9 locus appears diagnostic of cateye syndrome (CES), the dual specificity of the 14/22 centromeric probe leaves the possibility of a poor prognosis 14 derivation when the CES probe is negative. Therefore, it is imperative that proximal long arm 13, 14, 21 and more proximal 15 FISH probes be implemented so that a phenotypically correlated database may indicate the proper FISH probes necessary for accurate prognosis. Bisatellited markers is which a bipartite centromeric probe signal was found were considered to be higher risk than those with the single signal in counseling.

  18. The value of the Ki-67 proliferation marker as a prognostic factor in gastroenteropancreatic neuroendocrine tumours.

    Science.gov (United States)

    Foltyn, Wanda; Zajęcki, Wojciech; Marek, Bogdan; Kajdaniuk, Dariusz; Siemińska, Lucyna; Zemczak, Anna; Kos-Kudła, Beata

    2012-01-01

    Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are a heterogenous group of tumours of various clinical presentations. Proliferative activity of tumour cells is an essential parameter determining the course of the disease and affecting the prognosis. The Ki-67 antigen is an important marker of cell proliferation, which shows activity in all the phases of the cell cycle, excluding the G0 phase. To assess the expression of Ki-67 in GEP NETs and to examine the association of Ki-67 with the stage of the tumour (tumour size, presence of metastases) and the hormonal function of the tumour. We included 61 patients with GEP NETs (25 males and 36 females aged between 20 and 82 years [mean age: 56 years]). The proliferative activity was examined in paraffin blocks containing surgically removed tumour samples and in core-needle biopsies of primary and metastatic tumours. The presence of the Ki-67 antigen was assessed by immunohistochemistry using MIB‑1 monoclonal antibodies. Based on the Ki-67 proliferative index we determined the tumour grade. In addition, we determined the tumour stage according to the TNM classification. In all the subjects we determined the levels of the non-specific NET marker (chromogranin A) and of specific NET markers (serotonin, insulin and gastrin in the blood and 5‑hydroxyindoleacetic acid [5‑HIAA] in 24-hour urine). The diagnoses of low-grade (Ki‑67 ≤ 2%), intermediate-grade (Ki-67 3-20%) and high-grade (Ki‑67 > 20%) NET were established in 38, 12 and 11 patients, respectively. Metastatic disease was diagnosed in 36/61 patients. A significantly higher expression of K-67 was observed in patients with metastatic disease (p = 0.01). A positive correlation was demonstrated between Ki-67 and the stage of the disease (p = 0.01) and between the histologic grade of the tumour and the stage of the disease (p = 0.01). No association between Ki-67 and the levels of chromogranin A, serotonin, insulin, gastrin and 5-HIAA was shown. There

  19. MicroRNA Levels as Prognostic Markers for the Differentiation Potential of Human Mesenchymal Stromal Cell Donors.

    Science.gov (United States)

    Georgi, Nicole; Taipaleenmaki, Hanna; Raiss, Christian C; Groen, Nathalie; Portalska, Karolina Janaeczek; van Blitterswijk, Clemens; de Boer, Jan; Post, Janine N; van Wijnen, Andre J; Karperien, Marcel

    2015-08-15

    The ability of human mesenchymal stromal/stem cells (hMSCs) to differentiate into various mesenchymal cell lineages makes them a promising cell source for the use in tissue repair strategies. Since the differentiation potential of hMSCs differs between donors, it is necessary to establish biomarkers for the identification of donors with high differentiation potential. In this study, we show that microRNA (miRNA) expression levels are effective for distinguishing donors with high differentiation potential from low differentiation potential. Twenty hMSC donors were initially tested for marker expression and differentiation potential. In particular, the chondrogenic differentiation potential was evaluated on the basis of histological matrix formation, mRNA expression levels of chondrogenic marker genes, and quantitative glycosaminoglycan deposition. Three donors out of twenty were identified as donors with high chondrogenic potential, whereas nine showed moderate and eight showed low chondrogenic potential. Expression profiles of miRNAs involved in chondrogenesis and cartilage homeostasis were used for the distinction between high-performance hMSCs and low-performance hMSCs. Global mRNA expression profiles of the donors before the onset of chondrogenic differentiation revealed minor differences in gene expression between low and high chondrogenic performers. However, analysis of miRNA expression during a 7-day differentiation period identified miR-210 and miR-630 as positive regulators of chondrogenesis. In contrast, miR-181 and miR-34a, which are negative regulators of chondrogenesis, were upregulated during differentiation in low-performing donors. In conclusion, profiling of hMSC donors for a specific panel of miRNAs may have a prognostic value for selecting donors with high differentiation potential to improve hMSC-based strategies for tissue regeneration.

  20. Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as prognostic markers in idiopathic membranous nephropathy.

    Science.gov (United States)

    Maas, Rutger Jh; van den Brand, Jan Ajg; Waanders, Femke; Meijer, Esther; Goor van, Harry; Peters, Hilde P; Hofstra, Julia M; Wetzels, Jack Fm

    2016-01-01

    Urinary excretion of alpha-1-microglobulin and beta-2-microglobulin reflects tubular damage and predicts outcome in patients with idiopathic membranous nephropathy with reasonable accuracy. Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin are novel biomarkers of tubular damage. We investigated if these markers could improve prediction of outcome in idiopathic membranous nephropathy. We measured kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in urine samples from patients with idiopathic membranous nephropathy, who had nephrotic proteinuria and normal renal function. Excretion of alpha-1-microglobulin and beta-2-microglobulin had been measured previously. Progression was defined as a serum creatinine rise >30%, a rise in serum creatinine to an absolute value of ≥135 µmol/L, or a clinical decision to start immunosuppressive therapy. Remission was defined as proteinuria 50% reduction from baseline. Sixty-nine patients were included. Median follow-up was 35 months (interquartile range 18-63 months). Progression occurred in 30 patients (44%), and spontaneous remission in 36 (52%). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates were significantly correlated with each other, and with alpha-1-microglobulin and beta-2-microglobulin. The areas under the receiver operating characteristic curves for progression were 0.75 (0.62-0.87) for kidney injury molecule-1 and 0.74 (0.62-0.87) for neutrophil gelatinase-associated lipocalin. In multivariate analysis with either alpha-1-microglobulin and beta-2-microglobulin, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not independently predict outcome. Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion rates correlated with excretion rates of other tubular damage markers and predicted outcome in patients with idiopathic membranous nephropathy. They did not add prognostic value

  1. Proinflammatory and Anti-Inflammatory Cytokines Mediated by NF-κB Factor as Prognostic Markers in Mammary Tumors

    Directory of Open Access Journals (Sweden)

    Gustavo Rodrigues Martins

    2016-01-01

    Full Text Available Inflammation results in the production of cytokines, such as interleukin- (IL- 4 and IL-10 with immunosuppressive properties or IL-6 and TNF-α with procarcinogenic activity. Furthermore, NF-κB is the major link between inflammation and tumorigenesis. This study verified the interaction between active inflammatory cytokines in the tumor microenvironment and serum of female dogs with mammary tumors and their correlation with the clinicopathological characteristics and overall survival. Measurement of gene expression was performed by qPCR and protein levels by ELISA/Luminex. High gene and protein expression levels of NF-κB, IL-6, and TNF-α were found in association with characteristics that reflect worse prognosis and a negative correlation between TNF-α protein expression and survival time was observed (p<0.05. In contrast, high gene and protein expression levels of IL-4 and IL-10 were associated with characteristics of better prognosis and an increased level of IL-4 and a longer survival time of animals were obtained (p<0.05. In addition, there was a positive correlation between TNF-α and IL-6 expression in association with NF-κB. The results show a significant correlation of these cytokines with tumor development, associated with NF-κB expression and cytokines promodulation, showing that these biological factors could be used as predictive and prognostic markers in breast cancer.

  2. Identification of Gelatinases involved in the Rous sarcoma Virus-induced Tumors in Chicks as Prognostic Markers

    Directory of Open Access Journals (Sweden)

    A.M. Kotresh and Meena Kataria

    Full Text Available The present work is undertaken to study the expression of levels of gelatinases in tumorogenesis by Rous sarcoma virus(RSV in layer chicks and explored the possibility of using gelatinases as potential biological markers in metastatic neoplasms. Two days old chicks (40 were divided into two groups (Gp I and Gp II. Gp-I (20 treated with Rous sarcoma virus for tumor induction. The Gp II (control was inoculated with RPMI-1640. Tumors appeared earliest by three days post infection with RSV and were progressive leading to mortality of birds by twenty eight days. Distant tumors were observed in liver, heart, lung, and kidney on post mortem. A prominent band of gelatinase of around 75 kDa was detected in plasma of infected chicks by gelatin zymography. Results indicate over expression of gelatinases and are leaked into plasma on Rous sarcoma virus infection. Expression of gelatinases in primary tumors, metastasized liver, heart, lung and kidney and corresponding tissues in healthy control chicks was determined by RT-PCR analysis. Over expression of gelatinase gene was observed in metastaic tissues and primary tumors than control. The described assays could be used as a prognostic assay method for detection of proteases in metastatic neoplasms of animals. [Veterinary World 2010; 3(11.000: 500-502

  3. Single nucleotide polymorphisms as susceptibility, prognostic, and therapeutic markers of nonsmall cell lung cancer

    Directory of Open Access Journals (Sweden)

    Zienolddiny S

    2011-12-01

    Full Text Available Shanbeh Zienolddiny, Vidar SkaugSection for Toxicology and Biological Work Environment, National Institute of Occupational Health, Oslo, NorwayAbstract: Lung cancer is a major public health problem throughout the world. Among the most frequent cancer types (prostate, breast, colorectal, stomach, lung, lung cancer is the leading cause of cancer-related deaths worldwide. Among the two major subtypes of small cell lung cancer and nonsmall cell lung cancer (NSCLC, 85% of tumors belong to the NSCLC histological types. Small cell lung cancer is associated with the shortest survival time. Although tobacco smoking has been recognized as the major risk factor for lung cancer, there is a great interindividual and interethnic difference in risk of developing lung cancer given exposure to similar environmental and lifestyle factors. This may indicate that in addition to chemical and environmental factors, genetic variations in the genome may contribute to risk modification. A common type of genetic variation in the genome, known as single nucleotide polymorphism, has been found to be associated with susceptibility to lung cancer. Interestingly, many of these polymorphisms are found in the genes that regulate major pathways of carcinogen metabolism (cytochrome P450 genes, detoxification (glutathione S-transferases, adduct removal (DNA repair genes, cell growth/apoptosis (TP53/MDM2, the immune system (cytokines/chemokines, and membrane receptors (nicotinic acetylcholine and dopaminergic receptors. Some of these polymorphisms have been shown to alter the level of mRNA, and protein structure and function. In addition to being susceptibility markers, several of these polymorphisms are emerging to be important for response to chemotherapy/radiotherapy and survival of patients. Therefore, it is hypothesized that single nucleotide polymorphisms will be valuable genetic markers in individual-based prognosis and therapy in future. Here we will review some of the most

  4. Neopterin as a prognostic marker in patients with chronic heart failure.

    Science.gov (United States)

    Wietlicka-Kokoszanek, Irmina; Jablecka, Anna; Smolarek, Iwona; Bogdanski, Pawel; Chmara, Ewa; Korzeniowska, Katarzyna; Kazmierczak, Mirosław; Kazmierczak, Ewa; Musialik, Katarzyna

    2010-05-01

    The study aimed at evaluating neopterin concentration in relation to heart failure etiology and determining basal neopterin concentration in relation to the clinical state of patients after 12 months of standard treatment. The examined group was composed of 47 patients with NYHA class II and III heart failure and 20 healthy volunteers. Neopterin concentration in blood serum was determined with a radioimmunological assay. Twelve months after the patients had left the hospital, their quality of life and clinical symptoms of heart failure were evaluated. Statistically significantly higher basal concentrations of neopterin in the group of patients with CHF than in the control group (p<0.001) were noted. A higher concentration was found in NYHA class III than in NYHA class II CHF patients (p<0.001). No difference in relation to heart failure etiology was detected. The basal neopterin concentration determined patients' clinical status after the 12-month standard chronic heart failure treatment. In the 12-month observation, a relationship was detected between neopterin concentration and heart failure progression, which may point to neopterin as a marker of heart failure progression.

  5. PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma.

    Science.gov (United States)

    Khalid, Ayesha; Hussain, Tabinda; Manzoor, Sobia; Saalim, Muhammad; Khaliq, Saba

    2017-06-01

    PTEN is the second most frequently mutated tumor suppresser gene in cancers after p53. Genetic and epigenetic alterations in the PTEN gene and its regulatory regions have been reported in various studies. PTEN is a crucial downregulator of the pro-survival phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway and also suppresses insulin signaling. Failure to regulate these pathways leads to increase in cell proliferation and migration which in turn promotes tumorigenesis. PTEN underexpression is mediated by a variety of cytokines and stress kinases which seem to collectively induce the RAS/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In the context of hepatocellular carcinoma, reduced expression of PTEN is seen in nearly half of the cases on average. In some cases, PTEN has been observed to be either mutated or methylated which can also lead to reduced expression or in some cases, complete loss of expression. On the cellular level, PTEN is also a target in the pathogenic pathway of hepatitis C virus core protein and hepatitis B virus X protein. These viruses appear to alter PTEN regulation and pro-apoptotic ability to enhance the process of tumor formation. In perspective of the crucial role PTEN plays in balancing proliferation and apoptosis, we propose PTEN as a valuable marker in the diagnosis, assessment of tumor grade, and disease stage in hepatocellular carcinoma patients.

  6. Circulating Inflammatory Mediators as Potential Prognostic Markers of Human Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Giuseppe Di Caro

    Full Text Available Cytokines and chemokines in the tumor microenvironment drive metastatic development and their serum levels might mirror the ongoing inflammatory reaction at the tumor site. Novel highly sensitive tools are needed to identify colorectal cancer patients at high risk of recurrence that should be more closely monitored during post-surgical follow up. Here we study whether circulating inflammatory markers might be used to predict recurrence in CRC patients.Circulating levels of the inflammatory cytokines IL-1, IL-6, IL-10, TNFalpha, CCL2, CXCL8, VEGF and the acute phase protein Pentraxin-3 were measured by ELISA in preoperative serum samples prospectively collected from a cohort of sixty-nine patients undergoing surgical resection for stage 0-IV CRC and associated with post-operative disease recurrence.Cox multivariate analysis showed that combined high levels (≥ROC cut off-value of CXCL8, VEGF and Pentraxin3 were associated with increased risk of disease recurrence [HR: 14.28; 95%CI: (3.13-65.1] independently of TNM staging. Kaplan-Meier analysis showed that CXCL8, VEGF and Pentraxin3 levels were significantly associated with worse survival (P<0.001.Circulating inflammatory mediators efficiently predicted postoperative recurrence after CRC surgery. Therefore, this study suggest that their validation in large-scale clinical trials may help in tailoring CRC post-surgical management.

  7. Phospho-histone H2AX is a diagnostic and prognostic marker for epithelial ovarian cancer.

    Science.gov (United States)

    Mei, Ling; Hu, Qian; Peng, Jing; Ruan, Jiaying; Zou, Juan; Huang, Qin; Liu, Shanling; Wang, He

    2015-01-01

    Histone H2AX phosphorylation is a sensitive marker for DSB which contributes to both genomic instability and cancer treatment. Monitoring its formation may be a sensitive means to monitor cancer progression and treatment effect. To define the role of phospho-H2AX (pH2AX) expression in development and prognosis of epithelial ovarian cancer (EOC). The expression of pH2AX in 87 EOC samples and 28 samples of normal ovarian tissues were examined by immunohistochemistry (IHC). The results were semi-quantitatively scored and analyzed by chi-square test. The overall survival time (OS) and disease free interval (DFI) were collected by follow-up and analyzed by Kaplan-Meier analysis. The expression level of pH2AX protein in EOC were higher than that in normal tissues (P<0.001). Among the sensitive cases, high expression of pH2AX was found in 53.2% cases while for resistant cases, high expression rate was 80% (P=0.025). However, pH2AX expression was not significantly correlated with age, histopathological type, tumor differentiation, lymph node metastasis or FIGO stages. Kaplan-Meier analysis found that DFI was negatively correlated with the pH2AX expression, where higher expression of pH2AX resulted in shorter DFI while no OS difference was detected in our study. pH2AX may be used to detect EOC at an early stage and identify women at higher risk for relapse.

  8. A comparison of gamma-glutamyl transferase and alkaline phosphatase as prognostic markers in patients with coronary heart disease.

    Science.gov (United States)

    Ndrepepa, G; Holdenrieder, S; Cassese, S; Fusaro, M; Xhepa, E; Laugwitz, K-L; Schunkert, H; Kastrati, A

    2018-01-01

    Whether gamma-glutamyl transferase (GGT) or alkaline phosphatase (ALP) is a better prognostic marker in patients with coronary heart disease (CHD) remains unknown. The aim of this study was to compare the prognostic value of GGT and ALP in patients with CHD. This study included 3768 patients with CHD. The main study outcome was 3-year all-cause mortality. The median values of GGT and ALP were 36.2 U/L and 69.3 U/L. Patients were divided into subgroups according to GGT or ALP activity > or ≤median. Overall, there were 304 deaths: 195 deaths occurred in patients with GGT >median (n = 1882) and 109 deaths occurred in patients with GGT ≤median (n = 1886); Kaplan-Meier [KM] estimates of all-cause mortality were 11.9% and 6.4% (unadjusted hazard ratio [HR] = 1.85, 95% confidence interval [CI], 1.46 to 2.34]; P median (n = 1883) and 118 deaths occurred in patients with ALP ≤median (n = 1885); KM estimates of all-cause mortality were 11.4% and 7.1% (unadjusted HR = 1.64 [1.30-2.06]; P < 0.001). After adjustment, GGT (adjusted HR = 1.32 [1.11-1.58]; P = 0.002) but not ALP (adjusted HR = 1.20 [1.00-1.43]; P = 0.051, with both HR calculated per 1 unit increment in logarithmic GGT or ALP scale) remained significantly associated with the risk for mortality. The C statistic of the mortality model with GGT was greater than the C statistic of the model with ALP (0.831 [0.802-0.859] vs. 0.826 [0.793-0.855]; P < 0.001). In patients with CHD, GGT was a stronger correlate of all-cause mortality than ALP. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

  9. HGF and NRG1 protein expression are not poor prognostic markers in surgically resected lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Pan B

    2015-05-01

    Full Text Available Bin Pan,1,2 Rui Wang,1,2 Yangle Huang,1,2 David Garfield,3 Jie Zhang,1,2 Haiquan Chen1,2 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3University of Colorado Comprehensive Cancer Center, Aurora, CO, USA Purpose: Although over-expression of hepatocyte growth factor (HGF and neuregulin-1 (NRG1 are important mechanisms involved in acquired drug-resistance in many cancers, few reports have evaluated their clinicopathologic features and prognostic significance. The aim of our study was to investigate protein expressions of HGF and NRG1 in lung adenocarcinomas and their association with clinicopathologic parameters, oncogenic mutations, and the prognosis. Methods: HGF and NRG1 protein tumor/stroma expressions were evaluated by immunohistochemistry (IHC in 115 surgically resected lung adenocarcinomas and were correlated with clinicopathologic and molecular variables including tumor size, tumor node metastasis stage, differentiation, oncogenic mutations (EGFR, KRAS, HER2, BRAF and ALK fusions, relapse-free survival, and overall survival. Results: Positive IHC HGF tumor and stroma staining were found in 49 (42.61% and 12 (10.43% cases, respectively, while positive IHC NRG1 tumor and stroma staining were found in 56 (48.70% and eleven (9.57% cases, respectively. Dual positive IHC HGF and NRG1 tumor staining was 12.17%. EML4-ALK fusion more significantly existed in HGF-tumor positive samples (P=0.03, positive NRG1 protein stroma expression was significantly associated with male sex (P=0.04, while HGF and NRG1 dual tumor-positive mainly existed in the tumor size >3 cm group (P=0.0231. No significant clinically prognostic difference was found between patients with HGF/NRG1-positive expression and those with HGF/NRG1-negative expression. Conclusion: This study represents the

  10. Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients

    Science.gov (United States)

    Tsai, Wen-Sy; Chen, Jinn-Shiun; Shao, Hung-Jen; Wu, Jen-Chia; Lai-Ming, Jr.; Lu, Si-Hong; Hung, Tsung-Fu; Chiu, Yen-Chi; You, Jeng-Fu; Hsieh, Pao-Shiu; Yeh, Chien-Yuh; Hung, Hsin-Yuan; Chiang, Sum-Fu; Lin, Geng-Ping; Tang, Reiping; Chang, Ying-Chih

    2016-04-01

    Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had neoplasm, thus CTC may be as a simple, independent prognostic marker for the non-metastatic CRC patients who are at high risk of early recurrence.

  11. Long-term prognostic value of the combination of EORTC risk group calculator and molecular markers in non-muscle-invasive bladder cancer patients treated with intravesical Bacille Calmette-Guérin

    Directory of Open Access Journals (Sweden)

    Sultan S Alkhateeb

    2011-01-01

    Conclusion: Molecular markers have a long-term prognostic value when combined with EORTC scoring system and they may be used to improve the predictive accuracy of currently existing scoring system. Larger series are needed to confirm these findings.

  12. Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin.

    Science.gov (United States)

    Ak, Guntulu; Tada, Yuji; Shimada, Hideaki; Metintas, Selma; Ito, Masaaki; Hiroshima, Kenzo; Tagawa, Masatoshi; Metintas, Muzaffer

    2017-03-23

    We evaluated possible diagnostic and prognostic values of serum midkine in malignant pleural mesothelioma in comparison with those of serum mesothelin, a well-established diagnostic biomarker. Serum mesothelin and midkine levels were determined with an enzyme-linked immunosorbent assay. We examined specimens from 95 Turkish cases with malignant pleural mesothelioma, 56 metastatic cancers to pleura, 27 other types of benign pleural diseases and 20 benign asbestos pleurisy. The cut-off values were 1.5 nmol/L for mesothelin and 421 pg/mL for midkine. Sensitivity and specificity of mesothelin were 51.6 and 71.4%, 51.6 and 85.2%, and 51.6 and 85% for differentiating mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Sensitivity and specificity of midkine were 61.1 and 41.1%, 61.1 and 48.1%, and 61.1 and 75% to distinguish mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Combination of both biomarkers did not improve the differential diagnostic efficacy. Mesothelin levels were elevated in the epitheloid type and in the advanced cases, but were not related to the prognosis. In contrast, elevated baseline levels of midkine were independently associated with a poor prognosis of mesothelioma patients after adjusting for the stage, the histological subtypes and treatment schedules (HR = 1.84; 95% CI: 1.09-3.09) (p = 0.022). Serum mesothelin showed moderate sensitivity and high specificity to differentiate malignant pleural mesothelioma from metastatic malignancy to pleura and from benign pleural diseases. In contrast, midkine was a useful marker for predicting prognosis of mesothelioma patients.

  13. Hypoxia Marker GLUT-1 (Glucose Transporter 1) is an Independent Prognostic Factor for Survival in Bladder Cancer Patients Treated with Radical Cystectomy.

    Science.gov (United States)

    Boström, P J; Thoms, J; Sykes, J; Ahmed, O; Evans, A; van Rhijn, B W G; Mirtti, T; Stakhovskyi, O; Laato, M; Margel, D; Pintilie, M; Kuk, C; Milosevic, M; Zlotta, A R; Bristow, R G

    2016-01-07

    Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7-12.6, Wald p  = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3-7.5, Wald p  = 0.0085 in the Turku cohort). GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

  14. Study of complement activation, C3 and interleukin-6 levels in burn patients and their role as prognostic markers

    Directory of Open Access Journals (Sweden)

    S Modi

    2014-01-01

    Full Text Available Purpose: The management of burn patients is always challenging for the clinician due to high risk of bacterial sepsis, multi-organ failure and death. Our objective was to study complement activation, C3 and interleukin-6 (IL-6 levels in burn patients and evaluate their role as prognostic markers. Materials and Methods: A total of 63 burn patients and 60 healthy controls were included in this study. Blood was collected from patients within 24 h and at 7 th day of injury. Complement activation was determined by crossed electrophoresis and counter-current immunoelectrophoresis. C3 levels were measured using a single radial immunodiffusion. IL-6 was detected by ELISA. Results: All patients showed initial complement activation. Mean C3 levels showed an inverse correlation with the severity of burn. Patients with ≥20% burns had lower C3 than the controls (P < 0.001 and those with <20% burns (P < 0.001. Patients with ≥40% burns had activated complement and low C3 in 2 nd week; they subsequently developed infection. Complement was inactive and C3 levels recovered in patients with <40% burns. The non-survivors showed significantly lower C3 than the survivors (P < 0.05 in 2 nd samples. Patients who developed infection had C3 significantly lower than those who remained free of infection (P < 0.05. All patients showed initial elevation in IL-6 levels. Patients with ≥60% burns had significantly higher IL-6 than controls (P < 0.001 and those with <60% burns (P < 0.001. Non-survivors had higher IL-6 than survivors in both samples (P < 0.001. Patients who developed infection showed significantly higher IL-6 in 2 nd samples than those without infection (P < 0.001. Conclusions: Complement activation, C3 and IL-6 levels correlated well with the severity of injury and development of infection in burn patients. These parameters can be used to predict the onset of infection, septicaemia and mortality in burn patients.

  15. E3 Ubiquitin Ligases as Cancer Targets and Biomarkers

    Directory of Open Access Journals (Sweden)

    Yi Sun

    2006-08-01

    Full Text Available E3 ubiquitin ligases are a large family of proteins that are engaged in the regulation of the turnover and activity of many target proteins. Together with ubiquitinactivating enzyme El and ubiquitin-conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a variety of biologically significant protein substrates for targeted degradation through the 26S proteasome, as well as for nonproteolytic regulation of their functions or subcellular localizations. E3 ubiquitin ligases, therefore, play an essential role in the regulation of many biologic processes. Increasing amounts of evidence strongly suggest that the abnormal regulation of some E3 ligases is involved in cancer development. Furthermore, some E3 ubiquitin ligases are frequently overexpressed in human cancers, which correlates well with increased chemoresistance and poor clinic prognosis. In this review, E3 ubiquitin ligases (such as murine double minute 2, inhibitor of apoptosis protein, and Skpi-Cullin-F-box protein will be evaluated as potential cancer drug targets and prognostic biomarkers. Extensive study in this field would lead to a better understanding of the molecular mechanism by which E3 ligases regulate cellular processes and of how their deregulations contribute to carcinogenesis. This would eventually lead to the development of a novel class of anticancer drugs targeting specific E3 ubiquitin ligases, as well as the development of sensitive biomarkers for cancer treatment, diagnosis, and prognosis.

  16. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  17. Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

    OpenAIRE

    Kang, Ho Won; Kim, Ye-Hwan; Jeong, Pildu; Park, Cheol; Kim, Won Tae; Ryu, Dong Hee; Cha, Eun-Jong; Ha, Yun-Sok; Kim, Tae-Hwan; Kwon, Tae Gyun; Moon, Sung-Kwon; Choi, Yung Hyun; Yun, Seok-Joong; Kim, Wun-Jae

    2017-01-01

    The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, a...

  18. Clinical and prognostic significance of aberrant T-cell marker expression in 225 cases of de novo diffuse large B-cell lymphoma and 276 cases of other B-cell lymphomas

    Science.gov (United States)

    Tsuyama, Naoko; Ennishi, Daisuke; Yokoyama, Masahiro; Baba, Satoko; Asaka, Reimi; Mishima, Yuko; Terui, Yasuhito; Hatake, Kiyohiko; Takeuchi, Kengo

    2017-01-01

    Expression of T-cell markers, generally investigated for immunophenotyping of T-cell lymphomas, is also observed in several types of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We previously reported that CD5 expression in DLBCL is an inferior prognostic factor in the era of rituximab. However, data regarding the frequencies, histological relevance, and prognostic importance of T-cell markers other than CD5 are currently unavailable. In the present study, we comprehensively evaluated the expression of T-cell markers (CD2, CD3, CD4, CD5, CD7, and CD8) in 501 B-cell lymphomas, including 225 DLBCLs, by flow cytometry and subsequent immunohistochemistry. T-cell markers other than CD5, such as CD2, CD4, CD7, and CD8, were expressed in 27 (5%) patients, and notably, all of these cases were classified as large B-cell lymphoma subtypes: 25 DLBCLs and 2 intravascular large B-cell lymphomas. CD5 and other T-cell markers were expressed in 15% (31/225) and 10% (25/225) of DLBCL cases, respectively. Five of them co-expressed CD5 and other T-cell markers. Retrospectively analyzing the prognostic relevance of T-cell markers in 169 patients with primary DLBCL treated with rituximab-based chemotherapy, we showed that only CD5 was a strong predictor of poor survival. This study provides information about the occurrence of T-cell markers other than CD5 in B-cell lymphomas, their frequent histological subtypes, and their prognostic significance in DLBCL. CD5 was reconfirmed as a negative prognostic marker in DLBCL patients receiving rituximab-inclusive chemotherapy, whereas T-cell markers other than CD5 were found to have no impact on clinicopathological and survival analyses. PMID:28380441

  19. The need for additional genetic markers for myelodysplastic syndrome stratification: what does the future hold for prognostication?

    Science.gov (United States)

    Otrock, Zaher K; Tiu, Ramon V; Maciejewski, Jaroslaw P; Sekeres, Mikkael A

    2013-02-01

    Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic disorders. Metaphase cytogenetics has been the gold standard for genetic testing in MDS, but it detects clonal cytogenetic abnormalities in only 50% of cases. New karyotyping tests include FISH, array-based comparative genomic hybridization and single-nucleotide polymorphism arrays. These techniques have increased the detected genetic abnormalities in MDS, many of which confer prognostic significance to overall and leukemia-free survival. This has eventually increased our understanding of MDS genetics. With the help of new technologies, we anticipate that the existing prognostic scoring systems will incorporate mutational data into their parameters. This review discusses the progress in MDS diagnosis through the use of array-based technologies. The authors also discuss the recently investigated genetic mutations in MDS and revisit the MDS classification and prognostic scoring systems.

  20. Ubiquitin and ubiquitine-like systems in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    van de Pasch, L.A.L.

    2012-01-01

    Ubiquitin and ubiquitin-like modifiers are small proteins that exist in all eukaryotes, from yeast to humans. Ubiquitin(-like) modifiers can be coupled to other proteins, which is mediated specific combinations of enzymes. The attachment of a ubiquitin(-like) modifier to a protein is important for

  1. Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67 and apoptosis (p53 in the neuroblastoma group of tumors

    Directory of Open Access Journals (Sweden)

    Katarzyna Taran

    2016-02-01

    Full Text Available Introduction: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG and has been identified as a regulator of primary neural crest cells. It is believed that Bmi‑1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors.Material/Methods: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer’s instructions.Results: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients.Conclusions: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue.

  2. Overexpression of Yes Associated Protein 1, an Independent Prognostic Marker in Patients With Pancreatic Ductal Adenocarcinoma, Correlated With Liver Metastasis and Poor Prognosis.

    Science.gov (United States)

    Salcedo Allende, Maria Teresa; Zeron-Medina, Jorge; Hernandez, Javier; Macarulla, Teresa; Balsells, Joaquim; Merino, Xavier; Allende, Helena; Tabernero, Josep; Ramon Y Cajal Agüeras, Santiago

    2017-08-01

    Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Overexpression of Yes associated protein 1 (YAP1), a downstream target of Hippo pathway, implicated in regulation of cell growth and apoptosis, has been reported in several human tumor types. The objective of this study was to investigate YAP1 expression in patients with PDAC and its prognostic values. We evaluated YAP1 expression in 64 PDAC and 15 chronic pancreatitis (CP) cases and its related pancreatic intraepithelial neoplasia (PanIN) lesions and in 5 control subjects. Yes associated protein 1 expression was determined by immunohistochemistry. Association of YAP1 with clinicopathologic features in PDAC, disease-free survival, and overall survival was analyzed. We found a higher positive rate of nuclear expression of YAP1 in PDAC than in CP (P = 0.000) and lower expression of YAP1 in PanIN lesions in CP in contrast with expression in PanIN lesions in PDAC. Nuclear overexpression of YAP1 in PDAC is associated with hepatic metastasis (P = 0.0280) and is a prognostic factor (P = 0.0320), as well as surgical margin involvement (P = 0.0013) and tumoral stage (P = 0.0109). Overexpression of YAP1 may occur as a part of tumorigenesis of PDAC. Yes associated protein 1 is an independent prognostic marker for overall survival of PDAC and associated with liver metastasis, being a potential therapeutic target.

  3. The inflammatory biomarker YKL-40 as a new prognostic marker for all-cause mortality in patients with heart failure

    DEFF Research Database (Denmark)

    Harutyunyan, Marina; Christiansen, Michael; Johansen, Julia S

    2011-01-01

    peptide (NT-proBNP) could be a new prognostic biomarker for all-cause mortality in patients with HF. METHODS AND RESULTS: A total of 717 of the 1000 patients with severe left ventricular systolic dysfunction included in the EchoCardiography and Heart Outcome Study were included in Denmark and had blood......-CRP, and renal function). CONCLUSION: Serum YKL-40 is significantly associated with all-cause mortality in patients with HF and could potentially be a new prognostic biomarker in these patients....

  4. Tumor-derived CCL-2 and CXCL-8 as possible prognostic markers of breast cancer: correlation with estrogen and progestrone receptor phenotyping.

    Science.gov (United States)

    Ghoneim, H M; Maher, Sara; Abdel-Aty, Asmaa; Saad, A; Kazem, A; Demian, S R

    2009-01-01

    Prognosis of breast cancer is believed to be a multifactorial process best achieved by complex factors including host and tumor-derived biomarkers together with traditional clinicopathological parameters and tumor histologic markers. The present study aimed at evaluating the prognostic significance of chemokine ligand-2 (CCL-2) and interleukin-8 (CXCL-8) expression in extracts of breast carcinomas through correlation with clinicopathological aspects as well as estrogen receptor (ER) and progesterone receptor (PR) phenotyping. The study was conducted on 30 Egyptian breast cancer patients diagnosed by fine needle aspiration cytology (FNAC) and subjected to modified radical mastectomy. Excised tissues were used to prepare tissue sections and extracts for histopathological and immunohistochemical studies. Expression of CCL-2 and CXCL-8 was determined by enzyme-linked immunosorbent assay (ELISA). 26 patients had invasive ductal carcinoma, grades II and III with metastasis to axillary lymph nodes and ER and PR positive phenotype. Expression of CCL-2 and CXCL-8 was significantly influenced by patient's age, menopausal status, nodal involvement, tumor grade and the ER phenotype. In contrast, it was not affected by either tumor size or PR staining pattern. Both chemokines correlated positively to each other and to tumor grade and negatively to age, menopausal status of patients and ER phenotyping. It is concluded that the angiogenic chemokine CXCL-8 and the macrophage chemoattractant CCL-2 might be useful prognostic markers where their routine follow up might be of importance in assessment of tumor aggressiveness in clinical settings.

  5. Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Boscolo-Rizzo, Paolo; Rampazzo, Enrica; Perissinotto, Egle; Piano, Maria Assunta; Giunco, Silvia; Baboci, Lorena; Spinato, Giacomo; Spinato, Roberto; Tirelli, Giancarlo; Da Mosto, Maria Cristina; Del Mistro, Annarosa; De Rossi, Anita

    2015-05-01

    The aim of the present study was to investigate the pattern of telomere length and telomerase expression in cancer tissues and the surrounding mucosa (SM), as markers of field cancerization and clinical outcome in patients successfully treated for with head and neck squamous cell carcinoma (HNSCC). This investigation was a prospective cohort study. Telomere length and levels of telomerase reverse transcriptase (TERT) transcripts were quantified by real-time PCR in cancer tissues and SM from 139 and 90 patients with HNSCC, respectively. No correlation was found between age and telomere length in SM. Patients with short telomeres in SM had a higher risk of mucosal failure (adjusted HR=4.29). Patients with high TERT levels in cancer tissues had a higher risk of regional failure (HR=2.88), distant failure (HR=7.27), worse disease-specific survival (HR for related death=2.62) but not mucosal failure. High-risk patients having both short telomeres in SM and high levels of TERT in cancer showed a significantly lower overall survival (HR=2.46). Overall these findings suggest that telomere shortening in SM is a marker of field cancerization and may precede reactivation of TERT. Short telomeres in SM are strongly prognostic of mucosal failure, whereas TERT levels in cancer tissues increase with the aggressiveness of the disease and are prognostic of tumor spread. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. International collaborative validation of intraneural invasion as a prognostic marker in adenoid cystic carcinoma of the head and neck

    DEFF Research Database (Denmark)

    Amit, Moran; Binenbaum, Yoav; Trejo-Leider, Leonor

    2015-01-01

    BACKGROUND: The purpose of this study was to characterize the incidence, pattern of spread, and prognostic correlation of nerve invasion in patients with adenoid cystic carcinoma (ACC). METHODS: Using 3 different pathological categories of perineural invasion, intraneural invasion, and perineural...... Wiley Periodicals, Inc. Head Neck, 2014....

  7. Tumor budding as a useful prognostic marker in T1-stage squamous cell carcinoma of the esophagus.

    Science.gov (United States)

    Teramoto, Hitoshi; Koike, Masahiko; Tanaka, Chie; Yamada, Suguru; Nakayama, Goro; Fujii, Tsutomu; Sugimoto, Hiroyuki; Fujiwara, Michitaka; Suzuki, Yasuhiko; Kodera, Yasuhiro

    2013-07-01

    Establishing a new prognostic factor for early-stage cancer may seem difficult due to the small number of disease-specific deaths. Tumor budding has been recognized as a useful microscopic finding reflecting biological activity of the tumor. Tumor budding stand for isolated single cancer cells and cell clusters scattered beyond the tumor margin at the invasive front. It was searched for in the resected esophagus with T1 squamous cell carcinoma (SCC), and the correlation between the tumor budding, patient survival, and various pathologic factors were analyzed to verify whether tumor budding is a prognostic factor in superficial esophageal cancer. Seventy-nine patients undergoing curative esophagectomy were assigned to frequent (n = 29) and rare (n = 50) groups according to the microscopically observed frequency of tumor budding in the tumor. Three-year survival rates after esophagectomy were 48.8% for the frequent group and 94.5% for the rare group. Multivariate analysis using the Cox proportional hazards model identified this morphological variable as a significant independent prognostic factor. Tumor budding reflects the biological activity of the tumor and may be a useful prognostic indicator even in early-stage SCC of esophagus. Copyright © 2013 Wiley Periodicals, Inc.

  8. Realizing the Translational Potential of Telomere Length Variation as a Tissue Based Prognostic Marker for Prostate Cancer

    Science.gov (United States)

    2016-10-01

    pathologic prognostic factors are imperfect predictors of outcome in the men with clinically localized prostate cancer, the majority of men diagnosed...E, De Vivo I, Platz EA. Circulating leukocyte telomere length and risk of overall and aggressive prostate cancer. Br J Cancer. 2015 Feb 17;112(4

  9. Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin?

    DEFF Research Database (Denmark)

    Carneiro, Ana; Francis, Princy; Bendahl, Pär-Ola

    2009-01-01

    Soft tissue sarcoma (STS) diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC arrays and gene expression profiling to 18 extremity soft tissue LMS and...

  10. γ-H2AX: A Novel Prognostic Marker in a Prognosis Prediction Model of Patients with Early Operable Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    E. Chatzimichail

    2014-01-01

    Full Text Available Cancer is a leading cause of death worldwide and the prognostic evaluation of cancer patients is of great importance in medical care. The use of artificial neural networks in prediction problems is well established in human medical literature. The aim of the current study was to assess the prognostic value of a series of clinical and molecular variables with the addition of γ-H2AX—a new DNA damage response marker—for the prediction of prognosis in patients with early operable non-small cell lung cancer by comparing the γ-H2AX-based artificial network prediction model with the corresponding LR one. Two prognostic models of 96 patients with 27 input variables were constructed by using the parameter-increasing method in order to compare the predictive accuracy of neural network and logistic regression models. The quality of the models was evaluated by an independent validation data set of 11 patients. Neural networks outperformed logistic regression in predicting the patient’s outcome according to the experimental results. To assess the importance of the two factors p53 and γ-H2AX, models without these two variables were also constructed. JR and accuracy of these models were lower than those of the models using all input variables, suggesting that these biological markers are very important for optimal performance of the models. This study indicates that neural networks may represent a potentially more useful decision support tool than conventional statistical methods for predicting the outcome of patients with non-small cell lung cancer and that some molecular markers, such as γ-H2AX, enhance their predictive ability.

  11. Copeptin (C-terminal pro arginine-vasopressin) is an independent long-term prognostic marker in heart failure with reduced ejection fraction.

    Science.gov (United States)

    Pozsonyi, Zoltán; Förhécz, Zsolt; Gombos, Tímea; Karádi, István; Jánoskuti, Lívia; Prohászka, Zoltán

    2015-04-01

    The level of copeptin, a stable fragment of pro-arginine-vasopressin (AVP), correlates with disease severity. It is an established, short-term prognostic marker for patients with heart failure with reduced ejection fraction (HFREF). We aimed to examine the association between copeptin and long-term mortality. We also studied the clinical usefulness of copeptin as a prognostic biomarker by analysing the improvement of net reclassification. Copeptin concentrations were measured in a cohort of 195 consecutive patients with HFREF. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was recorded after five-year follow-up. One hundred and ten patients died during the five-year follow-up (five-year mortality rate: 0.56). Univariate analysis identified copeptin (HR 2.168 [95% CI 1.740-2.700]) as a predictor of mortality. The final, multivariable Cox survival model identified a number of independent predictors of death. These included higher NHYA functional class, previous MI, at least one hospitalisation for worsening HF (within the two years before inclusion into the study), elevated blood urea nitrogen, NT-proBNP-, and copeptin levels, as well as increased red blood cell distribution width, and decreased GFR. The addition of copeptin alone to the baseline predictive model (NT-proBNP only) resulted in a minor (8.21%) improvement, whereas the final, multivariable model showed a significant increase in net reclassification (10.26%, p=0.015). These data indicate that copeptin is an independent long-term prognostic marker in HFREF, with possible clinical relevance for multimarker risk prediction algorithms. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

  12. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis.

    Science.gov (United States)

    Jawhar, M; Schwaab, J; Hausmann, D; Clemens, J; Naumann, N; Henzler, T; Horny, H-P; Sotlar, K; Schoenberg, S O; Cross, N C P; Fabarius, A; Hofmann, W-K; Valent, P; Metzgeroth, G; Reiter, A

    2016-12-01

    We evaluated the impact of clinical and molecular characteristics on overall survival (OS) in 108 patients with indolent (n=41) and advanced systemic mastocytosis (SM) (advSM, n=67). Organomegaly was measured by magnetic resonance imaging-based volumetry of the liver and spleen. In multivariate analysis of all patients, an increased spleen volume ⩾450 ml (hazard ratio (HR), 5.2; 95% confidence interval (CI), (2.1-13.0); P=0.003) and an elevated alkaline phosphatase (AP; HR 5.0 (1.1-22.2); P=0.02) were associated with adverse OS. The 3-year OS was 100, 77, and 39%, respectively (P<0.0001), for patients with 0 (low risk, n=37), 1 (intermediate risk, n=32) or 2 (high risk, n=39) parameters. For advSM patients with fully available clinical and molecular data (n=60), univariate analysis identified splenomegaly ⩾1200 ml, elevated AP and mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel as significant prognostic markers. In multivariate analysis, mutations in S/A/R (HR 3.2 (1.1-9.6); P=0.01) and elevated AP (HR 2.6 (1.0-7.1); P=0.03) remained predictive adverse prognostic markers for OS. The 3-year OS was 76 and 38%, respectively (P=0.0003), for patients with 0-1 (intermediate risk, n=28) or 2 (high risk, n=32) parameters. We conclude that splenomegaly, elevated AP and mutations in the S/A/R gene panel are independent of the World Health Organization classification and provide the most relevant prognostic information in SM patients.

  13. A STUDY OF SILVER STAINING NUCLEOLAR ORGANISING REGIONS AGNOR SCORE AS PROGNOSTIC MARKER IN BREAST LESIONS IN A TERTIARY CARE HOSPITAL IN HYDERABAD

    Directory of Open Access Journals (Sweden)

    Bhavani Shankar Nithyananda

    2017-10-01

    Full Text Available BACKGROUND Nucleolar Organising Regions (NORS are segments of DNA closely associated with nucleolus, which code for ribosomal DNA consisting of non-histone proteins, which are argyrophilic. They are demonstrated as black, brown spots on staining with silver colloidal staining technique. Hence, they are called AgNORs. The assessment of AgNORs correlates with rate of proliferation, cell cycle time, since shorter the cell cycle, greater the ribosomal activity and protein synthesis higher AgNOR count. 1 AgNORs have been studied on NHL, GIT neoplasms, skin, gynaecological neoplasms, pulmonary neoplasms, prostate, bladder and breast cancer. In breast cancer, AgNOR can be used for early detection, grading and staging of disease. In this study, we have tried to correlate AgNOR character to morphological prognostic markers. MATERIALS AND METHODS A total of 159 cases presenting with lump in the breast were included in the study. Specimens were subjected to histopathological examination. Sections cut three micron thickness were stained for AgNOR with silver colloidal AgNOR staining technique. AgNOR count was done on both benign and malignant lesions. RESULTS Benign breast lesions were more common compared to malignant lesions. The age of the patients ranged from 15-79 yrs. The mean age for benign lesions was 31 yrs. and for malignant lesions 43 yrs. The most common benign lesion was fibroadenoma and most common malignant lesion was infiltrating ductal carcinoma. AgNOR spots were seen as black/brown spots. AgNOR score was higher in malignant lesions when compared to benign lesions. Among malignant lesions, AgNOR score was found to be higher in high grade, metastatic tumours. CONCLUSION AgNOR count is a useful technique, which can supplement other prognostic markers like Ki-67, mitotic index. A long follow up study is required to confirm the prognostic utility of AgNOR count done in this study

  14. Decreased Norton's functional score is an independent long-term prognostic marker in hospital survivors of acute myocardial infarction. Soroka Acute Myocardial Infarction II (SAMI-II) project.

    Science.gov (United States)

    Silber, Hagar; Shiyovich, Arthur; Gilutz, Harel; Ziedenberg, Hanna; Abu Tailakh, Muhammad; Plakht, Ygal

    2017-02-01

    Patient function is a risk factor of mortality following acute myocardial infarction (AMI). Norton scale (NS) was originally developed to estimate the risk for pressure ulcers. It contains 5 domains: mental condition, physical condition, mobility, activity in daily living and incontinence. To evaluate NS as long-term prognostic marker following AMI. A retrospective study based on computerized medical records of AMI patient hospitalized in a tertiary medical center in 2004-2012. NS scores and patients' characteristics were collected from computerized databases. The primary outcome was all-cause long-term (up-to 10-years) mortality. Overall 6964 patients were included; mean age 67.3±14.1years, 68.1% males. Mean NS score was 17.8±3; of which 21.1% had low-NS (≤16). Patients with low-NS had increased prevalence of hypertension, diabetes and renal disease, 3-vessel coronary artery disease, more often Non ST-Elevation Myocardial Infarction (NSTEMI) and in-hospital complications. Throughout the follow-up period cumulative mortality rate in patients with low- and high-NS groups were 97.3% and 43% respectively (AdjHR 1.66; 95% CI: 1.521-1.826; p<0.001). Furthermore, a reduction in one point in the NS score inversely associated with increased risk for mortality (AdjHR 1.10; 95% CI: 1.12-1.22; p<0.001). NS is an independent long-term prognostic marker for all-cause mortality in hospital survivors with a gradual "dose-response" effect. This data emphasizes the importance prognostic implication of the general functional status on the prognosis of AMI patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. A comparison of prognostic significance of strong ion gap (SIG) with other acid-base markers in the critically ill: a cohort study.

    Science.gov (United States)

    Ho, Kwok M; Lan, Norris S H; Williams, Teresa A; Harahsheh, Yusra; Chapman, Andrew R; Dobb, Geoffrey J; Magder, Sheldon

    2016-01-01

    This cohort study compared the prognostic significance of strong ion gap (SIG) with other acid-base markers in the critically ill. The relationships between SIG, lactate, anion gap (AG), anion gap albumin-corrected (AG-corrected), base excess or strong ion difference-effective (SIDe), all obtained within the first hour of intensive care unit (ICU) admission, and the hospital mortality of 6878 patients were analysed. The prognostic significance of each acid-base marker, both alone and in combination with the Admission Mortality Prediction Model (MPM0 III) predicted mortality, were assessed by the area under the receiver operating characteristic curve (AUROC). Of the 6878 patients included in the study, 924 patients (13.4 %) died after ICU admission. Except for plasma chloride concentrations, all acid-base markers were significantly different between the survivors and non-survivors. SIG (with lactate: AUROC 0.631, confidence interval [CI] 0.611-0.652; without lactate: AUROC 0.521, 95 % CI 0.500-0.542) only had a modest ability to predict hospital mortality, and this was no better than using lactate concentration alone (AUROC 0.701, 95 % 0.682-0.721). Adding AG-corrected or SIG to a combination of lactate and MPM0 III predicted risks also did not substantially improve the latter's ability to differentiate between survivors and non-survivors. Arterial lactate concentrations explained about 11 % of the variability in the observed mortality, and it was more important than SIG (0.6 %) and SIDe (0.9 %) in predicting hospital mortality after adjusting for MPM0 III predicted risks. Lactate remained as the strongest predictor for mortality in a sensitivity multivariate analysis, allowing for non-linearity of all acid-base markers. The prognostic significance of SIG was modest and inferior to arterial lactate concentration for the critically ill. Lactate concentration should always be considered regardless whether physiological, base excess or physical-chemical approach

  16. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma

    DEFF Research Database (Denmark)

    Jensen, T.O.; Schmidt, H.; Moller, H.J.

    2009-01-01

    PURPOSE: To evaluate the prognostic role of soluble CD163 (sCD163) in serum and macrophage infiltration in primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. The scavenger receptor CD163 is associated with anti-inflammatory macrophages, and it is s......PURPOSE: To evaluate the prognostic role of soluble CD163 (sCD163) in serum and macrophage infiltration in primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. The scavenger receptor CD163 is associated with anti-inflammatory macrophages......, and it is shed from their surface. PATIENTS AND METHODS: Serum samples from 227 patients with stage I/II melanoma obtained before definitive surgery (baseline) and during 5 years of follow-up were analyzed for sCD163 by enzyme-linked immunosorbent assay. Excised formalin-fixed, paraffin-embedded primary...

  17. Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0 breast carcinoma.

    Directory of Open Access Journals (Sweden)

    Fabien Reyal

    Full Text Available BACKGROUND: Genomic grade (GG is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score. METHODS: A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up. GG was computed using MapQuant Dx(R. RESULTS: GG was low (GG-1 in 48%, high (GG-3 in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02. CONCLUSIONS: In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i the relatively close prognostic values of GG and Ki67, (ii the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma.

  18. Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0) breast carcinoma.

    Science.gov (United States)

    Reyal, Fabien; Bollet, Marc A; Caly, Martial; Gentien, David; Carpentier, Sabrina; Peyro-Saint-Paul, Hélène; Pierga, Jean-Yves; Cottu, Paul; Dieras, Véronique; Sigal-Zafrani, Brigitte; Vincent-Salomon, Anne; Sastre-Garau, Xavier

    2012-01-01

    Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score. A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R). GG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02). In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma.

  19. External validation of leukocytosis and neutrophilia as a prognostic marker in anal carcinoma treated with definitive chemoradiation.

    Science.gov (United States)

    Schernberg, Antoine; Huguet, Florence; Moureau-Zabotto, Laurence; Chargari, Cyrus; Rivin Del Campo, Eleonor; Schlienger, Michel; Escande, Alexandre; Touboul, Emmanuel; Deutsch, Eric

    2017-07-01

    To validate the prognostic value of leukocyte disorders in anal squamous cell carcinoma (SCC) patients receiving definitive concurrent chemoradiation. Bi-institutional clinical records from consecutive patients treated between 2001 and 2015 with definitive chemoradiation for anal SCC were retrospectively reviewed. Prognostic value of pretreatment leukocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as leukocyte or neutrophil count exceeding 10G/L and 7G/L, respectively. We identified 133 patients, treated in two institutions. Eight% and 7% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year overall survival (OS) and progression-free survival (PFS) were 88% and 77%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS (p<0.01), locoregional control (LRC) and Distant Metastasis Control (DMC) (p<0.05), also after stratification by each institution. In multivariate analysis, leukocytosis and neutrophilia remained as independent risk factors associated with poorer OS, PFS, LRC and DMC (p<0.05). This study validates leukocytosis and neutrophilia as independent prognostic factors in anal SCC patients treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters are clinically relevant biomarkers to be considered for further clinical investigations. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. S100A16, a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Katono K

    2017-11-01

    Full Text Available Ken Katono,1 Yuichi Sato,2 Makoto Kobayashi,3 Ryo Nagashio,2 Shinichiro Ryuge,1 Satoshi Igawa,1 Masaaki Ichinoe,4 Yoshiki Murakumo,4 Makoto Saegusa,4 Noriyuki Masuda1 1Department of Respiratory Medicine, School of Medicine, 2Department of Molecular Diagnostics, School of Allied Health Sciences, 3Department of Applied Tumor Pathology, Graduate School of Medical Sciences, 4Department of Pathology, School of Medicine, Kitasato University, Minami-ku, Sagamihara, Kanagawa, Japan Purpose: Although cisplatin-based adjuvant chemotherapy improves the survival of patients with resected non-small-cell lung cancer, not all patients show a survival benefit, and some patients experience severe toxicity. Therefore, identifying biomarkers is important for selecting subgroups of patients who may show improved survival with platinum-based adjuvant chemotherapy. S100A16 is thought to play key roles during different steps of tumor progression. The aim of this study was to evaluate the use of S100A16 expression as a prognostic marker in patients with completely resected lung adenocarcinoma receiving platinum-based adjuvant chemotherapy. Methods: S100A16 expression was immunohistochemically studied in 65 consecutive lung adenocarcinoma patients who underwent complete resection and received platinum-based adjuvant chemotherapy. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate the effect of S100A16 expression on disease-free survival (DFS and overall survival (OS.Results: S100A16 expression was detected in 26 of the 65 (40.0% lung adenocarcinoma patients. Although S100A16 expression was not correlated with DFS (P=0.062, it was significantly correlated with OS (P=0.009. In addition, multivariable analysis revealed that S100A16 expression independently predicted a poorer survival (HR =4.79; 95% CI =1.87–12.23; P=0.001. Conclusion: The present study revealed that S100A16 is a promising candidate as a prognostic marker for

  1. Expression levels of FGFR3 as a prognostic marker for the progression of primary pT1 bladder cancer and its association with mutation status

    Science.gov (United States)

    Kang, Ho Won; Kim, Ye-Hwan; Jeong, Pildu; Park, Cheol; Kim, Won Tae; Ryu, Dong Hee; Cha, Eun-Jong; Ha, Yun-Sok; Kim, Tae-Hwan; Kwon, Tae Gyun; Moon, Sung-Kwon; Choi, Yung Hyun; Yun, Seok-Joong; Kim, Wun-Jae

    2017-01-01

    The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test. FGFR3 mutations were identified in 48/120 (40.0%) patients with pT1 BC. FGFR3 mRNA expression level was significantly higher in those with BC harboring FGFR3 mutations (PFGFR3 expression level was associated with high-grade tumors and cancer progression (P=0.006 and P=0.001), whereas FGFR3 mutation status was not associated with cancer progression. Kaplan-Meier analysis revealed a similar result (log-rank, PFGFR3 expression level (odds ratio, 3.300; 95% confidence interval, 1.310–8.313; P=0.011) as an independent predictor of cancer progression. Stratification by exon site of FGFR3 mutations yielded significant differences in mRNA expression level. None of the patients with BC harboring FGFR3 mutations in exon 9 demonstrated disease progression. The mRNA expression level of the FGFR3 gene may be used to precisely identify subsets of patients with pT1 BC that have a relatively better prognosis. The prognostic influences of FGFR3 mutations may be modulated by the exon site of FGFR3 mutations. PMID:28927152

  2. Clinical value of octamer-binding transcription factor 4 as a prognostic marker in patients with digestive system cancers: A systematic review and meta-analysis.

    Science.gov (United States)

    Chen, Zhiqiang; Zhang, Long; Zhu, Qin; Wang, Xiaowei; Wu, Jindao; Wang, Xuehao

    2017-03-01

    The role of octamer-binding transcription factor 4 (Oct4) has been implicated in the clinical prognosis of various kinds of digestive system cancers, but the results remain controversial. The purpose of this meta-analysis is to assess the potential role of Oct4 as a prognostic marker in digestive system tumors. Relevant articles were retrieved from Pubmed, Web of Science, and Cochrane Library up to July 2016. The software Stata 12.0 was used to analyze the outcomes, including overall survival (OS), disease-free survival, recurrence-free survival, and clinicopathological characteristics. A total of 13 eligible studies with 1538 patients were included. Elevated Oct4 expression was significantly associated with poor OS (pooled hazard ratio [HR] = 2.183, 95% confidence interval [CI]: 1.824-2.612), disease-free survival (pooled HR = 1.973, 95% CI: 1.538-2.532), and recurrence-free survival (pooled HR = 2.209, 95% CI: 1.461-3.338) of digestive system malignancies. Subgroup analyses showed that cancer type, sample size, study quality, and laboratory detection method did not alter the significant prognostic value of Oct4. Additionally, Oct4 expression was found to be an independent predictive factor for OS (HR = 2.068, 95% CI: 1.633-2.619). No significant association was found between Oct4 and clinicopathological features of digestive system malignancies. This study provided evidence of Oct4 and/or its closely related homolog protein as a predictive factor for patients with digestive system cancers. More large-scale clinical studies on the prognostic value of Oct4 are warranted. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  3. Creactive protein and interleukin-6 as markers of systemic inflammatory response and as prognostic factors for metastatic colorectal cancer. Data from the randomized phase III NORDIC-VII study

    DEFF Research Database (Denmark)

    Thomsen, M.; Kersten, C.; Sorbye, H.

    2015-01-01

    Background: A systemic inflammatory response (SIR) affects prognosis and treatment outcome in metastatic colorectal cancer (mCRC). The aim of the study was to explore the prognostic significance of several SIR-derived markers and the correlation between the best marker of SIR and plasma interleukin...... of platelets and levels of C-reactive protein (CRP) on survival were analyzed by Kaplan-Meier plots, logrank test, and Cox Proportional Hazards model. Further, the relationship between CRP, IL-6 and RAS and BRAF mutation status was examined. Results: 374 patients were eligible for the comparison of markers...... of SIR and 393 were eligible for the final analysis related to CRP, IL-6 and RAF and BRAF mutation status. The prognostic significance of CRP was at least as good as the other markers of SIR. CRP together with IL-6 were selected for further investigation. Logtrans-formed CRP and IL-6 were highly...

  4. Machine learning classification with confidence: application of transductive conformal predictors to MRI-based diagnostic and prognostic markers in depression.

    Science.gov (United States)

    Nouretdinov, Ilia; Costafreda, Sergi G; Gammerman, Alexander; Chervonenkis, Alexey; Vovk, Vladimir; Vapnik, Vladimir; Fu, Cynthia H Y

    2011-05-15

    There is rapidly accumulating evidence that the application of machine learning classification to neuroimaging measurements may be valuable for the development of diagnostic and prognostic prediction tools in psychiatry. However, current methods do not produce a measure of the reliability of the predictions. Knowing the risk of the error associated with a given prediction is essential for the development of neuroimaging-based clinical tools. We propose a general probabilistic classification method to produce measures of confidence for magnetic resonance imaging (MRI) data. We describe the application of transductive conformal predictor (TCP) to MRI images. TCP generates the most likely prediction and a valid measure of confidence, as well as the set of all possible predictions for a given confidence level. We present the theoretical motivation for TCP, and we have applied TCP to structural and functional MRI data in patients and healthy controls to investigate diagnostic and prognostic prediction in depression. We verify that TCP predictions are as accurate as those obtained with more standard machine learning methods, such as support vector machine, while providing the additional benefit of a valid measure of confidence for each prediction. Copyright © 2010 Elsevier Inc. All rights reserved.

  5. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas.

    Science.gov (United States)

    Yanagisawa, Nobuyuki; Hana, Kiyomi; Nakada, Norihiro; Ichinoe, Masaaki; Koizumi, Wasaburo; Endou, Hitoshi; Okayasu, Isao; Murakumo, Yoshiki

    2014-10-01

    Oncocytic L-type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki-67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki-67 labeling index (LI). Kaplan-Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1-high and -low scores, whereas LAT2 and CD98 expression and Ki-67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1-high/LAT2-low than LAT1-low/LAT2-high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  6. Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

    Science.gov (United States)

    Sperduto, Paul W; Jiang, Wen; Brown, Paul D; Braunstein, Steve; Sneed, Penny; Wattson, Daniel A; Shih, Helen A; Bangdiwala, Ananta; Shanley, Ryan; Lockney, Natalie A; Beal, Kathryn; Lou, Emil; Amatruda, Thomas; Sperduto, William A; Kirkpatrick, John P; Yeh, Norman; Gaspar, Laurie E; Molitoris, Jason K; Masucci, Laura; Roberge, David; Yu, James; Chiang, Veronica; Mehta, Minesh

    2017-11-15

    To update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers. The original Melanoma-GPA is based on data from 483 patients whose conditions were diagnosed between 1985 and 2005. This is a multi-institutional retrospective database analysis of 823 melanoma patients with newly diagnosed brain metastases from January 1, 2006, to December 31, 2015. Multivariable analyses identified significant prognostic factors, which were weighted and included in the updated index (Melanoma-molGPA). Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios to design the updated Melanoma-molGPA in which scores of 4.0 and 0.0 are associated with the best and worst prognoses, as with all of the diagnosis-specific GPA indices. Log-rank tests were used to compare adjacent classes. There were 5 significant prognostic factors for survival (age, Karnofsky performance status [KPS], extracranial metastases [ECM], number of brain metastases, and BRAF status), whereas only KPS and the number of brain metastases were significant in the original Melanoma-GPA. Median survival improved from 6.7 to 9.8 months between the 2 treatment eras, and the median survival times for patients with Melanoma-molGPA of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 4.9, 8.3, 15.8, and 34.1 months (Pmelanoma patients with brain metastases has improved significantly. The updated Melanoma-molGPA, a user-friendly tool to estimate survival, will facilitate clinical decision making regarding whether and which treatment is appropriate and will also be useful for stratification of future clinical trials. To further simplify use, a free online/smart phone app is available at brainmetgpa.com. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. FLT3 Mutation as a Significant Prognostic Marker in de novo Acute Myeloid Leukemia Patients: Incidence, Distribution and Association with Cytogenetic Findings in a Study from South India

    Directory of Open Access Journals (Sweden)

    Santhi Sarojam

    2014-10-01

    Full Text Available Background: Fms-like tyrosine kinase 3 is a tyrosine kinase receptor that plays an important role in proliferation and differentiation of hematopoietic stem cells. Internal tandem duplication and tyrosine kinase domain mutation are the two most common types of fms-like tyrosine kinase 3 mutations frequently reported in acute myeloid leukemia associated with pathogenesis of this disease. The present study investigates the prevalence and distribution pattern in different acute myeloid leukemia sub- and cytogenetic groups, the association with clinical parameters and the prognostic importance of these mutations in acute myeloid leukemia patients from South India. Methods:Mutation analysis was performed in 276 de novo acute myeloid leukemia patients by polymerase chain reaction restriction fragment length polymorphism using specific restriction enzymes followed by sequencing to confirm the mutations. Kaplan-Meier survival analysis was performed to detect the prognosis. Results: Fms-like tyrosine kinase 3 internal tandem duplication mutations were observed in 20%, tyrosine kinase domain mutation in 4% and dual mutations in 0.3% of the analyzed cases. The internal tandem duplication mutations ranged from 15-107 nucleotides with the majority at the juxta membrane domain of the receptor. Three types of tyrosine kinase domain point mutations were identified: D835Y, D835H and D835V. We observed a significant association between fms-like tyrosine kinase 3 mutations and increased WBC and LDH counts (P<0.001 and blast percentage but not with age, gender and FAB subtypes. A significant association with normal karyotype was observed for the mutants (P=0.002. Survival analysis revealed that the fms-like tyrosine kinase 3 gene mutation was a negative prognostic marker for acute myeloid leukemia patients. The risk stratified analysis showed the mutation to be a risk factor for the intermediate karyotype group, especially for those with normal cytogenetics

  8. The inflammatory biomarker YKL-40 as a new prognostic marker for all-cause mortality in patients with heart failure

    DEFF Research Database (Denmark)

    Harutyunyan, Marina; Christiansen, Michael; Johansen, Julia S

    2011-01-01

    YKL-40 II to IV quartiles, respectively following multivariable adjustment for cardiovascular risk factors (age, left ventricular ejection fraction, gender, history of heart failure, ischemic heart disease, chronic pulmonary disease, diabetes mellitus, stroke, hypertension, NT-proBNP, hs......BACKGROUND: Despite progress in management of patients with heart failure (HF) these patients still have a poor prognosis. We tested the hypothesis whether the inflammatory biomarker YKL-40 alone or in combination with high-sensitivity C-reactive protein (hs-CRP) and/or N-terminal-pro-B natriuretic...... peptide (NT-proBNP) could be a new prognostic biomarker for all-cause mortality in patients with HF. METHODS AND RESULTS: A total of 717 of the 1000 patients with severe left ventricular systolic dysfunction included in the EchoCardiography and Heart Outcome Study were included in Denmark and had blood...

  9. Could (Disseminated and Residual Minimal Disease be a useful prognostic marker in non-Hodgkin paediatric Lymphomas?

    Directory of Open Access Journals (Sweden)

    Lara Mussolin

    2014-06-01

    Full Text Available Minimal Disseminated Disease (MDD represents the small number of tumour cells in the patients' bone marrow at the time of diagnosis, whereas Minimal Residual Disease (MRD represents the small number of tumour cells remaining in the bone marrow during treatment. Generally, MDD and MRD are measured by polymerase chain reaction, a highly sensitive technique. For a long time, bone marrow involvement has been considered an uncommon event in solid tumours. However, in recent years, several studies demonstrated that MDD and MRD could be powerful tools in paediatric non-Hodgkin lymphoma for stratifying patients in different prognostic groups. Risk stratification in future clinical trials on non-Hodgkin lymphoma based on these newly identified risk categories should be useful to improve therapies in order to increase survival for high-risk patients and decrease toxicity for low-risk patients.http://dx.doi.org/10.7175/cmi.v8i2.902 

  10. HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature

    DEFF Research Database (Denmark)

    Jørgensen, Jan Trøst; Hersom, Maria Nathalie Selch

    2012-01-01

    Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since...... the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill...... the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between...

  11. Pro-atrial natriuretic peptide is a prognostic marker in sepsis, similar to the APACHE II score: an observational study.

    Science.gov (United States)

    Morgenthaler, Nils G; Struck, Joachim; Christ-Crain, Mirjam; Bergmann, Andreas; Müller, Beat

    2005-02-01

    Additional biomarkers in sepsis are needed to tackle the challenges of determining prognosis and optimizing selection of high-risk patients for application of therapy. In the present study, conducted in a cohort of medical intensive care unit patients, our aim was to compare the prognostic value of mid-regional pro-atrial natriuretic peptide (ANP) levels with those of other biomarkers and physiological scores. Blood samples obtained in a prospective observational study conducted in 101 consecutive critically ill patients admitted to the intensive care unit were analyzed. The prognostic value of pro-ANP levels was compared with that of the Acute Physiology and Chronic Health Evaluation (APACHE) II score and with those of various biomarkers (i.e. C-reactive protein, IL-6 and procalcitonin). Mid-regional pro-ANP was detected in EDTA plasma from all patients using a new sandwich immunoassay. On admission, 53 patients had sepsis, severe sepsis, or septic shock, and 68 had systemic inflammatory response syndrome. The median pro-ANP value in the survivors was 194 pmol/l (range 20-2000 pmol/l), which was significantly lower than in the nonsurvivors (median 853.0 pmol/l, range 100-2000 pmol/l; P protein, and similar to the AUC for the APACHE II score. Pro-ANP appears to be a valuable tool for individual risk assessment in sepsis patients and for stratification of high-risk patients in future intervention trials. Further studies are needed to validate our results.

  12. IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas.

    Science.gov (United States)

    Etxaniz, Olatz; Carrato, Cristina; de Aguirre, Itziar; Queralt, Cristina; Muñoz, Ana; Ramirez, José L; Rosell, Rafael; Villà, Salvador; Diaz, Rocio; Estival, Ana; Teixidor, Pilar; Indacochea, Alberto; Ahjal, Sara; Vilà, Laia; Balañá, Carme

    2017-11-01

    Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG.

  13. Prognostic value of some tumor markers in unresectable stage IV oropharyngeal carcinoma patients treated with concomitant radiochemotherapy

    Directory of Open Access Journals (Sweden)

    Soba Erika

    2015-12-01

    Full Text Available Background. The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy.

  14. The c-MET Network as Novel Prognostic Marker for Predicting Bladder Cancer Patients with an Increased Risk of Developing Aggressive Disease.

    Directory of Open Access Journals (Sweden)

    Young-Won Kim

    Full Text Available Previous studies have shown that c-MET is overexpressed in cases of aggressive bladder cancer (BCa. Identification of crosstalk between c-MET and other RTKs such as AXL and PDGFR suggest that c-MET network genes (c-MET-AXL-PDGFR may be clinically relevant to BCa. Here, we examine whether expression of c-MET network genes can be used to identify BCa patients at increased risk of developing aggressive disease. In vitro analysis, c-MET knockdown suppressed cell proliferation, invasion, and migration, and increased sensitivity to cisplatin-induced apoptosis. In addition, c-MET network gene (c-MET, AXL, and PDGFR expression allowed discrimination of BCa tissues from normal control tissues and appeared to predict poor disease progression in non-muscle invasive BCa patients and poor overall survival in muscle invasive BCa patients. These results suggest that c-MET network gene expression is a novel prognostic marker for predicting which BCa patients have an increased risk of developing aggressive disease. These genes might be a useful marker for co-targeting therapy, and are expected to play an important role in improving both response to treatment and survival of BCa patients.

  15. Evaluation of MCT1, MCT4 and CD147 Genes in Peripheral Blood Cells of Breast Cancer Patients and Their Potential Use as Diagnostic and Prognostic Markers.

    Science.gov (United States)

    Luz, Maria Cláudia de B; Perez, Matheus M; Azzalis, Ligia A; Sousa, Luiz Vinícius de A; Adami, Fernando; Fonseca, Fernando L A; Alves, Beatriz da C A

    2017-03-23

    Patients with breast cancer-the deadliest cancer among women-are at constant risk of developing metastasis. Oxidative stress and hypoxia are common feature of tumor cells that can proliferate even in a resultant metabolic acidosis. Despite the low extracellular pH, intracellular pH of tumor cells remains relatively normal, or even more alkaline due to the action of a membrane protein family known as monocarboxylate transporters (MCTs). The objective of this study was to verify the diagnostic and prognostic value of MCT1, MCT4 and CD147 in tumor and peripheral blood samples of patients with breast cancer undergoing chemotherapic treatment. Differential expression of MCT1, MCT4 and CD147 obtained by qPCR was determined by 2-ΔΔCq method between biological samples (tumor and serial samples of peripheral) of patients (n = 125) and healthy women (n = 25). tumor samples with higher histological grades have shown higher expression of these markers; this higher expression was also observed in blood samples obtained at diagnosis of patients when compared to healthy women and in patients with positive progression of the disease (metastasis development). markers studied here could be a promising strategy in routine laboratory evaluations as breast cancer diagnosis and prognosis.

  16. Soluble urokinase plasminogen activator receptor as a prognostic marker of all-cause and cardiovascular mortality in a black population

    DEFF Research Database (Denmark)

    Botha, Shani; Fourie, Carla M T; Schutte, Rudolph

    2015-01-01

    BACKGROUND: Elevated inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are well-known risk factors for cardiovascular mortality. The less familiar marker, soluble urokinase plasminogen activator receptor (suPAR), is known to predict cancer, infections and all......-cause mortality. We determined whether suPAR, CRP and IL-6 are predictive of both all-cause and cardiovascular mortality in a black population, highly burdened by cardiovascular disease and HIV infection. METHODS: We included 1425 black South Africans, of which 208 died within five years after baseline data...... collection. EDTA plasma biomarker levels were determined, while all-cause and cardiovascular mortality were used as endpoints. RESULTS: At baseline suPAR, CRP and IL-6 were higher in non-survivors than in survivors (PCRP (HR 1...

  17. Plasma N‐terminal pro‐B‐type natriuretic peptide as long‐term prognostic marker after major vascular surgery

    Science.gov (United States)

    Feringa, Harm H H; Schouten, Olaf; Dunkelgrun, Martin; Bax, Jeroen J; Boersma, Eric; Elhendy, Abdou; de Jonge, Robert; Karagiannis, Stefanos E; Vidakovic, Radosav; Poldermans, Don

    2007-01-01

    Objective To assess the long‐term prognostic value of plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) after major vascular surgery. Design A single‐centre prospective cohort study. Patients 335 patients who underwent abdominal aortic aneurysm repair or lower extremity bypass surgery. Interventions Prior to surgery, baseline NT‐proBNP level was measured. Patients were also evaluated for cardiac risk factors according to the Revised Cardiac Risk Index. Dobutamine stress echocardiography (DSE) was performed to detect stress‐induced myocardial ischaemia. Main outcome measures The prognostic value of NT‐proBNP was evaluated for the endpoints all‐cause mortality and major adverse cardiac events (MACE) during long‐term follow‐up. Results In this patient cohort (mean age: 62 years, 76% male), median NT‐proBNP level was 186 ng/l (interquartile range: 65–444 ng/l). During a mean follow‐up of 14 (SD 6) months, 49 patients (15%) died and 50 (15%) experienced a MACE. Using receiver operating characteristic curve analysis for 6‐month mortality and MACE, NT‐proBNP had the greatest area under the curve compared with cardiac risk score and DSE. In addition, an NT‐proBNP level of 319 ng/l was identified as the optimal cut‐off value to predict 6‐month mortality and MACE. After adjustment for age, cardiac risk score, DSE results and cardioprotective medication, NT‐proBNP ⩾319 ng/l was associated with a hazard ratio of 4.0 for all‐cause mortality (95% CI: 1.8 to 8.9) and with a hazard ratio of 10.9 for MACE (95% CI: 4.1 to 27.9). Conclusion Preoperative NT‐proBNP level is a strong predictor of long‐term mortality and major adverse cardiac events after major non‐cardiac vascular surgery. PMID:16914484

  18. Pituitary tumor transforming gene and insulin-like growth factor 1 receptor expression and immunohistochemical measurement of Ki-67 as potential prognostic markers of pituitary tumors aggressiveness.

    Science.gov (United States)

    Sánchez-Tejada, Laura; Sánchez-Ortiga, Ruth; Moreno-Pérez, Oscar; Montañana, Carmen Fajardo; Niveiro, Maria; Tritos, Nicholas A; Alfonso, Antonio M Picó

    2013-01-01

    The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46±36 months. Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p=0.04). IGF1R expression changed depending on histological subtype (p=0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69±3.84 NCN vs. 5.44±3.55 NCN, p=0.014). Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples. Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.

  19. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Science.gov (United States)

    Karan-Djurasevic, Teodora; Marjanovic, Irena; Tosic, Natasa; Mitrovic, Mirjana; Djunic, Irena; Colovic, Natasa; Vidovic, Ana; Suvajdzic-Vukovic, Nada; Tomin, Dragica; Pavlovic, Sonja

    2016-01-01

    Abstract Background Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. Patients and methods In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. Results IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. Conclusions Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection. PMID:27904446

  20. Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer.

    Science.gov (United States)

    Beyer, Susanne; Zhu, Junyan; Mayr, Doris; Kuhn, Christina; Schulze, Sandra; Hofmann, Simone; Dannecker, Christian; Jeschke, Udo; Kost, Bernd P

    2017-02-23

    Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology.

  1. Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Susanne Beyer

    2017-02-01

    Full Text Available Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology.

  2. Role of Soluble ST2 as a Prognostic Marker in Patients with Acute Heart Failure and Renal Insufficiency.

    Science.gov (United States)

    Kim, Min-Seok; Jeong, Tae-Dong; Han, Seung-Bong; Min, Won-Ki; Kim, Jae-Joong

    2015-05-01

    This study sought to assess the relationship between serum concentrations of the soluble ST2 (sST2) and B-type natriuretic peptide (BNP) and investigate the role of sST2 as a prognosticator in patients hospitalized with acute heart failure (HF) and renal insufficiency. sST2 was measured at admission and discharge in 66 patients hospitalized with acute decompensated HF and renal insufficiency (estimated glomerular filtration rate [eGFR] renal insufficiency (eGFR renal function, even though BNP level was much higher in patients with severe renal insufficiency. During 3 month follow-up, 9 (13.6%) died and 16 (24.2%) were readmitted due to HF aggravation.On multivariate analysis, sST2 at discharge was independently associated with death or HF readmission during 3 months after discharge (hazard ratio, 1.038; 95% confidence interval, 1.011-1.066, P = 0.006). In conclusion, sST2 is not affected by renal function compared with BNP in acute HF patients. The measurement of predischarge sST2 can be helpful in predicting short-term outcomes in acute decompensated HF patients with renal insufficiency.

  3. IL-8-Positive Tumor-Infiltrating Inflammatory Cells Are a Novel Prognostic Marker in Pancreatic Ductal Adenocarcinoma Patients.

    Science.gov (United States)

    Fang, Yuan; Saiyin, Hexige; Zhao, Xinping; Wu, Yanhua; Han, Xu; Lou, Wenhui

    2016-01-01

    Tumor-infiltrating inflammatory cells (TIICs) in pancreatic ductal adenocarcinoma (PDAC) are reported to initiate and exacerbate invasion and metastasis. Interleukin-8 (IL-8), a proinflammatory cytokine, is expressed in both neoplastic cells and TIICs in PDAC tissues and increased in patient serum. The aim of this study is to evaluate the values of IL-8 expression profiles in tumor tissues and predict the source of serum IL-8 in PDAC patients. We used 2 independent groups of PDAC patient samples that included 240 cases. Tissue expression profiles of cytokines were evaluated with immunohistochemistry and serum levels with human IL-8 assay. The prognostic values of the variables were assessed by Kaplan-Meier or Cox regression analysis. Higher levels of IL-8-positive TIICs but not tumor cells in PDAC patients correlated with worse prognosis (P = 0.009) and higher blood serum IL-8 levels (P = 0.002). Controlling other independent factors, the relative hazard ratio for PDAC with higher IL-8-positive TIIC levels compared with those with lower TIIC levels was 1.588 (95% confidence interval, 1.04-2.42). Higher IL-8-positive TIIC levels in PDAC tumors indicate poorer prognosis and positively correlate with serum IL-8 concentrations and vice versa. These data suggested that IL-8 might have a potential target for PDAC therapies.

  4. The role of BRAF V600E mutation as a potential marker for prognostic stratification of papillary thyroid carcinoma: a long-term follow-up study.

    Science.gov (United States)

    Daliri, Mahdi; Abbaszadegan, Mohammad Reza; Bahar, Mostafa Mehrabi; Arabi, Azadeh; Yadollahi, Mona; Ghafari, Azar; Taghehchian, Negin; Zakavi, Seyed Rasoul

    2014-01-01

    Abstract Papillary carcinoma is the most prevalent malignancy of thyroid gland, and its incidence has been recently increased. The BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF(V600E) mutation as a potential prognostic factor has been controversially reported in different studies, with short-term follow-up. In this study, we evaluated the role of BRAF(V600E) mutation as a potential marker for prognostic stratification of patients with PTC in long-term follow-up. We studied 69 PTC patients with a mean follow-up period of 63.9 months (median: 60 m). The BRAF(V600E) mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence or absence of the BRAF(V600E) mutation, clinicopathological features and prognosis of PTC patients were studied. The BRAF(V600E) mutation was found in 28 of 69 (40.6%) PTC patients, and it was significantly more frequent in older patients (p history of radiation exposure (p = 0.037). Incomplete response to treatment in PTC patients was significantly correlated with certain clinicopathological characteristics (follow-up time, distant metastases, advanced stage, first thyroglobulin (fTg) level, history of reoperation and external radiotherapy and delay in iodine therapy) but it was not related to the presence of BRAF(V600E) mutation. Prevalence of BRAF(V600E) mutation was 40.6% in patients with papillary thyroid cancer in northeast of Iran. The BRAF(V600E) mutation was associated with older age and advanced tumor stage but was not correlated with incomplete response during follow-up.

  5. BRCA1 mRNA expression as a predictive and prognostic marker in advanced esophageal squamous cell carcinoma treated with cisplatin- or docetaxel-based chemotherapy/chemoradiotherapy.

    Directory of Open Access Journals (Sweden)

    Yong Gao

    Full Text Available BACKGROUND: The molecular backgrounds that determine therapeutic effectiveness in esophageal cancer remain largely unknown. Breast cancer susceptibility gene 1 (BRCA1 expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy. It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qPCR was performed to examine BRCA1 mRNA expressions in paraffin-embedded specimens from 144 patients with advanced or metastatic esophageal squamous cell carcinoma who received cisplatin- or docetaxel-based first-line treatments. RESULTS: Low BRCA1 mRNA expression correlated with increased response rate (RR; P = 0.025 and 0.017, respectively and median overall survival (mOS; P = 0.002 and P<0.001, respectively in cisplatin-based chemotherapy or chemoradiotherapy group and also correlated with decreased RR (P = 0.017 and 0.024, respectively and mOS (both P<0.001 in docetaxel-based chemotherapy or chemoradiotherapy group. Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007 or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001 group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05-12.28; P<0.001 or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001 group. CONCLUSIONS: BRCA1 mRNA expression could be used as a predictive and prognostic marker in esophageal cancer who underwent first-line cisplatin- or docetaxel-based treatments.

  6. Intensive induction is effective in selected octogenarian acute myeloid leukemia patients: prognostic significance of karyotype and selected molecular markers used in the European LeukemiaNet classification.

    Science.gov (United States)

    Wetzler, Meir; Mrózek, Krzysztof; Kohlschmidt, Jessica; Dombret, Hervé; Döhner, Hartmut; Pilorge, Sylvain; Krug, Utz; Carroll, Andrew J; Larson, Richard A; Marcucci, Guido; Hiddemann, Wolfgang; Büchner, Thomas; Bloomfield, Clara D

    2014-02-01

    We investigated whether octogenarian patients with acute myeloid leukemia enrolled onto Cooperative Group clinical trials and treated with intensive induction therapy could be cured, and whether karyotype and selected molecular markers had any prognostic significance in these patients. Among 138 patients with cytogenetic information, normal karyotype was the most common (47.1%) followed by complex karyotype (14.5%) and sole +8 (9.4%). Among these patients, the relapse-free survival rate at 1 year was 37% and 13% at 3 years, and the respective overall survival rates were 24% and 8%. Whereas the 90 patients who survived beyond 30 days had the same relapse-free survival rates, their 1-year and 3-year overall survival rates were 36% and 11%, respectively. Of the 66 patients surviving beyond 30 days who could be classified into European LeukemiaNet genetic groups, those in the intermediate-I group had better overall survival than patients in the adverse group (P=0.01). Among patients with cytogenetically normal acute myeloid leukemia who were tested for the European LeukemiaNet-associated molecular alterations, FLT3-internal tandem duplication and NPM1 mutations, it was found that FLT3-internal tandem duplication (detected in 29% of patients) did not associate with overall survival (P=0.31), whereas NPM1 mutations (30%) were associated with a significantly longer overall survival (P=0.002). We conclude that intensive induction is effective and indicated in selected octogenarians with acute myeloid leukemia, that their overall survival varies among the European LeukemiaNet genetic groups and that NPM1 mutations may be of prognostic significance among octogenarian patients with cytogenetically normal acute myeloid leukemia.

  7. Interleukin-6 Levels Act as a Diagnostic Marker for Infection and a Prognostic Marker in Patients with Organ Dysfunction in Intensive Care Units.

    Science.gov (United States)

    Takahashi, Waka; Nakada, Taka-Aki; Yazaki, Megumi; Oda, Shigeto

    2016-09-01

    There are significant unmet requirements for rapid differential diagnosis of infection in patients admitted to intensive care units. Serum levels of interleukin-6 (IL-6), procalcitonin (PCT), presepsin, and C-reactive protein (CRP) are measured in clinical practice; however, their clinical utility in patients with organ dysfunction has not been tested adequately. Thus, we investigated the diagnostic and prognostic value of IL-6, PCT, presepsin, and CRP in critically ill patients who had organ dysfunction with suspicion of infection. In 100 consecutive critically ill patients with organ dysfunction and suspected infection, serum levels of IL-6, PCT, presepsin, and CRP were measured upon suspicion of infection and serially every other day up to 7 days (cohort 1). The primary outcome variable was the presence of infections. The diagnostic value of IL-6 was further tested in cohort 2 (n = 72, case-control matched). The secondary outcome variables were the sequential organ failure assessment (SOFA) score, serum creatinine levels, and 28-day mortality. Among the four biomarkers, serum IL-6 levels had the highest area under the curve (AUC) value of 0.824 (95% confidence interval [CI] 0.735-0.913) for diagnosing infection in critically ill patients with organ dysfunction and suspected infection in cohort 1 (AUC [95% CI] for the other biomarkers: PCT, 0.813 [0.714-0.911]; CRP, 0.764 [0.645-0.883]; presepsin, 0.681 [0.513-0.849]). In cohort 2, the sensitivity and specificity of IL-6 for diagnosing infection were 0.861 and 0.806, respectively. The presepsin levels were significantly correlated with the SOFA score and serum creatinine levels upon suspicion of infection (r > 0.5), especially serum creatinine levels in the patients without infection (r = 0.789). Serum IL-6 levels were significant predictors of 28-day mortality. The AUC value of serum IL-6 levels for 28-day mortality increased over time; the serum IL-6 levels on Day 7 had the highest AUC value of 0

  8. N-terminal pro-brain natriuretic peptide is a useful prognostic marker in patients with pre-capillary pulmonary hypertension and renal insufficiency.

    Directory of Open Access Journals (Sweden)

    Lars Harbaum

    Full Text Available N-terminal pro-brain natriuretic peptide (NT-proBNP is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH. As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR ≤60 ml/min/1.73 m2 were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8% were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m2. Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r2 = 0.167. PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001. Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001 and survival (>2212 ng/l, p = 0.047 in patients with renal insufficiency. Multivariate Cox's proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007. Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with

  9. Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study.

    Science.gov (United States)

    Schroeder, Lea; Boscolo-Rizzo, Paolo; Dal Cin, Elisa; Romeo, Salvatore; Baboci, Lorena; Dyckhoff, Gerhard; Hess, Jochen; Lucena-Porcel, Carlota; Byl, Anne; Becker, Nikolaus; Alemany, Laia; Castellsagué, Xavier; Quer, Miquel; León, Xavier; Wiesenfarth, Manuel; Pawlita, Michael; Holzinger, Dana

    2017-03-01

    Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998-2004 to 23% during 2005-2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Expression of TRAF6 and ubiquitin mRNA in skeletal muscle of gastric cancer patients

    Directory of Open Access Journals (Sweden)

    Sun Yuan-Shui

    2012-09-01

    Full Text Available Abstract Objective To investigate the prognostic significance of tumor necrosis factor receptor (TNFR,-associated factor 6 (TRAF6,-and ubiquitin in gastric cancer patients. Methods Biopsies of the rectus abdominis muscle were obtained intra operatively from 102 gastric cancer patients and 29 subjects undergoing surgery for benign abdominal diseases, and muscle TRAF6 and ubiquitin mRNA expression and proteasome proteolytic activities were assessed. Results TRAF6 was significantly upregulated in muscle of gastric cancer compared with the control muscles. TRAF6 was upregulated in 67.65% (69/102 muscle of gastric cancer. Over expression of TRAF6 in muscles of gastric cancer were associated with TNM stage, level of serum albumin and percent of weight loss. Ubiquitin was significantly upregulated in muscle of gastric cancer compared with the control muscles. Ubiquitin was upregulated in 58.82% (60/102 muscles of gastric cancer. Over expression of ubiquitin in muscles of gastric cancer were associated with TNM (Tumor-Node-Metastasis stage and weight loss. There was significant relation between TRAF6 and ubiquitin expression. Conclusions We found a positive correlation between TRAF6 and ubiquitin expression, suggesting that TRAF6 may up regulates ubiquitin activity in cancer cachexia. While more investigations are required to understand its mechanisms of TRAF6 and ubiquitin in skeletal muscle. Correct the catabolic-anabolic imbalance is essential for the effective treatment of cancer cachexia.

  11. Androgen and oestrogen receptors as potential prognostic markers for patients with ductal carcinoma in situ treated with surgery and radiotherapy.

    Science.gov (United States)

    Ravaioli, Sara; Tumedei, Maria Maddalena; Foca, Flavia; Maltoni, Roberta; Rocca, Andrea; Massa, Ilaria; Pietri, Elisabetta; Bravaccini, Sara

    2017-11-28

    Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has been investigated less extensively than invasive breast cancer. Women with DCIS are mainly treated with conservative surgery almost exclusively followed by radiotherapy. However, as radiation treatment is not always effective, the search for biomarkers capable of identifying DCIS lesions that could progress to invasive cancer is ongoing. Although conventional biomarkers have been thoroughly studied in invasive tumours, little is known about the role played by androgen receptor (AR), widely expressed in DCIS. A series of 42 DCIS patients treated with quadrantectomy and radiotherapy were followed for a period of up to 95 months. Of these, 11 had recurrent DCIS or progressed to invasive cancer. All tumours were analysed for clinical pathological features. Conventional biomarkers and androgen receptor expression were determined by immunohistochemistry. Our results showed that AR was higher in tumours of relapsed patients than non-relapsed patients (P value: 0.0005). Conversely, oestrogen receptor (ER) was higher, albeit not significantly, in non-relapsed patients than in relapsed patients. AR/ER ratio was considerably different in the two subgroups (P value: 0.0033). Area under the curve (AUC) values were 0.85 for AR and 0.80 for the AR/ER ratio. These preliminary results highlight the potentially important role of both AR and the AR/ER ratio as prognostic markers in DCIS. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

  12. Androgen Receptor (AR, E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC Patients.

    Directory of Open Access Journals (Sweden)

    Giuseppina Rosaria Rita Ricciardi

    Full Text Available TNBC is an aggressive subset of breast cancer (BC without specific target therapy.This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS. Immunohistochemistry (IHC was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC.The AR was positive (IHC >10% in 26.6%. E-cadherin (CDH1 expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome.Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC.

  13. Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients.

    Science.gov (United States)

    Ricciardi, Giuseppina Rosaria Rita; Adamo, Barbara; Ieni, Antonio; Licata, Luana; Cardia, Roberta; Ferraro, Giuseppa; Franchina, Tindara; Tuccari, Giovanni; Adamo, Vincenzo

    2015-01-01

    TNBC is an aggressive subset of breast cancer (BC) without specific target therapy. This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC. The AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was ≥ 2. This expression was negative in 53.3% cases. The Ki-67 index was ≥ 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki-67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome. Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC.

  14. ATIP3, a novel prognostic marker of breast cancer patient survival, limits cancer cell migration and slows metastatic progression by regulating microtubule dynamics.

    Science.gov (United States)

    Molina, Angie; Velot, Lauriane; Ghouinem, Lydia; Abdelkarim, Mohamed; Bouchet, Benjamin Pierre; Luissint, Anny-Claude; Bouhlel, Imène; Morel, Marina; Sapharikas, Elène; Di Tommaso, Anne; Honoré, Stéphane; Braguer, Diane; Gruel, Nadège; Vincent-Salomon, Anne; Delattre, Olivier; Sigal-Zafrani, Brigitte; André, Fabrice; Terris, Benoit; Akhmanova, Anna; Di Benedetto, Mélanie; Nahmias, Clara; Rodrigues-Ferreira, Sylvie

    2013-05-01

    Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22 MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression.

  15. SCUD: Saccharomyces cerevisiae ubiquitination database.

    Science.gov (United States)

    Lee, Won-Chul; Lee, Minho; Jung, Jin Woo; Kim, Kwang Pyo; Kim, Dongsup

    2008-09-24

    Ubiquitination is an important post-translational modification involved in diverse biological processes. Therefore, genomewide representation of the ubiquitination system for a species is important. SCUD is a web-based database for the ubiquitination system in Saccharomyces cerevisiae (Baker's yeast). We first searched for all the known enzymes involved in the ubiquitination process in yeast, including E1, E2, E3, and deubiquitination enzymes. Then, ubiquitinated substrates were collected by literature search. Especially, E3 and deubiquitination enzymes are classified into classes and subclasses by their shared domains and unique functions. As a result, 42 different E3 enzymes were grouped into corresponding classes and subclasses, and 940 ubiquitinated substrates including mutant substrates were identified. All the enzyme and substrate information are interconnected by hyperlinks, which makes it easy to view the enzyme-specific ubiquitination information. This database aims to represent a comprehensive yeast ubiquitination system, and is easily expandable with the further experimental data. We expect that this database will be useful for the research on the ubiquitination systems of other higher organisms. SCUD is accessible at http://scud.kaist.ac.kr.

  16. Intra-abdominal pressure and procalcitonin are valid prognostic markers of acute pancreatitis severity (intra-abdominal pressure and procalcitonin

    Directory of Open Access Journals (Sweden)

    Stojanović Maja

    2017-01-01

    Full Text Available Introduction. Early assessment of the severity and etiology of acute pancreatitis is very important for further treatment procedures. The aim of the study was to investigate the association between intra-abdominal pressure (IAP and procalcitonin as an indicator of severity of acute pancreatitis. Method. The IAP is measured every 12 hours through the urinary catheter placed in the bladder, in 65 patients with acute pancreatitis. Procalcitonin is measured within 24 hours of receipt of the patient, after 48 hours and after 78 hours. These values of procalcitonin and IAP were compared to each other and in relation to the Acute Physiology, Age and Chronic Health Evaluation II (APACHE II scoring system. Patients with APACHE II score > 8 are defined with moderate and severe acute pancreatitis. Results. The values of IAP (18,1 ± 4,5 mmHg vs 8,9 ± 2,67 mmHg; p = 0,01 , procalcitonin (15,43 + 2,25 ng/ml vs 3,14 + 1,12 ng/ml; p =0,031 and APACHE II scoring system (17,3 ± 6,24 vs 6,5 ± 1,0; p = 0,013 were significantly higher in patients with moderate and severe acute pancreatitis. The increase in the value of IAP was accompanied by an increase in the value of procalcitonin (r = 0,581, p = 0,01. The sensitivity in the prediction of severe acute pancreatitis after 24 hours of receiving the patient is 91,7% for the IAP, 87,8% for procalcitonin and 84,9% for APACHE II scoring system. Conclusion. The increase in the value of the IAP is accompanied by an increase in the values of procalcitonin, also patients with higher values of APACHE II scoring sys­tem have higher values of IAP and procalcitonin. The values of IAP and procalcitonin can be used as markers of acute pancreatitis severity.

  17. Delta neutrophil index as a promising prognostic marker of emergent surgical intervention for acute diverticulitis in the emergency department.

    Science.gov (United States)

    Kang, Hee Seung; Cha, Yong Sung; Park, Kyung Hye; Hwang, Sung Oh

    2017-01-01

    Early identification of patients with acute diverticulitis who require emergent surgical intervention in the emergency department (ED) is important to the physician. Although computed tomography (CT) has an important role in evaluating the severity of diverticulitis, its findings alone may not predict the need for emergent surgical intervention in all patients with acute diverticulitis in the ED. Serum inflammation markers may help to differentiate severity of acute diverticulitis and predict the need for surgical intervention in clinical practice. No information is currently available on the clinical usefulness of the delta neutrophil index (DNI), with respect to the prediction of emergent surgical intervention in patients with acute diverticulitis at the ED. This was a retrospective observational study of consecutive adult patients with acute diverticulitis confirmed by CT in the ED, between January 2014 and December 2016. Recruited patients were divided into two groups: emergent surgical intervention and no surgical intervention. The following laboratory serum parameters were examined in the ED: DNI value, C-reactive protein (CRP) levels, white blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR). The patients were also examined for the presence or absence of complications by CT. A total of 132 patients were finally included in the study, with the emergent surgical intervention group constituting 52 patients. The median DNI value, CRP levels, neutrophil count, and NLR were significantly higher in the emergent surgical intervention group than in the no surgical intervention group. The area under the curve for predicting emergent surgical intervention, using the DNI was significantly higher than that of CRP levels, neutrophil count, or NLR. Moreover, the combination of initial DNI and CT was most powerful diagnostic modality. DNI values measured at the ED combined with CT were good predictors for emergent surgical intervention in acute

  18. Identification of gene expression-based prognostic markers in the hematopoietic stem cells of patients with myelodysplastic syndromes.

    Science.gov (United States)

    Pellagatti, Andrea; Benner, Axel; Mills, Ken I; Cazzola, Mario; Giagounidis, Aristoteles; Perry, Janet; Malcovati, Luca; Della Porta, Matteo G; Jädersten, Martin; Verma, Amit; McDonald, Emma-Jane; Killick, Sally; Hellström-Lindberg, Eva; Bullinger, Lars; Wainscoat, James S; Boultwood, Jacqueline

    2013-10-01

    The diagnosis of patients with myelodysplastic syndromes (MDS) is largely dependent on morphologic examination of bone marrow aspirates. Several criteria that form the basis of the classifications and scoring systems most commonly used in clinical practice are affected by operator-dependent variation. To identify standardized molecular markers that would allow prediction of prognosis, we have used gene expression profiling (GEP) data on CD34+ cells from patients with MDS to determine the relationship between gene expression levels and prognosis. GEP data on CD34+ cells from 125 patients with MDS with a minimum 12-month follow-up since date of bone marrow sample collection were included in this study. Supervised principal components and lasso penalized Cox proportional hazards regression (Coxnet) were used for the analysis. We identified several genes, the expression of which was significantly associated with survival of patients with MDS, including LEF1, CDH1, WT1, and MN1. The Coxnet predictor, based on expression data on 20 genes, outperformed other predictors, including one that additionally used clinical information. Our Coxnet gene signature based on CD34+ cells significantly identified a separation of patients with good or bad prognosis in an independent GEP data set based on unsorted bone marrow mononuclear cells, demonstrating that our signature is robust and may be applicable to bone marrow cells without the need to isolate CD34+ cells. We present a new, valuable GEP-based signature for assessing prognosis in MDS. GEP-based signatures correlating with clinical outcome may significantly contribute to a refined risk classification of MDS.

  19. Modified FOLFOX-6 chemotherapy in advanced gastric cancer: Results of phase II study and comprehensive analysis of polymorphisms as a predictive and prognostic marker

    Directory of Open Access Journals (Sweden)

    Lee Se-Hoon

    2008-05-01

    Full Text Available Abstract Background The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU, folinic acid and oxaliplatin (modified FOLFOX-6 in patients with advanced gastric cancer (AGC, as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin. Methods Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m2 and folinic acid (100 mg/m2 followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m2. Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC. Results The overall response rate (RR was 43.8%. Median time to progression (TTP and overall survival (OS were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034, and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038. The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032. Conclusion Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial.

  20. Integrated Phenotypic/Genotypic Analysis of Papillary Renal Cell Carcinoma Subtypes: Identification of Prognostic Markers, Cancer-related Pathways, and Implications for Therapy.

    Science.gov (United States)

    Saleeb, Rola M; Plant, Pamela; Tawedrous, Eriny; Krizova, Adriana; Brimo, Fadi; Evans, Andrew J; Wala, Samantha Jane; Bartlett, John; Ding, Qiang; Boles, Dina; Rotando, Fabio; Farag, Mina; Yousef, George M

    2016-09-22

    Two histologic subtypes are recognized for papillary renal cell carcinoma (PRCC). Studies have shown that the subtypes differ in characteristic genetic alterations and clinical behavior. Clinically, the subtypes are managed similarly. To analyze the biological differences between the two PRCC histological subtypes, in order to further guide their clinical management. PRCC cohort consisting of 317 patients from the Cancer Genome Atlas database and our institution. Patients were stratified according to histologic criteria as type 1, type 2, or not otherwise specified (NOS). Gene and miRNA expression data for the cohort were examined via unsupervised and supervised clustering. Significant molecular signatures for each subtype were used to unravel the implicated molecular pathways via bioinformatics analysis. Survival was compared between the subtypes. Newly discovered biomarkers were used to further stratify survival of patients in the NOS category. Tumor genotyping revealed two distinct PRCC subtypes. The top molecular pathways enriched in PRCC1 were WNT, Hedgehog, and Notch signaling (p=0.001-0.01); highlighting an embryonic developmental theme to the pathogenesis of this subtype. PRCC2 showed enrichment in the mTOR, VEGF (p=7.49E-09) and HIF (p=7.63E-05) signaling pathways. Overall survival and disease-free survival significantly differed between the types. ABCC2 expression was identified as a significant prognostic biomarker for the NOS group in univariate (log rank p11.63) and multivariate analysis (p=0.003; HR >2.12). ABCC2 expression and its effect on survival should be further validated at the protein level. The classical PRCC types 1 and 2 have two distinct genotypes. We unraveled pathways that indicate that the two types could potentially respond differently to current therapies. We also identified biomarkers that stratify tumors within the PRCC NOS category into prognostic subgroups. Our findings highlight the need for molecular markers to accurately

  1. Delta neutrophil index as a promising prognostic marker of emergent surgical intervention for acute diverticulitis in the emergency department.

    Directory of Open Access Journals (Sweden)

    Hee Seung Kang

    Full Text Available Early identification of patients with acute diverticulitis who require emergent surgical intervention in the emergency department (ED is important to the physician. Although computed tomography (CT has an important role in evaluating the severity of diverticulitis, its findings alone may not predict the need for emergent surgical intervention in all patients with acute diverticulitis in the ED. Serum inflammation markers may help to differentiate severity of acute diverticulitis and predict the need for surgical intervention in clinical practice. No information is currently available on the clinical usefulness of the delta neutrophil index (DNI, with respect to the prediction of emergent surgical intervention in patients with acute diverticulitis at the ED.This was a retrospective observational study of consecutive adult patients with acute diverticulitis confirmed by CT in the ED, between January 2014 and December 2016. Recruited patients were divided into two groups: emergent surgical intervention and no surgical intervention. The following laboratory serum parameters were examined in the ED: DNI value, C-reactive protein (CRP levels, white blood cell count, neutrophil count, and neutrophil-to-lymphocyte ratio (NLR. The patients were also examined for the presence or absence of complications by CT.A total of 132 patients were finally included in the study, with the emergent surgical intervention group constituting 52 patients. The median DNI value, CRP levels, neutrophil count, and NLR were significantly higher in the emergent surgical intervention group than in the no surgical intervention group. The area under the curve for predicting emergent surgical intervention, using the DNI was significantly higher than that of CRP levels, neutrophil count, or NLR. Moreover, the combination of initial DNI and CT was most powerful diagnostic modality.DNI values measured at the ED combined with CT were good predictors for emergent surgical intervention

  2. Meta-Analyses of Microarray Datasets Identifies ANO1 and FADD as Prognostic Markers of Head and Neck Cancer.

    Directory of Open Access Journals (Sweden)

    Ram Bhupal Reddy

    identified candidate markers correlated with disease outcome in HNSCC; further validation in a larger cohort of patients will establish their clinical relevance.

  3. Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups.

    Science.gov (United States)

    Vitiello, Glauco Akelinghton Freire; Losi Guembarovski, Roberta; Amarante, Marla Karine; Ceribelli, Jesus Roberto; Carmelo, Elaine Cristina Baraldi; Watanabe, Maria Angelica Ehara

    2018-03-01

    according to BC subtype, pointing this genetic variant as an interesting marker for breast carcinogenesis to be validated by further mechanistic and prospective studies with larger samples. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer.

    Directory of Open Access Journals (Sweden)

    Maria Schubert

    Full Text Available BACKGROUND: The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa. MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. METHODOLOGY AND PRINCIPAL FINDINGS: We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS vs. clinical failure (CF. We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361 that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98. Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. CONCLUSION: Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high

  5. Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure

    DEFF Research Database (Denmark)

    Dixen, Ulrik; Wallevik, Laura; Hansen, Maja

    2003-01-01

    To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF).......To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF)....

  6. Pathway-Centric Integrative Analysis Identifies RRM2 as a Prognostic Marker in Breast Cancer Associated with Poor Survival and Tamoxifen Resistance

    Directory of Open Access Journals (Sweden)

    Nagireddy Putluri

    2014-05-01

    Full Text Available Breast cancer (BCa molecular subtypes include luminal A, luminal B, normal-like, HER-2–enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance. Key mediators of the pathway were then characterized for their role in disease progression. Pyrimidine metabolism was altered in luminal versus basal BCa, whereas the combined expression of its associated genes or expression of one key gene, ribonucleotide reductase subunit M2 (RRM2 alone, associated significantly with decreased survival across all BCa subtypes, as well as in luminal patients resistant to tamoxifen. Increased RRM2 expression in tamoxifen-resistant patients was verified using tissue microarrays, whereas the metabolic products of RRM2 were higher in tamoxifen-resistant cells and in xenograft tumors. Both genetic and pharmacological inhibition of this key enzyme in tamoxifen-resistant cells significantly decreased proliferation, reduced expression of cell cycle genes, and sensitized the cells to tamoxifen treatment. Our study suggests for evaluating RRM2-associated metabolites as noninvasive markers for tamoxifen resistance and its pharmacological inhibition as a novel approach to overcome tamoxifen resistance in BCa.

  7. In vivo assessment of pulmonary arterial wall fibrosis by intravascular optical coherence tomography in pulmonary arterial hypertension: a new prognostic marker of adverse clinical follow-up.

    Science.gov (United States)

    Domingo, Enric; Grignola, Juan C; Aguilar, Rio; Montero, María Angeles; Arredondo, Christian; Vázquez, Manuel; López-Messeguer, Manuel; Bravo, Carlos; Bouteldja, Nadia; Hidalgo, Cristina; Roman, Antonio

    2013-01-01

    The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed. 19 patients, aged 54±16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area × 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure. OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4±0.8 mm(2), % fibrosis was 22.3±8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (≥ 22%) and 9 with a low fibrosis (right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01). In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome.

  8. Change in carbohydrate antigen 19-9 level as a prognostic marker of overall survival in locally advanced pancreatic cancer treated with concurrent chemoradiotherapy.

    Science.gov (United States)

    Kim, Yi-Jun; Koh, Hyeon Kang; Chie, Eui Kyu; Oh, Do-Youn; Bang, Yung-Jue; Nam, Eun Mi; Kim, Kyubo

    2017-12-01

    To investigate the significance of carbohydrate antigen 19-9 (CA19-9) levels for survival in locally advanced pancreatic cancer (LAPC) treated with concurrent chemoradiotherapy (CCRT). We retrospectively reviewed data from 97 LAPC patients treated with CCRT between 2000 and 2013. CA19-9 levels (initial and post-CCRT) and their changes [{(post-CCRT CA19-9 level - initial CA19-9 level)/(initial CA19-9 level)} × 100] were analyzed for overall survival. A cut-off point of 37 U/mL was used to analyze initial and post-CCRT CA19-9 levels. In order to define an optimal cut-off point for change in CA19-9 level, the maxstat package of R was applied. Median overall survival was 14.7 months (95% CI 13.4-16.0), and the 2-year survival rate was 16.5%. The estimated optimal cut-off point of CA19-9 level change was 94.4%. On univariate analyses, CA19-9 level change between initial and post-CCRT was significantly correlated with overall survival (median survival time 9.7 vs 16.3 months, p 94.4% might serve as a surrogate marker for poor survival in patients with LAPC undergoing CCRT, and the prognostic power surpassed other CA19-9 variables including initial and post-CCRT values.

  9. Role of type 1 IFNs in antiglioma immunosurveillance--using mouse studies to guide examination of novel prognostic markers in humans.

    Science.gov (United States)

    Fujita, Mitsugu; Scheurer, Michael E; Decker, Stacy A; McDonald, Heather A; Kohanbash, Gary; Kastenhuber, Edward R; Kato, Hisashi; Bondy, Melissa L; Ohlfest, John R; Okada, Hideho

    2010-07-01

    We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells. We induced de novo gliomas in Ifnar1(-/-) (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN-related genes. Ifnar1(-/-) mice exhibited accelerated tumor growth and death. Analyses of brain tumor-infiltrating lymphocytes in Ifnar1(-/-) mice revealed an increase of cells positive for CD11b(+)Ly6G(+) and CD4(+)FoxP3(+), which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8(+) cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1(-/-) mouse-derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1(-/-) mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G(+) cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas. The novel Sleeping Beauty-induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers.

  10. The Role of Ubiquitine Proteasome Pathway in Carcinogenesis

    Directory of Open Access Journals (Sweden)

    N.Ceren Sumer Turanligil

    2010-02-01

    Full Text Available Ubiquitin works as a marker protein which targets misfolded or injured proteins to cellular degradation. It brings the abnormal proteins to a subcellular organelle named proteasome and it maintains the degradation of proteins in limited lenghts of peptides by leaving the process withuout being changed. Mistakes in ubiquitin-dependent proteolysis in various steps of carcinogenesis is known. In this review, we dealed with the effects of ubiquitin-proteasome pathway (UPP on carcinogenesis via intercellular signaling molecules like Ras, transcription factors like NF-kB, cytokines like TNF-alfa Tumor necrosis factor, protooncogenes like p53 and MDM2(murine double minute 2, components of cell cycle and DNA repair proteins like BRCA1. We also focused on the relationship of UPP on antigen presentation which is active in immune response and its place in the aetiology of colon cancer to provide a specific example. [Archives Medical Review Journal 2010; 19(1.000: 36-55

  11. Volume-Based F-18 FDG PET/CT Imaging Markers Provide Supplemental Prognostic Information to Histologic Grading in Patients With High-Grade Bone or Soft Tissue Sarcoma

    DEFF Research Database (Denmark)

    Andersen, Kim Francis; Fuglo, Hanna Maria; Rasmussen, Sine Hvid

    2015-01-01

    to 2012 including 92 patients with histologically verified high-grade BS (N = 37) or STS (N = 55). All patients underwent a pretreatment F-18 FDG PET/CT scan. Clinical data were registered. Measurements of the accuracy of metabolic tumor volume with a preset threshold of 40% of the maximum standardized...... analysis. Kaplan-Meier survival estimates and log-rank test were used to compare the degree of equality of survival distributions. Prognostic variables with related hazard ratios (HR) were assessed using Cox proportional hazards regression analysis.Forty-one of 92 patients died during follow-up (45%; 12 BS.......05, HR 3.37 [95% CI 1.02-11.11]). No significant results were demonstrated for MTV40%.Volume-based F-18 FDG PET/CT imaging markers in terms of pretreatment estimation of TLG provide supplemental prognostic information to histologic grading, with significant independent properties for prediction...

  12. The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

    Directory of Open Access Journals (Sweden)

    Goethals Laurence

    2005-04-01

    Full Text Available Abstract Background Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC treated by radiotherapy ± chemotherapy. Methods We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67, immunohistochemistry for carbonic anhydrase IX (CA IX and glucose transporter-1 (GLUT-1 was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34, enzyme linked immunosorbent assay (ELISA was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF and interleukin-6 (IL-6 in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. Results For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02 and disease-free survival (p = 0.04 with a trend for regional control (p = 0.06. In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009, disease-free survival (p = 0.02 and overall survival (p = 0.005. Conclusion To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be

  13. Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure

    DEFF Research Database (Denmark)

    Dixen, Ulrik; Wallevik, Laura; Hansen, Maja

    2003-01-01

    To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF)....

  14. Cancer cachexia, sarcopenia and biochemical markers in patients with advanced non-small cell lung cancer-chemotherapy toxicity and prognostic value.

    Science.gov (United States)

    Srdic, Drazena; Plestina, Sanja; Sverko-Peternac, Ana; Nikolac, Nora; Simundic, Ana-Maria; Samarzija, Miroslav

    2016-11-01

    Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. The majority of studies of cancer cachexia and sarcopenia have been done in patients with solid tumors of different origins, and there are currently no good predictors of the benefit of chemotherapy or factors that predict survival in advanced cancer. The purpose of our prospective study was to evaluate prevalence of cachexia and sarcopenia using international consensus definition and criteria for diagnosis in patients with diagnosed advanced non-small cell lung cancer (NSCLC) stage IIIB and IV and their relation to chemotherapy toxicity and survival prediction. A secondary aim was to compare several biochemical markers (CRP, IL-6, protein, and albumin) with time to tumor progression in order to assess prognostic value or to guide a treatment. Between December 2013 and April 2015, the prospective cohort study of 100 Caucasian patients with advanced NSCLC stage IIIB or IV, who were referred consecutively to Department for Respiratory Diseases "Jordanovac," was evaluated. Anthropometric measurements and biochemical data (CRP, albumin, protein, IL-6, haemoglobin) together with body composition measurements (total muscle cross-sectional area, lumbar skeletal muscle index) were obtained for each patient before starting with platinum-doublet therapy. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment and time-to-tumor progression was determined prospectively. One hundred patients with advanced lung cancer were recruited: 67 were male and median age was 64 years. The median time to disease progression was 187 days. The prevalence of cachexia and sarcopenia in study cohort was 69 and 47 %, respectively. CRP, IL-6, and albumin concentration in cachectic compared to non-cachectic patients

  15. In situ localization of tumor cells associated with the epithelial-mesenchymal transition marker Snail and the prognostic impact of lymphocytes in the tumor microenvironment in invasive ductal breast cancer.

    Science.gov (United States)

    Alkatout, Ibrahim; Hübner, Friederike; Wenners, Antonia; Hedderich, Jürgen; Wiedermann, Meike; Sánchez, Cristina; Röcken, Christoph; Mathiak, Micaela; Maass, Nicolai; Klapper, Wolfram

    2017-04-01

    Tumor surgery is aimed at complete resection of the lesion while ensuring a sufficient tumor-specific safety distance. Nevertheless, in many cases the most peripheral part - the invasion front - remains in situ. Tumor cells at the tumor margin have been reported to lose their epithelial properties and acquire features of mesenchymal cells. The process of epithelial-to-mesenchymal transition (EMT) is believed to be of prime importance for tissue and vessel invasion. Furthermore, the detection of tumor-infiltrating lymphocytes in the microenvironment of breast cancer might serve as a reliable prognostic marker. We investigated tissue microarrays of 352 breast cancer patients with regard to the presence and distribution of the EMT factor Snail, and the presence of FoxP3, CD3 and CD8 in the immune microenvironment. The expression of the transcription factor Snail is strongly associated with longer disease-free and overall survival. The presence of CD3, CD8 or FoxP3 is associated with a better outcome, although statistically significant results were noted only for FoxP3. The prognostic significance of FoxP3 and Snail were also proven in multivariate analysis. Based on previous studies concerning the intratumoral heterogeneity of EMT, our results suggest that Snail and FoxP3 are possible prognostic markers for breast cancer. The diverse presence of lymphocytes in the tumor microenvironment (CD3 and CD8) was confirmed. Although the importance of these markers is known, their specific role in tumor invasion and metastasis as well as their hierarchical organization in these tumors remain unclear. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as diagnostic and prognostic marker in neonatal sepsis.

    Science.gov (United States)

    Adly, Amira A M; Ismail, Eman A; Andrawes, Nevine G; El-Saadany, Marwa A

    2014-02-01

    Triggering receptor expressed on myeloid cells-1 (TREM-1) is an important receptor involved in the innate inflammatory response and sepsis. We assessed soluble TREM-1 (sTREM-1) in 112 septic neonates (63 culture-positive and 49 culture-negative) and 40 healthy controls as a potential early diagnostic and prognostic marker for neonatal sepsis (NS). Studied neonates were evaluated for early- or late-onset sepsis using clinical and laboratory indicators upon admission. sTREM-1 was measured on initial sepsis evaluation and at 48h after antibiotic therapy. For ethical reasons, cord blood samples were collected from control neonates and only samples from neonates that proved to be healthy by clinical examination and laboratory analysis were further analyzed for sTREM-1. Baseline sTREM-1 levels were significantly elevated in culture-proven (1461.1±523pg/mL) and culture-negative sepsis (1194±485pg/mL) compared to controls (162.2±61pg/mL) with no significant difference between both septic groups. Culture-positive or negative septic preterm neonates had significantly higher sTREM-1 compared to full term neonates. sTREM-1 was significantly higher in neonates with early sepsis than late sepsis and was associated with high mortality. sTREM-1 was significantly decreased 48h after antibiotic therapy compared to baseline or levels in neonates with persistently positive cultures. sTREM-1 was positively correlated to white blood cells (WBCs), absolute neutrophil count, immature/total neutrophil (I/T) ratio, C-reactive protein (hs-CRP) and sepsis score while negatively correlated to gestational age and weight. hs-CRP and sepsis score were independently related to sTREM-1 in multiregression analysis. sTREM-1 cutoff value of 310pg/mL could be diagnostic for NS with 100% sensitivity and specificity (AUC, 1.0 and 95% confidence interval [CI], 0.696-1.015) while the cutoff value 1100pg/mL was predictive of survival with 100% sensitivity and 97% specificity (AUC, 0.978 and 95% CI, 0

  17. Diagnostic and prognostic values of the V-index, a novel ECG marker quantifying spatial heterogeneity of ventricular repolarization, in patients with symptoms suggestive of non-ST-elevation myocardial infarction.

    Science.gov (United States)

    Abächerli, Roger; Twerenbold, Raphael; Boeddinghaus, Jasper; Nestelberger, Thomas; Mächler, Patrick; Sassi, Roberto; Rivolta, Massimo W; Roonizi, Ebadollah Kheirati; Mainardi, Luca T; Kozhuharov, Nikola; Rubini Giménez, Maria; Wildi, Karin; Grimm, Karin; Sabti, Zaid; Hillinger, Petra; Puelacher, Christian; Strebel, Ivo; Cupa, Janosch; Badertscher, Patrick; Roux, Isabelle; Schmid, Ramun; Leber, Remo; Osswald, Stefan; Mueller, Christian; Reichlin, Tobias

    2017-06-01

    The V-index is an ECG marker quantifying spatial heterogeneity of ventricular repolarization. We prospectively assessed the diagnostic and prognostic values of the V-index in patients with suspected non-ST-elevation myocardial infarction (NSTEMI). We prospectively enrolled 497 patients presenting with suspected NSTEMI to the emergency department (ED). Digital 12-lead ECGs of five-minute duration were recorded at presentation. The V-index was automatically calculated in a blinded fashion. Patients with a QRS duration >120ms were ruled out from analysis. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24months of follow-up. NSTEMI was the final diagnosis in 14% of patients. V-index levels were higher in patients with AMI compared to other causes of chest pain (median 23ms vs. 18ms, pV-index in addition to conventional ECG-criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by area under the ROC curve from 0.66 to 0.73 (p=0.001) and the sensitivity of the ECG for AMI from 41% to 86% (pV-index (pV-index remained an independent predictor of death. The V-index, an ECG marker quantifying spatial heterogeneity of ventricular repolarization, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI and independently predicts mortality during follow-up. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment

    DEFF Research Database (Denmark)

    Blyme, Adam; Asferg, Camilla; Nielsen, Olav W

    2015-01-01

    AIMS: To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). METHODS AND RESULTS: In 1620 SEAS patients, we m...

  19. Prognostic Value of Vitamin D Level for All-cause Mortality, and Association With Inflammatory Markers, in HIV-infected Persons

    NARCIS (Netherlands)

    Shepherd, Leah; Souberbielle, Jean-Claude; Bastard, Jean-Philippe; Fellahi, Soraya; Capeau, Jaqueline; Reekie, Joanne; Reiss, Peter; Blaxhult, Anders; Bickel, Markus; Leen, Clifford; Kirk, Ole; Lundgren, Jens D.; Mocroft, Amanda; Viard, Jean-Paul; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; de Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A.-B. E.; Skinhøj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Ristola, M.; Katlama, C.; Viard, J.-P.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Bogner, J.; Fätkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; Hassoun, G.; Maayan, S.; d'Arminio, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Maria, S.; Vullo, V.; Lichtner, M.; Chirianni, A.; Montesarchio, E.; Gargiulo, M.; Antonucci, G.; Testa, A.; D'Offizi, G.; Vlassi, C.; Zaccarelli, M.; Antorini, A.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Sacco, L.; Rozentale, B.; Zeltina, I.; Chaplinskas, S.; Staub, T.; Hemmer, R.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Boron-Kaczmarska, A.; Pynka, M.; Parczewski, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Antunes, F.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Duiculescu, D.; Rakhmanova, A.; Buzunova, S.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Mokráš, M.; Staneková, D.; Tomazic, J.; González-Lahoz, J.; Soriano, V.; Labarga, P.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miró, J. M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Medrano, J.; Blaxhult, A.; Flamholc, L.; Sonnerborg, A.; Ledergerber, B.; Weber, R.; Francioli, P.; Cavassini, M.; Hirschel, B.; Boffi, E.; Battegay, M.; Elzi, L.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Servitskiy, S.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Mercey, D.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Gatell, J.; d'Arminio Monforte, A.; Lundgren, J.; Kirk, O.; Podlekareva, D.; Kjær, J.; Peters, L.; Nielsen, J. E.; Tverland, J.; Fischer, A. H.; Bojesen, A.

    2014-01-01

    Background. Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with

  20. Insulin-like growth factor receptor 1 mRNA expression as a prognostic marker in advanced non-small cell lung cancer

    DEFF Research Database (Denmark)

    Vilmar, Adam; Santoni-Rugiu, Eric; Cillas, Jesus Garcia-Fon

    2014-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain...

  1. Nm23/nucleoside diphosphate kinase-A as a potent prognostic marker in invasive pancreatic ductal carcinoma identified by proteomic analysis of laser micro-dissected formalin-fixed paraffin-embedded tissue

    Directory of Open Access Journals (Sweden)

    Takadate Tatsuyuki

    2012-06-01

    Full Text Available Abstract Background Pancreatic cancer is among the most lethal malignancies worldwide. This study aimed to identify a novel prognostic biomarker, facilitating treatment selection, using mass spectrometry (MS-based proteomic analysis with formalin-fixed paraffin-embedded (FFPE tissue. Results The two groups with poor prognosis (n = 4 and with better prognosis (n = 4 had been carefully chosen among 96 resected cases of pancreatic cancer during 1998 to 2007 in Tohoku University Hospital. Although those 2 groups had adjusted background (UICC-Stage IIB, Grade2, R0, gemcitabine adjuvant, there was a significant difference in postoperative mean survival time (poor 21.0 months, better 58.1 months, P = 0.0067. Cancerous epithelial cells collected from FFPE tissue sections by laser micro-dissection (LMD were processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS. In total, 1099 unique proteins were identified and 6 proteins showed different expressions in the 2 groups by semi-quantitative comparison. Among these 6 proteins, we focused on Nm23/Nucleoside Diphosphate Kinase A (NDPK-A and immunohistochemically confirmed its expression in the cohort of 96 cases. Kaplan-Meier analysis showed high Nm23/NDPK-A expression to correlate with significantly worse overall survival (P = 0.0103. Moreover, in the multivariate Cox regression model, Nm23/NDPK-A over-expression remained an independent predictor of poor survival with a hazard ratio of 1.97 (95% CI 1.16-3.56, P = 0.0110. Conclusions We identified 6 candidate prognostic markers for postoperative pancreatic cancer using FFPE tissues and immunohistochemically demonstrated high Nm23/NDPK-A expression to be a useful prognostic marker for pancreatic cancer.

  2. Prognostic Value of Prothrombin Time International Normalized Ratio in Acute Decompensated Heart Failure – A Combined Marker of Hepatic Insufficiency and Hemostatic Abnormality

    National Research Council Canada - National Science Library

    Okada, Atsushi; Sugano, Yasuo; Nagai, Toshiyuki; Takashio, Seiji; Honda, Satoshi; Asaumi, Yasuhide; Aiba, Takeshi; Noguchi, Teruo; Kusano, Kengo F; Ogawa, Hisao; Yasuda, Satoshi; Anzai, Toshihisa

    2016-01-01

    .... The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear.Methods...

  3. Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively

    Directory of Open Access Journals (Sweden)

    Qi Yu

    2017-01-01

    Full Text Available Background. Identifying diagnostic and prognostic biomarkers that could be targeted in the therapy of pancreatic cancer is essential. Objective. Investigations were conducted with respect to plasma miRNA (miR-21, miR-210, miR-155, miR-196a, miR-20a, and miR-25 expression and clinicopathologic factors to evaluate the prognostic value of miRNAs in pancreatic ductal adenocarcinoma (PDAC. Methods. Plasma miRNAs were detected by real-time quantitative PCR, and the association with clinicopathologic factors was subsequently performed by univariate and multivariate analyses. Results. Six miRNAs expressed significantly higher in PDAC patients than in normal individuals were identified. Receiver operating characteristic (ROC curves were constructed. It was evident that miRNA expression associated with PDAC, lymph node metastasis, serosal infiltration, and comprehensive therapy reached significance for overall survival. High miR-196a expression was associated with poor survival (P=0.001, whereas high miR-210 expression was significantly associated with improved survival (P=0.003. Multivariate survival analysis indicated that the miR-210 and miR-196a expression signature, lymph node metastasis, and comprehensive therapy were independent factors affecting overall survival. Conclusions. MiRNA expression profile is distinctive in PDAC. Aberrant expression of certain miRNAs was remarkably involved in shaping the overall survival time, which include miR-196a overexpression and decreased miR-210 expression.

  4. Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons

    DEFF Research Database (Denmark)

    Shepherd, Leah; Souberbielle, Jean-Claude; Bastard, Jean-Philippe

    2014-01-01

    BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological...... > .05). In patients with current 25(OH)D Vitamin D predicts short term mortality in HIV......-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated....

  5. Mammaglobin B is an independent prognostic marker in epithelial ovarian cancer and its expression is associated with reduced risk of disease recurrence

    Directory of Open Access Journals (Sweden)

    Bandiera Elisabetta

    2009-07-01

    Full Text Available Abstract Background Traditional prognostic factors in epithelial ovarian cancer (EOC are inadequate in predicting recurrence and long-term prognosis, but genome-wide cancer research has recently provided multiple potentially useful biomarkers. The gene codifying for Mammaglobin B (MGB-2 has been selected from our previous microarray analysis performed on 19 serous papillary epithelial ovarian cancers and its expression has been further investigated on multiple histological subtypes, both at mRNA and protein level. Since, to date, there is no information available on the prognostic significance of MGB-2 expression in cancer, the aim of this study was to determine its prognostic potential on survival in a large cohort of well-characterized EOC patients. Methods MGB-2 expression was evaluated by quantitative real time-PCR in fresh-frozen tissue biopsies and was validated by immunohistochemistry in matched formalin fixed-paraffin embedded tissue samples derived from a total of 106 EOC patients and 27 controls. MGB-2 expression was then associated with the clinicopathologic features of the tumors and was correlated with clinical outcome. Results MGB-2 expression was found significantly elevated in EOC compared to normal ovarian controls, both at mRNA and protein level. A good correlation was detected between MGB-2 expression data obtained by the two different techniques. MGB-2 expressing tumors were significantly associated with several clinicopathologic characteristics defining a less aggressive tumor behavior. Univariate survival analysis revealed a decreased risk for cancer-related death, recurrence and disease progression in MGB-2-expressing patients (p Conclusion This is the first report documenting that MGB-2 expression characterizes less aggressive forms of EOC and is correlated with a favorable outcome. These findings suggest that the determination of MGB-2, especially at molecular level, in EOC tissue obtained after primary surgery can

  6. The Prognostic Value of the Proliferation Marker Phosphohistone H3 (PPH3) in Luminal, Basal-Like and Triple Negative Phenotype Invasive Lymph Node-Negative Breast Cancer

    Science.gov (United States)

    Skaland, Ivar; Janssen, Emiel A. M.; Gudlaugsson, Einar; Guo, Lydia Hui Ru; Baak, Jan P. A.

    2009-01-01

    Purpose: Prognostic comparison of phosphohistone-H3 (PPH3) with Cytokeratin 5/6 and/or 14 positive (= basal-CK), triple (ER, PR, HER2)-negative (= TNP) and basal-like (= TNP and basal-CK positive) phenotype in invasive breast cancers. Patients and Methods: Classical variables, PPH3, ER, PR, basal-CK and HER2 in 240 T1–2N0M0 patients under 71 years. Results: TNP and basal-like cancers had higher PPH3 expression than the other cancers (mean 48 versus 11, P < 0.001). Fifteen percent of the patients in the whole group, but 32–38% of TNP and basal-like cancers recurred.With multivariate analysis, PPH3 < 13 (n = 156) versus ≥ 13 (n = 84 = 35% of all cases) was the strongest and only prognosticator (10-year survival 96% and 64%, P ≤ 0.001, Hazard ratio = 9.0). Conclusion: PPH3 is the strongest prognosticators in luminal, Triple negative and basal-like T1–2N0M0 invasive breast cancers. PMID:19633363

  7. Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

    Science.gov (United States)

    Guberina, M; Eberhardt, W; Stuschke, M; Gauler, T; Heinzelmann, F; Cheufou, D; Kimmich, M; Friedel, G; Schmidberger, H; Darwiche, K; Jendrossek, V; Schuler, M; Stamatis, G; Pöttgen, C

    2017-05-01

    Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death

  8. Sperm ubiquitination in epididymal feline semen.

    Science.gov (United States)

    Vernocchi, Valentina; Morselli, Maria Giorgia; Varesi, Sara; Nonnis, Simona; Maffioli, Elisa; Negri, Armando; Tedeschi, Gabriella; Luvoni, Gaia Cecilia

    2014-09-01

    Ubiquitin is a 8.5-kDa peptide that tags other proteins for proteasomal degradation. It has been proposed that ubiquitination might be responsible for the elimination of defective spermatozoa during transit through the epididymis in humans and cattle, but its exact biological function in seminal plasma has not yet been clarified. In the domestic cat (Felis catus), the percentage of immature, unviable, and abnormal spermatozoa decreases during the epididymal transit, indicating the existence of a mechanism that removes defective spermatozoa. Magnetic cell separation techniques, based on the use of magnetic beads coated with anti-ubiquitin antibodies, may allow the selective capture of ubiquitinated spermatozoa from semen, thus contributing to the identification of a potential correlation between semen quality and ubiquitination process. Moreover, the selective identification of all the ubiquitinated proteins in different epididymal regions could give a better understanding of the ubiquitin role in feline sperm maturation. The aims of this study were as follows: (1) to verify the possibility of separating ubiquitinated spermatozoa with magnetic ubiquitin beads and identify the morphological and acrosomal differences between whole sample and unbound gametes, (2) to characterize all the ubiquitinated proteins in spermatozoa retrieved in the three epididymal regions by a proteomic approach. The data indicated the presence of ubiquitinated proteins in cat epididymal semen. However, a correlation between abnormal and ubiquitinated spermatozoa has not been found, and ubiquitin cannot be considered as a biomarker of quality of epididymal feline spermatozoa. To the author's knowledge, this is the first identification of all the ubiquitinated proteins of cat spermatozoa collected from different epididymal regions. The proteomic pattern allows a further characterization of cat epididymal semen and represents a contribute to a better understanding of the ubiquitin role in

  9. The new histologic classification of lung primary adenocarcinoma subtypes is a reliable prognostic marker and identifies tumors with different mutation status: the experience of a French cohort.

    Science.gov (United States)

    Mansuet-Lupo, Audrey; Bobbio, Antonio; Blons, Hélène; Becht, Etienne; Ouakrim, Hanane; Didelot, Audrey; Charpentier, Marie-Christine; Bain, Serge; Marmey, Béatrice; Bonjour, Patricia; Biton, Jérôme; Cremer, Isabelle; Dieu-Nosjean, Marie-Caroline; Sautès-Fridman, Catherine; Régnard, Jean-François; Laurent-Puig, Pierre; Alifano, Marco; Damotte, Diane

    2014-09-01

    Histologic classification of lung adenocarcinoma subtype has a prognostic value in most studies. However, lung adenocarcinoma characteristics differ across countries. Here, we aimed at validating the prognostic value of this classification in a large French series of lung adenocarcinoma. We reviewed 407 consecutive lung adenocarcinomas operated on between 2001 and 2005 and reclassified them according to the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and subsequently graded them into low, intermediate, and high grade. We analyzed the relevance of this classification according to clinical, pathologic, and molecular analysis. Patients (median age, 61 years; 288 men) underwent lobectomy (n = 378) or pneumonectomy (n = 29). Patients' overall survival at 5 and 10 years was 53.2% and 32.6%, respectively. Union for International Cancer Control stage distribution was 189 stage I, 104 stage II, 107 stage III, and seven stage IV. Low-grade tumor was found in one patient, intermediate grade in 275 patients, and high grade in 131 patients. KRAS and EGFR mutations were detected in 34% and 9.6%, respectively. Histologic grade was significantly correlated with extent of resection (P = .01), thyroid transcriptional factor-1 expression (P = .00000001), vascular emboli (P = .03), and EGFR mutations (P = .01). Mucinous adenocarcinomas were associated with KRAS mutations (P = .003). At univariate analysis, age, extent of resection, histologic grade, pleural invasion, vascular emboli, pathologic T and N, and stage were predictive of survival. At multivariate analysis, age (P = .0001), histologic grade (P = .03), and stage (P = .000003) were independent prognostic factors. IASLC/ATS/ERS classification of lung adenocarcinomas predicts survival in French population. Histologic grade correlates with clinical, pathologic and molecular parameters suggesting different oncogenic pathways.

  10. SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString).

    Science.gov (United States)

    Walter, Robert Fred Henry; Mairinger, Fabian Dominik; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Zarogoulidis, Konstantinos; Schmid, Kurt Werner; Zarogoulidis, Paul; Wohlschlaeger, Jeremias

    2015-01-01

    Neuroendocrine tumors of the lung (NELC) account for 25% of all lung cancer cases and transcription factors may drive dedifferentiation of these tumors. This study was conducted to identify supportive diagnostic and prognostic biomarkers. A total of 16 TC, 13 AC, 16 large cell neuroendocrine carcinomas and 15 small cell lung cancer were investigated for the mRNA expression of 11 transcription factors and related genes (MYB, MYBBP1A, OCT4, PAX6, PCDHB, RBP1, SDCBP, SOX2, SOX4, SOX11, TEAD2). SOX4 (p = 0.0002), SOX11 (p < 0.0001) and PAX6 (p = 0.0002) were significant for tumor type. Elevated PAX6 and SOX11 expression correlated with poor outcome in large cell neuroendocrine carcinomas and small cell lung cancer (p < 0.0001 and p = 0.0232, respectively) based on survival data of 34 patients (57%). Aggressiveness of NELC correlated with increasing expression of transcription factors. SOX11 seems to be a highly valuable diagnostic and prognostic marker for aggressive NELC.

  11. Insulin-like Growth Factor Receptor 1 mRNA Expression as a Prognostic Marker in Advanced Non-small Cell Lung Cancer

    DEFF Research Database (Denmark)

    Vilmar, Adam; Santoni-Rugiu, Eric; Cillas, Jesus Garcia-Fon

    2014-01-01

    BACKGROUND: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain...... reaction (qRT-PCR) and immunohistochemistry (IHC). MATERIALS AND METHODS: Analyses of IGF1R were performed on patients with advanced NSCLC, included in a randomized chemotherapy trial, having large, representative tissue samples. IGF1R mRNA and protein expression were correlated to clinical end...

  12. Lymphatic vessel invasion detected by the endothelial lymphatic marker D2-40 (podoplanin is predictive of regional lymph node status and an independent prognostic factor in patients with resected esophageal cancer

    Directory of Open Access Journals (Sweden)

    Jerzy Laudański

    2011-04-01

    Full Text Available The discovery of markers to lymphatic endothelial cells and the development of novel antibodies to these markers have brought increasing attention to the lymphatics and progress in the understanding of lymphangiogenesis and cancer metastasis. In this study, we investigate the presence of lymphatic vessel invasion (LVI detected by D2-40 immunohistochemical staining in resected esophageal cancer and correlated with clinicopathologic data and patient survival. Sixty nine patients, who had a primary resection of esophageal cancer, were analyzed by univariate and multivariate logistic regression, and univariate and multivariate survival analysis. The total rate of LVI was 72% (50/69. Positive LVI was significantly correlated with lymph node metastasis (p < 0.001, tumor size (p < 0.001, histological grading (p = 0.017, tumor depth (p = 0.001, and stage (p < 0.001. Multivariate logistic analysis identified LVI (p = 0.036 as a predictor of regional lymph node metastasis. On univariate survival analysis, patients with LVI had a significantly shorter disease-free survival, cancer-specific survival and overall survival. Multivariate analysis proved that LVI diagnosed by D2-40 is an independent prognostic factor of both disease-free survival (p = 0.04 and overall survival (p = 0.032 in resected esophageal cancer. These results show that LVI assessment identifies patients at high risk for regional lymph node metastasis and that LVI is an independent prognostic factor in patients with esophageal cancer. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 90–97

  13. MicroRNA-184 acts as a potential diagnostic and prognostic marker in epithelial ovarian cancer and regulates cell proliferation, apoptosis and inflammation.

    Science.gov (United States)

    Qin, Chong-Zhen; Lou, Xiao-Ya; Lv, Qiao-Li; Cheng, Lin; Wu, Na-Yiyuan; Hu, Lei; Zhou, Hong-Hao

    2015-10-01

    MicroRNA-184 (miR-184) is found to be significantly deregulated in human cancers associated with tumorigenesis and progression. In this study, we aimed to investigate the role and mechanism of miR-184 expression in epithelial ovarian cancer (EOC). Relative expression of miR-184 was measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) in 80 EOC patients. Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-184. Function assays including cell proliferation, apoptosis and inflammation were further explored in vitro. We found that miR-184 was down-regulated in EOC tissues and cell lines compared with paired non-cancerous tissues and IOSE, respectively. Moreover, miR-184 was expressed at significantly lower levels in late-stage (III/IV) EOC tissues. Cox regression multivariate analysis indicated that miR-184 and FIGO stage were independent prognostic indicators for EOC patients. Patients with high miR-184 level achieved significantly a higher 5-year survival rate compared with low level group (P 184 over-expression could suppress EOC cell proliferation as well as inflammation and induce apoptosis in vitro. Altogether, our results suggest that miR-184 together with pathologic diagnosis is critical for prognosis determination in EOC patients and help select treatment strategy.

  14. CD4:CD8 Ratio and CD8 Count as Prognostic Markers for Mortality in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC).

    Science.gov (United States)

    Trickey, Adam; May, Margaret T; Schommers, Philipp; Tate, Jan; Ingle, Suzanne M; Guest, Jodie L; Gill, M John; Zangerle, Robert; Saag, Mike; Reiss, Peter; Monforte, Antonella d'Arminio; Johnson, Margaret; Lima, Viviane D; Sterling, Tim R; Cavassini, Matthias; Wittkop, Linda; Costagliola, Dominique; Sterne, Jonathan A C

    2017-09-15

    We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count. We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy (ART)-naive adults who started ART during 1996-2010, who were followed from the date they had CD4 count ≥350 cells/μL and were virologically suppressed (baseline). We used stratified Cox models to estimate unadjusted and adjusted (for sex, people who inject drugs, ART initiation year, and baseline age, CD4 count, AIDS, duration of ART) all-cause and cause-specific mortality hazard ratios for tertiles of CD4:CD8 ratio (0-0.40, 0.41-0.64 [reference], >0.64) and CD8 count (0-760, 761-1138 [reference], >1138 cells/μL) and examined the shape of associations using cubic splines. During 276526 person-years, 1834 of 49865 patients died (249 AIDS-related; 1076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11 (95% confidence interval [CI], 1.00-1.25). The association of CD8 count with all-cause mortality was U-shaped: aHR for higher vs middle tertile was 1.13 (95% CI, 1.01-1.26). AIDS-related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. There was little evidence that CD4:CD8 ratio or CD8 count was prognostic for non-AIDS mortality. In this large cohort collaboration, the magnitude of adjusted associations of CD4:CD8 ratio or CD8 count with mortality was too small for them to be useful as independent prognostic markers in virally suppressed patients on ART.

  15. Ubiquitin domain proteins in disease

    Directory of Open Access Journals (Sweden)

    Hartmann-Petersen Rasmus

    2007-11-01

    Full Text Available Abstract The human genome encodes several ubiquitin-like (UBL domain proteins (UDPs. Members of this protein family are involved in a variety of cellular functions and many are connected to the ubiquitin proteasome system, an essential pathway for protein degradation in eukaryotic cells. Despite their structural similarity, the UBL domains appear to have a range of different targets, resulting in a considerable diversity with respect to UDP function. Here, we give a short summary of the biochemical and physiological roles of the UDPs, which have been linked to human diseases including neurodegeneration and cancer. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com.

  16. Non-degradative Ubiquitination of Protein Kinases.

    Directory of Open Access Journals (Sweden)

    K Aurelia Ball

    2016-06-01

    Full Text Available Growing evidence supports other regulatory roles for protein ubiquitination in addition to serving as a tag for proteasomal degradation. In contrast to other common post-translational modifications, such as phosphorylation, little is known about how non-degradative ubiquitination modulates protein structure, dynamics, and function. Due to the wealth of knowledge concerning protein kinase structure and regulation, we examined kinase ubiquitination using ubiquitin remnant immunoaffinity enrichment and quantitative mass spectrometry to identify ubiquitinated kinases and the sites of ubiquitination in Jurkat and HEK293 cells. We find that, unlike phosphorylation, ubiquitination most commonly occurs in structured domains, and on the kinase domain, ubiquitination is concentrated in regions known to be important for regulating activity. We hypothesized that ubiquitination, like other post-translational modifications, may alter the conformational equilibrium of the modified protein. We chose one human kinase, ZAP-70, to simulate using molecular dynamics with and without a monoubiquitin modification. In Jurkat cells, ZAP-70 is ubiquitinated at several sites that are not sensitive to proteasome inhibition and thus may have other regulatory roles. Our simulations show that ubiquitination influences the conformational ensemble of ZAP-70 in a site-dependent manner. When monoubiquitinated at K377, near the C-helix, the active conformation of the ZAP-70 C-helix is disrupted. In contrast, when monoubiquitinated at K476, near the kinase hinge region, an active-like ZAP-70 C-helix conformation is stabilized. These results lead to testable hypotheses that ubiquitination directly modulates kinase activity, and that ubiquitination is likely to alter structure, dynamics, and function in other protein classes as well.

  17. A panel of prognostic protein markers for progression in non-muscle invasive bladder cancer - a multicenter tissue microarray validation study

    DEFF Research Database (Denmark)

    Fristrup, Niels; Birkenkamp-Demtröder, Karin; Ulhøi, Benedicte Parm

    2012-01-01

    cohort of 283 patients with long-term follow-up. For validation of the results we used three independent patient cohorts with long-term follow-up from Sweden, Spain, and Taiwan. In total 649 primary NMIBC tissue-microarray specimens from patients with long-term follow-up were used. Protein expression...... in the independent NMIBC cohort with long-term follow-up. These results will be presented at AACR annual meeting 2012. We conclude that ADAM10, TRIM29, Aurora Kinase B, and Cyclin D1 may have prognostic value for guiding optimal treatment of NMIBC patients if successfully validated in the independent patient cohorts...... Ta and T1 urothelial carcinomas. Transcripts from the five genes encoding these proteins were previously included in gene expression signatures for outcome prediction for non-muscle invasive bladder cancer (NMIBC). As a training-set, we used primary NMIBC tissue-microarray specimens from a Danish...

  18. Prognostication in young and elderly breast cancer patients

    NARCIS (Netherlands)

    Kruijff, Esther Michelle de

    2015-01-01

    Part I describes the prognostic effect and interactions of the immune system in breast cancer patients. Part II of the thesis describes the prognostic effect of these prognostic immune parameters and biomarkers molecular subtypes and stem cell marker ALDH-1, which are known to be strong breast

  19. Enhancement of CIITA transcriptional function by ubiquitin.

    Science.gov (United States)

    Greer, Susanna F; Zika, Eleni; Conti, Brian; Zhu, Xin-Sheng; Ting, Jenny P-Y

    2003-11-01

    Although increasing evidence indicates that there is a direct link between ubiquitination and mono-ubiquitination and transcription in yeast, this link has not been demonstrated in higher eukaryotes. Here we show that the major histocompatibility complex (MHC) class II transactivator (CIITA), which is required for expression of genes encoding MHC class II molecules, is ubiquitinated. This ubiquitination enhanced the association of CIITA with both MHC class II transcription factors and the MHC class II promoter, resulting in an increase in transactivation function and in the expression of MHC class II mRNA. The degree of CIITA ubiquitination was controlled by histone acetylases (HATs) and deacetylases (HDACs), indicating that the crucial cellular processes mediated by these enzymes are linked to regulate transcription. Thus, ubiquitin positively regulates a mammalian coactivator by enhancing its assembly at the promoter.

  20. Ubiquitin-binding proteins: similar, but different

    DEFF Research Database (Denmark)

    Andersen, Katrine M; Hofmann, Kay; Hartmann-Petersen, Rasmus

    2005-01-01

    described. UBA (ubiquitin-associated) domain-containing proteins is the largest family and includes members involved in different cell processes. The smaller groups of UIM (ubiquitin-interacting motif), GAT [GGA (Golgi-associated gamma-adaptin homologous) and Tom1 (target of Myb 1)], CUE (coupling......Covalent modification of proteins with ubiquitin is a common regulatory mechanism in eukaryotic cells. Typically, ubiquitinated proteins are targeted for degradation by the 26 S proteasome. However, more recently the ubiquitin signal has also been connected with many other cell processes, including...... endocytosis, vesicle fusion, DNA repair and transcriptional silencing. Hence ubiquitination may be comparable with phosphorylation in its importance as an intracellular switch, controlling various signal-transduction pathways. Similar to the regulation of the extent of phosphorylation by kinases...

  1. Neurofibrillary tangles in dementia pugilistica are ubiquitinated.

    OpenAIRE

    Dale, G E; Leigh, P. N.; P. Luthert; Anderton, B H; Roberts, G. W.

    1991-01-01

    Ubiquitin, a protein thought to be involved in the ATP-dependent non-lysosomal degradation of abnormal proteins, has already been identified as a component of neurofibrillary tangles in Alzheimer's disease. We have examined ubiquitin immunoreactivity in a unique collection of brains from 16 ex-boxers including 11 with dementia pugilistica. Neurofibrillary tangles of dementia pugilistica were labelled with an affinity purified antiserum to ubiquitin, and BF10, a monoclonal antibody to a neurof...

  2. Sites of ubiquitin attachment in Saccharomyces cerevisiae.

    Science.gov (United States)

    Starita, Lea M; Lo, Russell S; Eng, Jimmy K; von Haller, Priska D; Fields, Stanley

    2012-01-01

    Sites of ubiquitin modification have been identified by mass spectrometry based on the increase in molecular mass of a tryptic peptide carrying two additional glycine residues from the ubiquitin moiety. However, such peptides with GG shifts have been difficult to discover. We identify 870 unique sites of ubiquitin attachment on 438 different proteins of the yeast Saccharomyces cerevisiae. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Prognostic Significance of Melanoma Differentiation and Trans-Differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Maddodi, Nityanand; Setaluri, Vijayasaradhi, E-mail: setaluri@wisc.edu [Department of Dermatology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, B25, Madison WI 53706 (United States)

    2010-05-26

    Cutaneous malignant melanomas share a number of molecular attributes such as limitless replicative potential that define capabilities acquired by most malignancies. Accordingly, much effort has been focused on evaluating and validating protein markers related to these capabilities to function as melanoma prognostic markers. However, a few studies have also highlighted the prognostic value of markers that define melanocytic differentiation and the plasticity of melanoma cells to trans-differentiate along several other cellular pathways. Here, we provide a comprehensive review and evaluation of the prognostic significance of melanocyte-lineage markers such as MITF and melanogenic proteins, as well as markers of vascular epithelial and neuronal differentiation.

  4. Auto-ubiquitination of Mdm2 Enhances Its Substrate Ubiquitin Ligase Activity*

    Science.gov (United States)

    Ranaweera, Ruchira S.; Yang, Xiaolu

    2013-01-01

    The RING domain E3 ubiquitin ligase Mdm2 is the master regulator of the tumor suppressor p53. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Like most E3 ligases, Mdm2 can also ubiquitinate itself. How Mdm2 auto-ubiquitination may influence its substrate ubiquitin ligase activity is undefined. Here we show that auto-ubiquitination of Mdm2 is an activating event. Mdm2 that has been conjugated to polyubiquitin chains, but not to single ubiquitins, exhibits substantially enhanced activity to polyubiquitinate p53. Mechanistically, auto-ubiquitination of Mdm2 facilitates the recruitment of the E2 ubiquitin-conjugating enzyme. This occurs through noncovalent interactions between the ubiquitin chains on Mdm2 and the ubiquitin binding domain on E2s. Mutations that diminish the noncovalent interactions render auto-ubiquitination unable to stimulate Mdm2 substrate E3 activity. These results suggest a model in which polyubiquitin chains on an E3 increase the local concentration of E2 enzymes and permit the processivity of substrate ubiquitination. They also support the notion that autocatalysis may be a prevalent mode for turning on the activity of latent enzymes. PMID:23671280

  5. Nasopharyngeal and Oropharyngeal Colonization by Staphylococcus aureus and Streptococcus pneumoniae and Prognostic Markers in Children with Sickle Cell Disease from the Northeast of Brazil.

    Science.gov (United States)

    Rocha, Larissa C; Carvalho, Magda O S; Nascimento, Valma M L; Dos Santos, Milena S; Barros, Tânia F; Adorno, Elisângela V; Reis, Joice N; da Guarda, Caroline C; Santiago, Rayra P; Gonçalves, Marilda de Souza

    2017-01-01

    We investigated the nasopharynx and oropharynx microbiota in sickle cell disease (SCD) to identify the microorganisms, antibiotic sensitivity, prevalent serotypes, and association of with laboratorial markers. Oropharynx/nasopharynx secretions were investigated in 143 SCD children aging 6 months to 17 years. Pathogens were isolated using standard procedures, and laboratorial markers were performed by automated methods. Staphylococcus aureus (S. aureus) was isolated from nasopharynx and oropharynx of 64 and of 17 SCD children respectively. Streptococcus pneumoniae (S. pneumoniae) was isolated from the nasopharynx and oropharynx of eight SCD patients. Serotypes of S. pneumoniae were 19F, 23F, and 14. All isolates were susceptible to penicillin, and patients whose nasopharynx and oropharynx were colonized by S. pneumoniae had high concentrations of aspartate transaminase, alanine transaminase, and ferritin. S. pneumoniae isolated were not penicillin-resistant serotypes suggesting that the use of penicillin for prophylaxis and/or treatment of infections is safe. Our finding of colonization and laboratory evaluation in SCD patients suggests that microorganisms are involved in the modulation of chronic inflammatory. The association of colonized microorganisms and laboratorial markers suggest a new approach to these patients follow-up, and additional studies of microorganism colonization and their association with SCD patients' clinical outcome will improve control and prevention strategies.

  6. The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

    Science.gov (United States)

    Hooper, C E; Lyburn, I D; Searle, J; Darby, M; Hall, T; Hall, D; Morley, A; White, P; Rahman, N M; De Winton, E; Clive, A; Masani, V; Arnold, D T; Dangoor, A; Guglani, S; Jankowska, P; Lowndes, S A; Harvey, J E; Braybrooke, J P; Maskell, N A

    2015-03-31

    Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLRTGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

  7. High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy.

    Science.gov (United States)

    Blyme, Adam; Asferg, Camilla; Nielsen, Olav W; Sehestedt, Thomas; Kesäniemi, Y Antero; Gohlke-Bärwolf, Christa; Boman, Kurt; Willenheimer, Ronnie; Ray, Simon; Nienaber, Christoph A; Rossebø, Anne; Wachtell, Kristian; Olsen, Michael H

    2015-01-01

    To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow-up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low-density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP. The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP. NCT00092677.

  8. Ubiquitin enzymes in the regulation of immune responses.

    Science.gov (United States)

    Ebner, Petra; Versteeg, Gijs A; Ikeda, Fumiyo

    2017-08-01

    Ubiquitination plays a central role in the regulation of various biological functions including immune responses. Ubiquitination is induced by a cascade of enzymatic reactions by E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase, and reversed by deubiquitinases. Depending on the enzymes, specific linkage types of ubiquitin chains are generated or hydrolyzed. Because different linkage types of ubiquitin chains control the fate of the substrate, understanding the regulatory mechanisms of ubiquitin enzymes is central. In this review, we highlight the most recent knowledge of ubiquitination in the immune signaling cascades including the T cell and B cell signaling cascades as well as the TNF signaling cascade regulated by various ubiquitin enzymes. Furthermore, we highlight the TRIM ubiquitin ligase family as one of the examples of critical E3 ubiquitin ligases in the regulation of immune responses.

  9. Diagnostic and prognostic values of antikeratin antibodies (AKA ...

    African Journals Online (AJOL)

    Ehab

    prognostic predictors 2. Antikeratin antibodies (AKA) are detectable at the time of initial diagnosis of adult. RA and its positivity may have prognostic significance in the disease course 3,4. Furthermore, it is considered now as one of the specific serological markers of RA 5. PIIINP is a marker of type III collagen synthesis as.

  10. Prognostic Value of Proliferation Markers: Immunohistochemical Ki-67 Expression and Cytometric S-Phase Fraction of Women with Breast Cancer in Libya

    Directory of Open Access Journals (Sweden)

    Eramah Ermiah, Abdelbaset Buhmeida, Fathi Abdalla, Ben Romdhane Khaled, Nada Salem, Seppo Pyrhönen, Yrjö Collan

    2012-01-01

    Full Text Available Background: We evaluated the association of the immunohistochemical Ki-67 expression, and S-phase fraction with clinicopathological variables and patient outcome.Patients and methods: Histological samples from 100 primary Libyan breast carcinoma patients were retrospectively studied with monoclonal antibody to Ki-67. S-phase fraction was determined by DNA image cytometry.Results: The median Ki-67 percentage for all tumors was 27.5%, ranging from 1 to 80% and the median S-phase fraction (SPF was 11%, ranging from 0 to 62 %. Tumors with high Ki-67 expression were found in 76% of patients and with high SPF values in 56%. Ki-67 expression was more frequent in tumors with high SPF than low SPF. High Ki-67 and high SPF were associated with advanced stages, poor differentiation of tumors, positive lymph nodes, and distant metastasis. The Ki-67 was associated with hormone receptor negative tumors. The SPF was higher in young patients (<50 years than in older patients. In the overall population (median follow-up 49 months, patients with high Ki-67 and high SPF had shorter survival time and predicted recurrence than patients with low Ki-67 and low SPF. In a Cox multivariate analysis, high SPF (p= 0.007, hormonal status (p= 0.001 and clinical stage (p=0.005 were independent predictors of disease-specific survival. The Ki-67 (p=0.065 in borderline significance proved to be independent predictor of disease-free survival. The SPF showed more statistically significance with a high grade of malignancy and survival time than Ki-67.Conclusions: The SPF value is useful cell proliferation marker to assess tumor prognosis. These markers may reflect the aggressive behavior of Libyan breast cancer and predict of the recurrence. It is therefore important to take these markers into consideration to select a high risk subgroup of the patients for intensive treatment.

  11. A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer.

    Science.gov (United States)

    Humphries, Matthew P; Sundara Rajan, Sreekumar; Droop, Alastair; Suleman, Charlotte A B; Carbone, Carmine; Nilsson, Cecilia; Honarpisheh, Hedieh; Cserni, Gabor; Dent, Jo; Fulford, Laura; Jordan, Lee B; Jones, J Louise; Kanthan, Rani; Litwiniuk, Maria; Di Benedetto, Anna; Mottolese, Marcella; Provenzano, Elena; Shousha, Sami; Stephens, Mark; Walker, Rosemary A; Kulka, Janina; Ellis, Ian O; Jeffery, Margaret; Thygesen, Helene H; Cappelletti, Vera; Daidone, Maria G; Hedenfalk, Ingrid A; Fjällskog, Marie-Louise; Melisi, Davide; Stead, Lucy F; Shaaban, Abeer M; Speirs, Valerie

    2017-05-15

    Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required. Clin Cancer Res; 23(10); 2575-83. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock.

    Science.gov (United States)

    Ríos-Toro, Juan-Jesús; Márquez-Coello, Mercedes; García-Álvarez, José-María; Martín-Aspas, Andrés; Rivera-Fernández, Ricardo; Sáez de Benito, Ana; Girón-González, José-Antonio

    2017-01-01

    The objective of this study was to explore the diagnostic and prognostic value of soluble triggering receptor expressed on myeloid cell 1 (sTREM-1), soluble cluster of differentiation 14 (sCD14), soluble cluster of differentiation 163 (sCD163), interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for patients with severe sepsis and septic shock in an intensive care unit (ICU). Fifty patients admitted at the ICU with the diagnosis of severe sepsis or septic shock were studied. SOFA and APACHE II scores as well as serum biomarkers were measured at days 0, 2 and 5. The influence of these variables on 28-day mortality was analyzed. Twenty healthy individuals served as controls. Baseline serum concentrations of sTREM-1, sCD163, IL-6 and PCT correlated with SOFA score. Only sTREM-1 levels correlated with APACHE II score. The 28-day mortality rate for all patients was 42%. The absence of risk factors for infection, presence of septic shock, baseline values of sCD14 and decrease of PCT and IL-6 from baseline to day 5 were variables associated to mortality in the univariate analysis. The unique independent factor associated to mortality in the multivariate analysis was a decrease of PCT higher than 50% from days 0 to 5. Serum levels of sTREM-1 are correlated with the severity of sepsis. A 50% decrease of PCT was the unique variable associated with survival in the multivariate analysis.

  13. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock.

    Directory of Open Access Journals (Sweden)

    Juan-Jesús Ríos-Toro

    Full Text Available The objective of this study was to explore the diagnostic and prognostic value of soluble triggering receptor expressed on myeloid cell 1 (sTREM-1, soluble cluster of differentiation 14 (sCD14, soluble cluster of differentiation 163 (sCD163, interleukin-6 (IL-6, procalcitonin (PCT, and C-reactive protein (CRP serum levels for patients with severe sepsis and septic shock in an intensive care unit (ICU.Fifty patients admitted at the ICU with the diagnosis of severe sepsis or septic shock were studied. SOFA and APACHE II scores as well as serum biomarkers were measured at days 0, 2 and 5. The influence of these variables on 28-day mortality was analyzed. Twenty healthy individuals served as controls.Baseline serum concentrations of sTREM-1, sCD163, IL-6 and PCT correlated with SOFA score. Only sTREM-1 levels correlated with APACHE II score. The 28-day mortality rate for all patients was 42%. The absence of risk factors for infection, presence of septic shock, baseline values of sCD14 and decrease of PCT and IL-6 from baseline to day 5 were variables associated to mortality in the univariate analysis. The unique independent factor associated to mortality in the multivariate analysis was a decrease of PCT higher than 50% from days 0 to 5.Serum levels of sTREM-1 are correlated with the severity of sepsis. A 50% decrease of PCT was the unique variable associated with survival in the multivariate analysis.

  14. Expression of E-cadherin and β-catenin in basaloid and conventional squamous cell carcinoma of the oral cavity: are potential prognostic markers?

    Science.gov (United States)

    Hanemann, João Adolfo Costa; Oliveira, Denise Tostes; Nonogaki, Suely; Nishimoto, Inês Nobuko; de Carli, Marina Lara; Landman, Gilles; Kowalski, Luiz Paulo

    2014-06-03

    Basaloid squamous cell carcinoma presents with a preference for the head and neck region, and shows a distinct aggressive behavior, with frequent local recurrences, regional and distant metastasis. The alterations in the cadherin-catenin complex are fundamental requirements for the metastasis process, and this is the first study to evaluate the immunostaining of E-cadherin and β-catenin in oral basaloid squamous cell carcinoma. Seventeen cases of this tumor located exclusively in the mouth were compared to 26 cases of poorly differentiated squamous cell carcinoma and 28 cases of well to moderately differentiated squamous cell carcinoma matched by stage and tumor site. The immunostaining of E-cadherin and β-catenin were evaluated in the three groups and compared to their clinicopathological features and prognosis. For groups poorly differentiated squamous cell carcinoma and basaloid squamous cell carcinoma, reduction or absence of E-cadherin staining was observed in more than 80.0% of carcinomas, and it was statistically significant compared to well to moderately differentiated squamous cell carcinoma (p = .019). A strong expression of β-catenin was observed in 26.9% and 20.8% of well to moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma, respectively, and in 41.2% of basaloid squamous cell carcinoma. The 5-year and 10-year overall and disease-free survival rates demonstrated no significant differences among all three groups. The clinical and biological behavior of three groups of the oral cavity tumors evaluated are similar. E-cadherin and β-catenin immunostaining showed no prognostic value for basaloid and conventional squamous cell carcinomas.

  15. Ubiquitination in Periodontal Disease: A Review

    Science.gov (United States)

    Tsuchida, Sachio; Satoh, Mamoru; Takiwaki, Masaki; Nomura, Fumio

    2017-01-01

    Periodontal disease (periodontitis) is a chronic inflammatory condition initiated by microbial infection that leads to gingival tissue destruction and alveolar bone resorption. The periodontal tissue’s response to dental plaque is characterized by the accumulation of polymorphonuclear leukocytes, macrophages, and lymphocytes, all of which release inflammatory mediators and cytokines to orchestrate the immunopathogenesis of periodontal disease. Ubiquitination is achieved by a mechanism that involves a number of factors, including an ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, and ubiquitin–protein ligase. Ubiquitination is a post-translational modification restricted to eukaryotes that are involved in essential host processes. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Increasing numbers of recent reports have provided evidence that many approaches are delivering promising reports for discovering the relationship between ubiquitination and periodontal disease. The scope of this review was to investigate recent progress in the discovery of ubiquitinated protein in diseased periodontium and to discuss the ubiquitination process in periodontal diseases. PMID:28698506

  16. P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27.

    Science.gov (United States)

    Fanelli, Mariel A; Montt-Guevara, Magdalena; Diblasi, Angela M; Gago, Francisco E; Tello, Olga; Cuello-Carrión, F Darío; Callegari, Eduardo; Bausero, Maria A; Ciocca, Daniel R

    2008-01-01

    The cadherin-catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin-catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin-catenin cell adhesion system. Beta-catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between beta-catenin and Hsp27. However, beta-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-beta-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography-tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, beta-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, beta-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when beta-catenin was present in the cytoplasm of the tumor cells and not when beta-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin-catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of beta-catenin in

  17. Molecular profiling of multiple human cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic cancer marker.

    Directory of Open Access Journals (Sweden)

    Saleh M Rachidi

    Full Text Available Immune evasion is one of the recognized hallmarks of cancer. Inflammatory responses to cancer can also contribute directly to oncogenesis. Since the immune system is hardwired to protect the host, there is a possibility that cancers, regardless of their histological origins, endow themselves with a common and shared inflammatory cancer-associated molecular pattern (iCAMP to promote oncoinflammation. However, the definition of iCAMP has not been conceptually and experimentally investigated.Genome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens from 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. A total of 96 inflammatory genes with consistent dysregulation were identified, including 44 up-regulated and 52 down-regulated genes. Protein expression was confirmed by immunohistochemistry for some of these genes. The iCAMP contains proteins whose roles in cancer have been implicated and others which are yet to be appreciated. The clinical significance of many iCAMP genes was confirmed in multiple independent cohorts of colon and ovarian cancer patients. In both cases, better prognosis correlated strongly with high CXCL13 and low level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An "Inflammatory Gene Integrated Score" was further developed from the combination of 18 iCAMP genes in ovarian cancer, which predicted overall survival. Noticeably, as a selective nuclear import protein whose immuno-regulatory function just begins to emerge, karyopherin alpha 2 (KPNA2 is uniformly up-regulated across cancer types. For the first time, the cancer-specific up-regulation of KPNA2 and its clinical significance were verified by tissue microarray analysis in colon and head-neck cancers.This work defines an inflammatory signature shared by seven epithelial cancer types and KPNA2 as a consistently up-regulated protein in cancer. Identification of iCAMP may not only serve as a novel biomarker for prognostication

  18. Serum Cytokinome Profile Evaluation: A Tool to Define New Diagnostic and Prognostic Markers of Cancer Using Multiplexed Bead-Based Immunoassays

    Directory of Open Access Journals (Sweden)

    Francesca Capone

    2016-01-01

    Full Text Available In recent years, many researchers are focusing their attention on the link between inflammation and cancer. The inflammation is involved in the tumor development and suppression, by stimulating the immune response. In particular, the transition from chronic inflammation to cancer produces angiogenic and growth factors able to repair the tissue and to promote cancer cell survival, implantation, and growth. In this contest, the cytokines contribute to the development of these processes becoming active before and during the inflammatory process and playing an important function at the various disease levels. Thus, these proteins can represent specific markers of tumor development and progression. Therefore the “cytokinome” term is used to indicate the evaluation of cytokine pattern by using an “omics” approach. Newly, specific protein chips of considerable and improved sensitivity are being developed to determine simultaneously several and different cytokines. This can be achieved by a multiplex technology that, through the use of small amounts of serum or other fluids, is used to determine the presence and the levels of underrepresented cytokines. Since this method is an accurate, sensitive, and reproducible cytokine assay, it is already used in many different studies. Thus, this review focuses on the more latest aspects related to cytokinome profile evaluation in different cancers.

  19. Serum Cytokinome Profile Evaluation: A Tool to Define New Diagnostic and Prognostic Markers of Cancer Using Multiplexed Bead-Based Immunoassays.

    Science.gov (United States)

    Capone, Francesca; Guerriero, Eliana; Sorice, Angela; Colonna, Giovanni; Ciliberto, Gennaro; Costantini, Susan

    2016-01-01

    In recent years, many researchers are focusing their attention on the link between inflammation and cancer. The inflammation is involved in the tumor development and suppression, by stimulating the immune response. In particular, the transition from chronic inflammation to cancer produces angiogenic and growth factors able to repair the tissue and to promote cancer cell survival, implantation, and growth. In this contest, the cytokines contribute to the development of these processes becoming active before and during the inflammatory process and playing an important function at the various disease levels. Thus, these proteins can represent specific markers of tumor development and progression. Therefore the "cytokinome" term is used to indicate the evaluation of cytokine pattern by using an "omics" approach. Newly, specific protein chips of considerable and improved sensitivity are being developed to determine simultaneously several and different cytokines. This can be achieved by a multiplex technology that, through the use of small amounts of serum or other fluids, is used to determine the presence and the levels of underrepresented cytokines. Since this method is an accurate, sensitive, and reproducible cytokine assay, it is already used in many different studies. Thus, this review focuses on the more latest aspects related to cytokinome profile evaluation in different cancers.

  20. Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

    Science.gov (United States)

    Ito, Daisuke; Yogosawa, Satomi; Mimoto, Rei; Hirooka, Shinichi; Horiuchi, Takashi; Eto, Ken; Yanaga, Katsuhiko; Yoshida, Kiyotsugu

    2017-08-01

    Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  1. The ubiquitin system, disease, and drug discovery

    Directory of Open Access Journals (Sweden)

    Petroski Matthew D

    2008-10-01

    Full Text Available Abstract The ubiquitin system of protein modification has emerged as a crucial mechanism involved in the regulation of a wide array of cellular processes. As our knowledge of the pathways in this system has grown, so have the ties between the protein ubiquitin and human disease. The power of the ubiquitin system for therapeutic benefit blossomed with the approval of the proteasome inhibitor Velcade in 2003 by the FDA. Current drug discovery activities in the ubiquitin system seek to (i expand the development of new proteasome inhibitors with distinct mechanisms of action and improved bioavailability, and (ii validate new targets. This review summarizes our current understanding of the role of the ubiquitin system in various human diseases ranging from cancer, viral infection and neurodegenerative disorders to muscle wasting, diabetes and inflammation. I provide an introduction to the ubiquitin system, highlight some emerging relationships between the ubiquitin system and disease, and discuss current and future efforts to harness aspects of this potentially powerful system for improving human health. Publication history Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com.

  2. Atg5-independent sequestration of ubiquitinated mycobacteria.

    Directory of Open Access Journals (Sweden)

    Cathleen A Collins

    2009-05-01

    Full Text Available Like several other intracellular pathogens, Mycobacterium marinum (Mm escapes from phagosomes into the host cytosol where it can polymerize actin, leading to motility that promotes spread to neighboring cells. However, only approximately 25% of internalized Mm form actin tails, and the fate of the remaining bacteria has been unknown. Here we show that cytosolic access results in a new and intricate host pathogen interaction: host macrophages ubiquitinate Mm, while Mm shed their ubiquitinated cell walls. Phagosomal escape and ubiquitination of Mm occurred rapidly, prior to 3.5 hours post infection; at the same time, ubiquitinated Mm cell wall material mixed with host-derived dense membrane networks appeared in close proximity to cytosolic bacteria, suggesting cell wall shedding and association with remnants of the lysed phagosome. At 24 hours post-infection, Mm that polymerized actin were not ubiquitinated, whereas ubiquitinated Mm were found within LAMP-1-positive vacuoles resembling lysosomes. Though double membranes were observed which sequestered Mm away from the cytosol, targeting of Mm to the LAMP-1-positive vacuoles was independent of classical autophagy, as demonstrated by absence of LC3 association and by Atg5-independence of their formation. Further, ubiquitination and LAMP-1 association did not occur with mutant avirulent Mm lacking ESX-1 (type VII secretion, which fail to escape the primary phagosome; apart from its function in phagosome escape, ESX-1 was not directly required for Mm ubiquitination in macrophages or in vitro. These data suggest that virulent Mm follow two distinct paths in the cytosol of infected host cells: bacterial ubiquitination is followed by sequestration into lysosome-like organelles via an autophagy-independent pathway, while cell wall shedding may allow escape from this fate to permit continued residence in the cytosol and formation of actin tails.

  3. Aberrant Promoter Methylation of Protocadherin8 (PCDH8) in Serum is a Potential Prognostic Marker for Low Gleason Score Prostate Cancer.

    Science.gov (United States)

    Lin, Ying-Li; Li, Yan-Li; Ma, Jian-Guo

    2017-10-13

    BACKGROUND PCDH8 is a newly-discovered suppressor gene that is frequently inactivated by aberrant methylation in several human cancers, including prostate cancer. The identification of PCDH8 methylation can be used as a potential predictive biomarker. Prostate cancer patients with high Gleason score are considered as being at high risk for tumor recurrence and progression, and adjuvant therapy is often routinely performed in clinical practice. In the present study, we did not measure the methylation of PCDH8 in these patients. The main purpose of the present study was to evaluate the clinical significance of PCDH8 methylation in serum of prostate cancer patients with low Gleason score. MATERIAL AND METHODS PCDH8 methylation in serum samples of 117 patients and 47 controls was checked by methylation-specific PCR (MSP). Then, we correlated PCDH8 methylation status with the clinicopathological parameters of prostate cancer patients with low Gleason score and patient outcomes. RESULTS We found that PCDH8 was more frequently methylated in serum samples of patients with prostate cancer than in controls. PCDH8 methylation was correlated with advanced clinical stage (P=0.021), higher level of preoperative PSA (P=0.008), and positive lymph node metastasis (P=0.010). Moreover, patients with PCDH8 methylation had worse biochemical recurrence (BCR)-free survival (PGleason score were: PCDH8 methylation in serum (Exp (B)=3.147, 95% CI: 1.152-7.961, P=0.007), clinical stage (Exp (B)=2.53, 95% CI: 1.032-4.763, P=0.025) and lymph node status (Exp (B)=1.476, 95% CI: 1.107-4.572, P=0.042). CONCLUSIONS Our study indicated that PCDH8 methylation in serum occurred frequently in prostate cancer patients and was correlated with risk factors for poor outcome. The methylation of PCDH8 in serum is a potential predictive marker for prostate cancer patients with low Gleason score after surgery.

  4. Met expression is an independent prognostic risk factor in patients with oesophageal adenocarcinoma

    NARCIS (Netherlands)

    J.B. Tuynman; S.M. Lagarde (Sjoerd); F.J.W. ten Kate (Fiebo); D.J. Richel (Dirk); J.J.B. van Lanschot (Jan)

    2008-01-01

    textabstractOesophageal adenocarcinoma is an aggressive malignancy with propensity for early lymphatic and haematogenous dissemination. Since conventional TNM staging does not provide accurate prognostic information, novel molecular prognostic markers and potential therapeutic targets are subject of

  5. Met expression is an independent prognostic risk factor in patients with oesophageal adenocarcinoma

    NARCIS (Netherlands)

    Tuynman, J. B.; Lagarde, S. M.; ten Kate, F. J. W.; Richel, D. J.; van Lanschot, J. J. B.

    2008-01-01

    Oesophageal adenocarcinoma is an aggressive malignancy with propensity for early lymphatic and haematogenous dissemination. Since conventional TNM staging does not provide accurate prognostic information, novel molecular prognostic markers and potential therapeutic targets are subject of intense

  6. Met1-linked Ubiquitination in Immune Signalling

    DEFF Research Database (Denmark)

    Fiil, Berthe Katrine; Gyrd-Hansen, Mads

    2014-01-01

    identification of physiological substrates for Met1-Ub in response to activation of innate immune receptors. These discoveries have significantly advanced our understanding of how non-degradative ubiquitin modifications control pro-inflammatory responses mediated by nuclear factor κB and mitogen......Methionine 1-linked ubiquitin chains (Met1-Ub), or linear ubiquitin, has emerged as a central post-translational modification in innate immune signalling. Molecular machinery that assembles, senses and, more recently, disassembles Met1-Ub has been identified, and technical advances have enabled...

  7. Prognostic stratification of ulcerated melanoma

    DEFF Research Database (Denmark)

    Bønnelykke-Behrndtz, Marie L; Schmidt, Henrik; Christensen, Ib J

    2014-01-01

    OBJECTIVES: For patients with melanoma, ulceration is an important prognostic marker and interestingly also a predictive marker for the response of adjuvant interferon. A consensual definition and accurate assessment of ulceration are therefore crucial for proper staging and clinical management. We...... stratification of ulcerated lesions. METHODS: From H&E-stained sections, the status (presence vs absence), extent (percentage of the total tumor length), and type (infiltrative vs attenuative) of ulceration and epidermal involvement were evaluated from 385 patients with cutaneous melanoma. RESULTS: The presence...... of ulceration (hazard ratio [HR], 1.83), an attenuative type of ulceration (HR, 3.02), and excessive ulceration (HR, 3.57) were independent predictors of poor melanoma-specific survival. Further subdivision of minimal/moderate ulceration showed independent prognostic value only for lesions with epidermal...

  8. Aircraft Anomaly Prognostics Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Ridgetop Group will leverage its proven Electromechanical Actuator (EMA) prognostics methodology to develop an advanced model-based actuator prognostic reasoner...

  9. Ubiquitination of specific mitochondrial matrix proteins

    Energy Technology Data Exchange (ETDEWEB)

    Lehmann, Gilad [The Janet and David Polak Tumor and Vascular Biology Research Center and the Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Haifa, 31096 (Israel); Ziv, Tamar [The Smoler Proteomics Center, Faculty of Biology – Technion-Israel Institute of Technology, Haifa, 32000 (Israel); Braten, Ori [The Janet and David Polak Tumor and Vascular Biology Research Center and the Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Haifa, 31096 (Israel); Admon, Arie [The Smoler Proteomics Center, Faculty of Biology – Technion-Israel Institute of Technology, Haifa, 32000 (Israel); Udasin, Ronald G. [The Janet and David Polak Tumor and Vascular Biology Research Center and the Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Haifa, 31096 (Israel); Ciechanover, Aaron, E-mail: aaroncie@tx.technion.ac.il [The Janet and David Polak Tumor and Vascular Biology Research Center and the Technion Integrated Cancer Center (TICC), The Rappaport Faculty of Medicine and Research Institute, Haifa, 31096 (Israel)

    2016-06-17

    Several protein quality control systems in bacteria and/or mitochondrial matrix from lower eukaryotes are absent in higher eukaryotes. These are transfer-messenger RNA (tmRNA), The N-end rule ATP-dependent protease ClpAP, and two more ATP-dependent proteases, HslUV and ClpXP (in yeast). The lost proteases resemble the 26S proteasome and the role of tmRNA and the N-end rule in eukaryotic cytosol is performed by the ubiquitin proteasome system (UPS). Therefore, we hypothesized that the UPS might have substituted these systems – at least partially – in the mitochondrial matrix of higher eukaryotes. Using three independent experimental approaches, we demonstrated the presence of ubiquitinated proteins in the matrix of isolated yeast mitochondria. First, we show that isolated mitochondria contain ubiquitin (Ub) conjugates, which remained intact after trypsin digestion. Second, we demonstrate that the mitochondrial soluble fraction contains Ub-conjugates, several of which were identified by mass spectrometry and are localized to the matrix. Third, using immunoaffinity enrichment by specific antibodies recognizing digested ubiquitinated peptides, we identified a group of Ub-modified matrix proteins. The modification was further substantiated by separation on SDS-PAGE and immunoblots. Last, we attempted to identify the ubiquitin ligase(s) involved, and identified Dma1p as a trypsin-resistant protein in our mitochondrial preparations. Taken together, these data suggest a yet undefined role for the UPS in regulation of the mitochondrial matrix proteins. -- Highlights: •Mitochondrial matrix contains ubiquitinated proteins. •Ubiquitination occurs most probably in the matrix. •Dma1p is a ubiquitin ligase present in mitochondrial preparations.

  10. Prokaryotic Ubiquitin-Like Protein Modification

    OpenAIRE

    Maupin-Furlow, Julie A.

    2014-01-01

    Prokaryotes form ubiquitin (Ub)-like isopeptide bonds on the lysine residues of proteins by at least two distinct pathways that are reversible and regulated. In mycobacteria, the C-terminal Gln of Pup (prokaryotic ubiquitin-like protein) is deamidated and isopeptide linked to proteins by a mechanism distinct from ubiquitylation in enzymology yet analogous to ubiquitylation in targeting proteins for destruction by proteasomes. Ub-fold proteins of archaea (SAMPs, small archaeal modifier protein...

  11. Valoración de la glucemia sérica como marcador pronóstico en el paciente séptico crítico Assessment of serum glycemia as a prognostic marker in critically septic patient

    Directory of Open Access Journals (Sweden)

    Hilev de las Mercedes Larrondo Muguercia

    2010-12-01

    Full Text Available La glucemia es factor de riesgo de infección, sin embargo, no existen evidencias suficientes que permitan utilizarla como marcador pronóstico de mortalidad en el paciente séptico crítico. Se realizó un estudio longitudinal y prospectivo, para evaluar la utilidad de la glucemia como factor pronóstico de mortalidad en pacientes sépticos críticos. Se incluyeron 206 pacientes que ingresaron de forma consecutiva en la Terapia Intensiva (piso 8 del Hospital "Hermanos Ameijeiras". La gravedad se evaluó a través de la escala Simplified Acute Physiology Score (SAPS-3. Se midió el valor diario de glucemia en ayunas durante los primeros 6 días de estadía, el valor más alto de los 3 primeros días y la diferencia de valores entre el tercer y el primer día. Se aplicó el coeficiente de correlación de Spearman para variables cuantitativas. Se estudió el valor independiente de la variable mediante varios modelos de regresión logística. Se consideró una significación estadística de pGlycemia is a infection risk factor, however, there are not enough evidences allowing its use as a prognostic marker of mortality in critical septic patients. Study includes 206 patients admitted in a consecutive way in Intensive Therapy Care (eight floor of the "Hermanos Ameijeiras" Clinical Surgical Hospital. Severity was assessed according to the Simplified Acute Physiology Score scale (SAPS-3. The fasting daily value of glycemia was measured for the first 6 days of stay, the higher value during the 3 first days and the values difference between the third and the first day. The Spearmen's correlation coefficient was applied for quantitative variables. The independent value of the variable was studied using several logistic regression forms. A statistic significance of p<0,05 was considered. There was association between SAPS-3 and the first day glycemia (p=0,01. Glycemia among the living and death persons haven't significant differences. The higher value of

  12. HUWE1 and TRIP12 Collaborate in Degradation of Ubiquitin-Fusion Proteins and Misframed Ubiquitin

    DEFF Research Database (Denmark)

    Poulsen, Esben G; Steinhauer, Cornelia; Lees, Michael

    2012-01-01

    In eukaryotic cells an uncleavable ubiquitin moiety conjugated to the N-terminus of a protein signals the degradation of the fusion protein via the proteasome-dependent ubiquitin fusion degradation (UFD) pathway. In yeast the molecular mechanism of the UFD pathway has been well characterized. Rec...

  13. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers

    DEFF Research Database (Denmark)

    Schwertman, Petra; Bekker-Jensen, Simon; Mailand, Niels

    2016-01-01

    DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. The swift recognition and faithful repair of such damage is crucial for the maintenance of genomic stability, as well as for cell and organismal fitness. Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs...

  14. Cellular contractility requires ubiquitin mediated proteolysis.

    Directory of Open Access Journals (Sweden)

    Yuval Cinnamon

    Full Text Available BACKGROUND: Cellular contractility, essential for cell movement and proliferation, is regulated by microtubules, RhoA and actomyosin. The RhoA dependent kinase ROCK ensures the phosphorylation of the regulatory Myosin II Light Chain (MLC Ser19, thereby activating actomyosin contractions. Microtubules are upstream inhibitors of contractility and their depolymerization or depletion cause cells to contract by activating RhoA. How microtubule dynamics regulates RhoA remains, a major missing link in understanding contractility. PRINCIPAL FINDINGS: We observed that contractility is inhibited by microtubules not only, as previously reported, in adherent cells, but also in non-adhering interphase and mitotic cells. Strikingly we observed that contractility requires ubiquitin mediated proteolysis by a Cullin-RING ubiquitin ligase. Inhibition of proteolysis, ubiquitination and neddylation all led to complete cessation of contractility and considerably reduced MLC Ser19 phosphorylation. CONCLUSIONS: Our results imply that cells express a contractility inhibitor that is degraded by ubiquitin mediated proteolysis, either constitutively or in response to microtubule depolymerization. This degradation seems to depend on a Cullin-RING ubiquitin ligase and is required for cellular contractions.

  15. Identification of Prostate Cancer Prognostic Markers

    Science.gov (United States)

    2014-10-01

    GABARAPL2 and LC3-I (to pcDNA-6 +siControl and normalized to actin). pcD NA -6 + siC ont rol pcD NA -6 + siG ate 16a pcD NA -6- GA BA RA PL2 +s iCo ntr...ol pcD NA 6-G AB AR AP L+s iGa te1 6a pcD NA 6 + siC ont rol pcD NA 6 + siG ate 16a pcD NA 6-G AB AR AP L2 +si Co ntr ol pcD NA -6- GA BA RA PL

  16. Identification of Prostate Cancer Prognostic Markers

    Science.gov (United States)

    2015-10-01

    differential basal expression of the ECI1 protein to perform overexpression; PC-3 (low) and 22Rv1 (high). 72 hours post transfection of PC-3 cells...inhibitor RAD001 augments radiation-induced growth inhibition in a hepatocellular carcinoma cell line by increasing autophagy. Int J Oncol, 2012. 41(4): p...that downregulation of GABARAPL2 with 2 different siRNAs significantly reduced cell growth, and that this effect was rescued by re- expressing

  17. Ubiquitin Accumulation on Disease Associated Protein Aggregates Is Correlated with Nuclear Ubiquitin Depletion, Histone De-Ubiquitination and Impaired DNA Damage Response.

    Directory of Open Access Journals (Sweden)

    Adi Ben Yehuda

    Full Text Available Deposition of ubiquitin conjugates on inclusion bodies composed of protein aggregates is a definitive cytopathological hallmark of neurodegenerative diseases. We show that accumulation of ubiquitin on polyQ IB, associated with Huntington's disease, is correlated with extensive depletion of nuclear ubiquitin and histone de-ubiquitination. Histone ubiquitination plays major roles in chromatin regulation and DNA repair. Accordingly, we observe that cells expressing IB fail to respond to radiomimetic DNA damage, to induce gamma-H2AX phosphorylation and to recruit 53BP1 to damaged foci. Interestingly ubiquitin depletion, histone de-ubiquitination and impaired DNA damage response are not restricted to PolyQ aggregates and are associated with artificial aggregating luciferase mutants. The longevity of brain neurons depends on their capacity to respond to and repair extensive ongoing DNA damage. Impaired DNA damage response, even modest one, could thus lead to premature neuron aging and mortality.

  18. Regulation of GPCR Trafficking by Ubiquitin.

    Science.gov (United States)

    Kennedy, Justine E; Marchese, Adriano

    2015-01-01

    G protein-coupled receptor (GPCR)-promoted signaling mediates cellular responses to a variety of stimuli involved in diverse physiological processes. In addition, GPCRs are also the largest class of target for many drugs used to treat a variety of diseases. Despite the role of GPCR signaling in health and disease, the molecular mechanisms governing GPCR signaling remain poorly understanding. Classically, GPCR signaling is tightly regulated by GPCR kinases and β-arrestins, which act in a concerted fashion to govern GPCR desensitization and also GPCR trafficking. Ubiquitination has now emerged as an important posttranslational modification that has multiple roles, either directly or indirectly, in governing GPCR trafficking. Recent studies have revealed a mechanistic link between GPCR phosphorylation, β-arrestins, and ubiquitination. Here, we review recent developments in our understanding of how ubiquitin regulates GPCR trafficking within the endocytic pathway. © 2015 Elsevier Inc. All rights reserved.

  19. Dss1 Is a 26S Proteasome Ubiquitin Receptor

    OpenAIRE

    Paraskevopoulos, Konstantinos; Kriegenburg, Franziska; Tatham, Michael H; Rösner, Heike I; Medina, Bethan; Larsen, Ida B; Brandstrup, Rikke; Hardwick, Kevin G; Hay, Ronald T; Kragelund, Birthe B; Hartmann-Petersen, Rasmus; Gordon, Colin

    2014-01-01

    Summary The ubiquitin-proteasome system is the major pathway for protein degradation in eukaryotic cells. Proteins to be degraded are conjugated to ubiquitin chains that act as recognition signals for the 26S proteasome. The proteasome subunits Rpn10 and Rpn13 are known to bind ubiquitin, but genetic and biochemical data suggest the existence of at least one other substrate receptor. Here, we show that the phylogenetically conserved proteasome subunit Dss1 (Sem1) binds ubiquitin chains linked...

  20. Principles of ubiquitin and SUMO modifications in DNA repair

    NARCIS (Netherlands)

    Bergink, Steven; Jentsch, Stefan

    2009-01-01

    With the discovery in the late 1980s that the DNA-repair gene RAD6 encodes a ubiquitin-conjugating enzyme, it became clear that protein modification by ubiquitin conjugation has a much broader significance than had previously been assumed. Now, two decades later, ubiquitin and its cousin SUMO are

  1. The biology of melanoma prognostic factors.

    NARCIS (Netherlands)

    Spatz, A.; Stock, N.; Batist, G.; Kempen, L.C.L.T. van

    2010-01-01

    Cutaneous melanoma still represents a paradox among all solid tumors. It is the cancer for which the best prognostic markers ever identified in solid tumors are available, yet there is very little understanding of their biological significance. This review focuses on recent biological data that shed

  2. Ubiquitin in signaling and protein quality control

    DEFF Research Database (Denmark)

    Al-Saoudi, Sofie Vincents

    Protein ubiquitylation is an important post-translational modification that holds a variety of cellular functions. This Ph.D. thesis is comprised of two studies, of which one focused on ubiquitylation related to inflammatory signaling, and the other on the role of the ubiquitin-proteasome system ...

  3. Endosome-lysosomes, ubiquitin and neurodegeneration.

    Science.gov (United States)

    Mayer, R J; Tipler, C; Arnold, J; Laszlo, L; Al-Khedhairy, A; Lowe, J; Landon, M

    1996-01-01

    Before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. The application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including Alzheimer's disease (AD), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD) and scrapie) are related by some form of intraneuronal inclusion which contains ubiquitin protein conjugates. In addition, disorders such as Alzheimer's disease, CJD and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins which may be associated with cytoskeletal reorganisation. Although our knowledge about these diseases is increasing, they remain largely untreatable. Recently, attention has focused on the mechanisms of production of different types of amyloid and the likely involvement within cells of the endosome-lysosome system, organelles which are immuno-positive for ubiquitin protein conjugates. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials or their precursors which subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Such common features of the disease processes give new direction to therapeutic intervention.

  4. Copper-triggered aggregation of ubiquitin.

    Directory of Open Access Journals (Sweden)

    Fabio Arnesano

    Full Text Available Neurodegenerative disorders share common features comprising aggregation of misfolded proteins, failure of the ubiquitin-proteasome system, and increased levels of metal ions in the brain. Protein aggregates within affected cells often contain ubiquitin, however no report has focused on the aggregation propensity of this protein. Recently it was shown that copper, differently from zinc, nickel, aluminum, or cadmium, compromises ubiquitin stability and binds to the N-terminus with 0.1 micromolar affinity. This paper addresses the role of copper upon ubiquitin aggregation. In water, incubation with Cu(II leads to formation of spherical particles that can progress from dimers to larger conglomerates. These spherical oligomers are SDS-resistant and are destroyed upon Cu(II chelation or reduction to Cu(I. In water/trifluoroethanol (80:20, v/v, a mimic of the local decrease in dielectric constant experienced in proximity to a membrane surface, ubiquitin incubation with Cu(II causes time-dependent changes in circular dichroism and Fourier-transform infrared spectra, indicative of increasing beta-sheet content. Analysis by atomic force and transmission electron microscopy reveals, in the given order, formation of spherical particles consistent with the size of early oligomers detected by gel electrophoresis, clustering of these particles in straight and curved chains, formation of ring structures, growth of trigonal branches from the rings, coalescence of the trigonal branched structures in a network. Notably, none of these ubiquitin aggregates was positive to tests for amyloid and Cu(II chelation or reduction produced aggregate disassembly. The early formed Cu(II-stabilized spherical oligomers, when reconstituted in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC liposomes and in POPC planar bilayers, form annular and pore-like structures, respectively, which are common to several neurodegenerative disorders including Parkinson's, Alzheimer

  5. DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination.

    Science.gov (United States)

    Qin, Weihua; Wolf, Patricia; Liu, Nan; Link, Stephanie; Smets, Martha; La Mastra, Federica; Forné, Ignasi; Pichler, Garwin; Hörl, David; Fellinger, Karin; Spada, Fabio; Bonapace, Ian Marc; Imhof, Axel; Harz, Hartmann; Leonhardt, Heinrich

    2015-08-01

    DNMT1 is recruited by PCNA and UHRF1 to maintain DNA methylation after replication. UHRF1 recognizes hemimethylated DNA substrates via the SRA domain, but also repressive H3K9me3 histone marks with its TTD. With systematic mutagenesis and functional assays, we could show that chromatin binding further involved UHRF1 PHD binding to unmodified H3R2. These complementation assays clearly demonstrated that the ubiquitin ligase activity of the UHRF1 RING domain is required for maintenance DNA methylation. Mass spectrometry of UHRF1-deficient cells revealed H3K18 as a novel ubiquitination target of UHRF1 in mammalian cells. With bioinformatics and mutational analyses, we identified a ubiquitin interacting motif (UIM) in the N-terminal regulatory domain of DNMT1 that binds to ubiquitinated H3 tails and is essential for DNA methylation in vivo. H3 ubiquitination and subsequent DNA methylation required UHRF1 PHD binding to H3R2. These results show the manifold regulatory mechanisms controlling DNMT1 activity that require the reading and writing of epigenetic marks by UHRF1 and illustrate the multifaceted interplay between DNA and histone modifications. The identification and functional characterization of the DNMT1 UIM suggests a novel regulatory principle and we speculate that histone H2AK119 ubiquitination might also lead to UIM-dependent recruitment of DNMT1 and DNA methylation beyond classic maintenance.

  6. Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study

    Directory of Open Access Journals (Sweden)

    Wang Facheng

    2008-10-01

    Full Text Available Abstract Background p27Kip1 plays a major role as a negative regulator of the cell cycle. The regulation of p27Kip1 degradation is mediated by its specific ubiquitin ligase subunits S-phase kinase protein (Skp 2 and cyclin-dependent kinase subunit (Cks 1. However, little is known regarding the prognostic utility of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma. Methods Immunohistochemistry was performed for p27Kip1, Skp2 and Cks1 in tissue microarrays of 482 renal cell carcinomas with follow-up. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. Results Immunoreactivity of p27Kip1, Skp2 and Cks1 was noted in 357, 71 and 82 patients, respectively. Skp2 and Cks1 expression were not noted in chromophobe cancers. A strong correlation was found between Skp2 and Cks1 expression (P Kip1 levels (P = 0.006 and P Kip1 expression and Skp2 expression were correlated with larger tumor size and higher stage, as well as tumor necrosis. Cks1 expression was only correlated with tumor size. In univariate analysis, low p27Kip1 expression, Skp2 and Cks1 expression were all associated with a poor prognosis, while in multivariate analysis, only low p27Kip1 expression were independent prognostic factors for both cancer specific survival and recurrence-free survival in patients with RCC. Conclusion Our results suggest that immunohistochemical expression levels of p27Kip1, Skp2 and Cks1 may serve as markers with prognostic value in renal cell carcinoma.

  7. Comparison of the prognostic potential of biomechanic stress markers - circulating stromelysin-1, matrix metalloprteinase-9 and N-terminal fragment of brain natriuretic peptide in patients with acute Q-wave myocardial infarction. Results of cohort study

    Directory of Open Access Journals (Sweden)

    T. Samura

    2012-04-01

    Full Text Available 85 patients after documented Q-wave myocardial infarction (MI were observed. Echocardiography was performed and circulating levels of such biomarkers as MMP-3, MMP-9 and NT-pro-BNP were detected on the day of hospitalization and diagnosis of acute IM, on 21 and 60 days after onset of acute MI. The analysis of revealed data has shown that increase of MMP-3 and MMP-9 above optimal cut-point (9.7 ng/ml and 18.1 ng/ml respectively was closely associated with up of 1-year cardiovascular mortality risk in patients after Q-MI. Used in prognostic model analysis of content of circulating MMP-3 and MMP-9 is corelated with increase of positive prognostic value of both of them rising up to 70% (prognostic sensitivity and specify are 84% and 82% respectively.

  8. The immunosuppressive activity and solution structures of ubiquitin fragments.

    Science.gov (United States)

    Jaremko, Lukasz; Jaremko, Mariusz; Pasikowski, Paweł; Cebrat, Marek; Stefanowicz, Piotr; Lisowski, Marek; Artym, Jolanta; Zimecki, Michał; Zhukov, Igor; Szewczuk, Zbigniew

    2009-06-01

    Recently, ubiquitin was suggested as a promising anti-inflammatory protein therapeutic. We found that a peptide fragment corresponding to the ubiquitin(50-59) sequence (LEDGRTLSDY) possessed the immunosuppressive activity comparable with that of ubiquitin. CD and NMR spectroscopies were used to determine the conformational preferences of LEDGRTLSDY in solution. The peptide mixture, obtained by pepsin digestion of ubiquitin, was even more potent than the intact protein. Although the peptide exhibited a well-defined conformation in methanol, its structure was distinct from the corresponding 50-59 fragment in the native ubiquitin molecule. (c) 2009 Wiley Periodicals, Inc. Biopolymers 91: 423-431, 2009.

  9. Functional constraints on adaptive evolution of protein ubiquitination sites.

    Science.gov (United States)

    Lu, Liang; Li, Yang; Liu, Zhongyang; Liang, Fengji; Guo, Feifei; Yang, Shuai; Wang, Dan; He, Yangzhige; Xiong, Jianghui; Li, Dong; He, Fuchu

    2017-01-05

    It is still unclear whether there exist functional constraints on the evolution of protein ubiquitination sites, because most previous studies regarded all protein ubiquitination sites as a whole or only focused on limited structural properties. We tried to clarify the relation between functional constraints and ubiquitination sites evolution. We investigated the evolutionary conservation of human ubiquitination sites in a broad evolutionary scale from G. gorilla to S. pombe, and we found that in organisms originated after the divergence of vertebrate, ubiquitination sites are more conserved than their flanking regions, while the opposite tendency is observed before this divergence time. By grouping the ubiquitination proteins into different functional categories, we confirm that many functional constraints like certain molecular functions, protein tissue expression specificity and protein connectivity in protein-protein interaction network enhance the evolutionary conservation of ubiquitination sites. Furthermore, by analyzing the gains of ubiquitination sites at different divergence time and their functional characters, we validate that the emergences of ubiquitination sites at different evolutionary time were also affected by the uncovered functional constraints. The above results suggest that functional constraints on the adaptive evolution of ubiquitination sites increase the opportunity for ubiquitination to synthetically regulate various cellular and developmental processes during evolution.

  10. Prognostic value of various molecular and cellular features in oral squamous cell carcinomas: a review.

    Science.gov (United States)

    Bryne, M

    1991-10-01

    Recent findings of prognostic value for oral squamous cell carcinomas (OSCCs) which may supplement clinical staging are reviewed. Many reports show that histopathologic grading, measurements of tumor-thickness and DNA-content have independent prognostic value and may thus be of clinical value. Features regarding cells at the invading margins of the tumors are probably of higher prognostic value than features within other parts of the tumors. Reportedly, various other cellular and serum markers have prognostic associations worthwhile further research.

  11. Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability

    Directory of Open Access Journals (Sweden)

    Minghua Nie

    2016-02-01

    Full Text Available Covalent attachment of ubiquitin (Ub or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with selective readers in the proteome, ubiquitin and SUMO can elicit distinct cellular responses, such as directing DNA lesions into different repair pathways. On the other hand, through the action of the SUMO-targeted ubiquitin ligase (STUbL family proteins, ubiquitin and SUMO can cooperate in the form of a hybrid signal. These mixed SUMO-ubiquitin chains recruit “effector” proteins such as the AAA+ ATPase Cdc48/p97-Ufd1-Npl4 complex that contain both ubiquitin and SUMO interaction motifs. This review will summarize recent key findings on collaborative and distinct roles that ubiquitin and SUMO play in orchestrating DNA damage responses.

  12. Ubiquitin in Influenza Virus Entry and Innate Immunity.

    Science.gov (United States)

    Rudnicka, Alina; Yamauchi, Yohei

    2016-10-24

    Viruses are obligatory cellular parasites. Their mission is to enter a host cell, to transfer the viral genome, and to replicate progeny whilst diverting cellular immunity. The role of ubiquitin is to regulate fundamental cellular processes such as endocytosis, protein degradation, and immune signaling. Many viruses including influenza A virus (IAV) usurp ubiquitination and ubiquitin-like modifications to establish infection. In this focused review, we discuss how ubiquitin and unanchored ubiquitin regulate IAV host cell entry, and how histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase with ubiquitin-binding activity, mediates IAV capsid uncoating. We also discuss the roles of ubiquitin in innate immunity and its implications in the IAV life cycle.

  13. Post-translationally modified muscle-specific ubiquitin ligases as circulating biomarkers in experimental cancer cachexia

    Science.gov (United States)

    Mota, Roberto; Rodríguez, Jessica E; Bonetto, Andrea; O’Connell, Thomas M; Asher, Scott A; Parry, Traci L; Lockyer, Pamela; McCudden, Christopher R; Couch, Marion E; Willis, Monte S

    2017-01-01

    Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Up to 80% of cancer patients experience cachexia, with 20-30% of cancer-related deaths directly linked to cachexia. Despite efforts to identify early cachexia and cancer relapse, clinically useful markers are lacking. Recently, we identified the role of muscle-specific ubiquitin ligases Atrogin-1 (MAFbx, FBXO32) and Muscle Ring Finger-1 in the pathogenesis of cardiac atrophy and hypertrophy. We hypothesized that during cachexia, the Atrogin-1 and MuRF1 ubiquitin ligases are released from muscle and migrate to the circulation where they could be detected and serve as a cachexia biomarker. To test this, we induced cachexia in mice using the C26 adenocarcinoma cells or vehicle (control). Body weight, tumor volume, and food consumption were measured from inoculation until ~day 14 to document cachexia. Western blot analysis of serum identified the presence of Atrogin-1 and MuRF1 with unique post-translational modifications consistent with mono- and poly- ubiquitination of Atrogin-1 and MuRF1 found only in cachectic serum. These findings suggest that both increased Atrogin-1 and the presence of unique post-translational modifications may serve as a surrogate marker specific for cachexia. PMID:28979816

  14. CD4:CD8 Ratio and CD8 Count as Prognostic Markers for Mortality in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC)

    NARCIS (Netherlands)

    Trickey, Adam; May, Margaret T.; Schommers, Philipp; Tate, Jan; Ingle, Suzanne M.; Guest, Jodie L.; Gill, M. John; Zangerle, Robert; Saag, Mike; Reiss, Peter; Monforte, Antonella d'Arminio; Johnson, Margaret; Lima, Viviane D.; Sterling, Tim R.; Cavassini, Matthias; Wittkop, Linda; Costagliola, Dominique; Sterne, Jonathan A. C.; Boulle, Andrew; Stephan, Christoph; Miro, Jose M.; Chêne, Geneviève; Dabis, François; Monforte, Antonella D.'Arminio; del Amo, Julia; van Sighem, Ard; Vehreschild, Jorg Janne; Gill, John; Guest, Jodie; Haerry, David Hans-Ulrich; Hogg, Robert; Justice, Amy; Shepherd, Leah; Obel, Niels; Crane, Heidi M.; Smith, Colette; Saag, Michael; Sterling, Tim; Teira, Ramon; Williams, Matthew; Sterne, Jonathan; May, Margaret; Ingle, Suzanne

    2017-01-01

    We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count. We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy

  15. Prognostic biomarkers in osteoarthritis

    Science.gov (United States)

    Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

    2013-01-01

    Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

  16. The Ubiquitin System and Jasmonate Signaling

    Directory of Open Access Journals (Sweden)

    Astrid Nagels Durand

    2016-01-01

    Full Text Available The ubiquitin (Ub system is involved in most, if not all, biological processes in eukaryotes. The major specificity determinants of this system are the E3 ligases, which bind and ubiquitinate specific sets of proteins and are thereby responsible for target recruitment to the proteasome or other cellular processing machineries. The Ub system contributes to the regulation of the production, perception and signal transduction of plant hormones. Jasmonic acid (JA and its derivatives, known as jasmonates (JAs, act as signaling compounds regulating plant development and plant responses to various biotic and abiotic stress conditions. We provide here an overview of the current understanding of the Ub system involved in JA signaling.

  17. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.

    Science.gov (United States)

    Liu, Yaobin; Huang, Xiangao; He, Xian; Zhou, Yanqing; Jiang, Xiaogang; Chen-Kiang, Selina; Jaffrey, Samie R; Xu, Guoqiang

    2015-12-01

    The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin-4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48-linked polyubiquitin chains and that thalidomide blocks the formation of CRBN-ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin-4 RING E3 ligase-mediated degradation of target proteins. © FASEB.

  18. Ubiquitin and ubiquitin-like proteins in the nucleolus: multitasking tools for a ribosome factory.

    Science.gov (United States)

    Shcherbik, Natalia; Pestov, Dimitri G

    2010-07-01

    Synthesis of new ribosomes is an essential process upregulated during cell growth and proliferation. Here, we review our current understanding of the role that ubiquitin and ubiquitin-like proteins (UBLs) play in ribosome biogenesis, with a focus on mammalian cells. One important function of the nuclear ubiquitin-proteasome system is to control the supply of ribosomal proteins for the assembly of new ribosomal subunits in the nucleolus. Mutations in ribosomal proteins or ribosome assembly factors, stress, and many anticancer drugs have been shown to disrupt normal ribosome biogenesis, triggering a p53-dependent response. We discuss how p53 can be activated by the aberrant ribosome formation, centering on the current models of the interaction between ribosomal proteins released from the nucleolus and the ubiquitin ligase Mdm2. Recent studies also revealed multiple ubiquitin- and UBL-conjugated forms of nucleolar proteins with largely unknown functions, indicating that many new details about the role of these modifications in the nucleolus await to be discovered.

  19. Imaging markers for Alzheimer disease

    Science.gov (United States)

    Bocchetta, Martina; Chételat, Gael; Rabinovici, Gil D.; de Leon, Mony J.; Kaye, Jeffrey; Reiman, Eric M.; Scheltens, Philip; Barkhof, Frederik; Black, Sandra E.; Brooks, David J.; Carrillo, Maria C.; Fox, Nick C.; Herholz, Karl; Nordberg, Agneta; Jack, Clifford R.; Jagust, William J.; Johnson, Keith A.; Rowe, Christopher C.; Sperling, Reisa A.; Thies, William; Wahlund, Lars-Olof; Weiner, Michael W.; Pasqualetti, Patrizio; DeCarli, Charles

    2013-01-01

    Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials. PMID:23897875

  20. Microscopical evaluation of prognostic factors in colorectal cancer

    NARCIS (Netherlands)

    Mesker, Wilhelmina Engelina

    2008-01-01

    Aims and outline of the thesis. Since Fearon and Vogelstein in 1990 presented the genetic model for the adeno-carcinoma sequence of colorectal cancer, many prognostic studies varying from early stage markers to markers involved in late progression and liver metastases have followed. As has become

  1. Ubiquitination in the control of photoperiodic flowering.

    Science.gov (United States)

    Piñeiro, Manuel; Jarillo, José A

    2013-01-01

    Triggering flowering at the appropriate time is a key factor for the successful reproduction of plants. Daylength perception allows plants to synchronize flowering with seasonal changes, a process systematically analyzed in the model species Arabidopsis thaliana. Characterization of molecular components that participate in the photoperiodic control of floral induction has revealed that photoreceptors and the circadian oscillator interact in a complex manner to modulate the floral transition in response to daylength and in fact, photoperiodic flowering can be regarded as an output pathway of the circadian oscillator. Recent observations indicate that besides transcriptional regulation, the promotion of flowering in response to photoperiod appears to be also regulated by modulation of protein stability and degradation. Therefore, the ubiquitin/26S proteasome system for targeted protein degradation has emerged as a key element in photoperiodic flowering regulation. Different E3 ubiquitin ligases are involved in the proteolysis of a variety of photoperiod-regulated pathway components including photoreceptors, clock elements and flowering time proteins, all of which participate in the control of this developmental process. Given the large variety of plant ubiquitin ligase complexes, it is likely that new factors involved in mechanisms of protein-targeted degradation will soon be ascribed to various aspects of flowering time control. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Chaperones, but not oxidized proteins, are ubiquitinated after oxidative stress

    DEFF Research Database (Denmark)

    Kästle, Marc; Reeg, Sandra; Rogowska-Wrzesinska, Adelina

    2012-01-01

    After oxidative stress proteins which are oxidatively modified are degraded by the 20S proteasome. However, several studies documented an enhanced ubiquitination of yet unknown proteins. Since ubiqutination is a prerequisite for degradation by the 26S proteasome in an ATP-dependent manner...... this raises the question whether these proteins are also oxidized and, if not, what proteins need to be ubiquitinated and degraded after oxidative conditions. By determination of oxidized- and ubiquitinated proteins we demonstrate here that most oxidized proteins are not preferentially ubiquitinated. However......, we were able to confirm an increase of ubiquitinated proteins 16h upon oxidative stress. Therefore, we isolated ubiquitinated proteins from hydrogen peroxide treated cells, as well as from control and lactacystin, an irreversible proteasome inhibitor, treated cells, and identified some...

  3. Ubiquitin is part of the retrovirus budding machinery

    Science.gov (United States)

    Patnaik, Akash; Chau, Vincent; Wills, John W.

    2000-11-01

    Retroviruses contain relatively large amounts of ubiquitin, but the significance of this finding has been unknown. Here, we show that drugs that are known to reduce the level of free ubiquitin in the cell dramatically reduced the release of Rous sarcoma virus, an avian retrovirus. This effect was suppressed by overexpressing ubiquitin and also by directly fusing ubiquitin to the C terminus of Gag, the viral protein that directs budding and particle release. The block to budding was found to be at the plasma membrane, and electron microscopy revealed that the reduced level of ubiquitin results in a failure of mature virus particles to separate from each other and from the plasma membrane during budding. These data indicate that ubiquitin is actually part of the budding machinery.

  4. Prognostic Performance Metrics

    Data.gov (United States)

    National Aeronautics and Space Administration — This chapter presents several performance metrics for offline evaluation of prognostics algorithms. A brief overview of different methods employed for performance...

  5. Prognostics for Microgrid Components

    Science.gov (United States)

    Saxena, Abhinav

    2012-01-01

    Prognostics is the science of predicting future performance and potential failures based on targeted condition monitoring. Moving away from the traditional reliability centric view, prognostics aims at detecting and quantifying the time to impending failures. This advance warning provides the opportunity to take actions that can preserve uptime, reduce cost of damage, or extend the life of the component. The talk will focus on the concepts and basics of prognostics from the viewpoint of condition-based systems health management. Differences with other techniques used in systems health management and philosophies of prognostics used in other domains will be shown. Examples relevant to micro grid systems and subsystems will be used to illustrate various types of prediction scenarios and the resources it take to set up a desired prognostic system. Specifically, the implementation results for power storage and power semiconductor components will demonstrate specific solution approaches of prognostics. The role of constituent elements of prognostics, such as model, prediction algorithms, failure threshold, run-to-failure data, requirements and specifications, and post-prognostic reasoning will be explained. A discussion on performance evaluation and performance metrics will conclude the technical discussion followed by general comments on open research problems and challenges in prognostics.

  6. Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Hotaru [Course for Biological Sciences, Faculty of Science, Kumamoto University, Kumamoto (Japan); Saitoh, Hisato, E-mail: hisa@kumamoto-u.ac.jp [Course for Biological Sciences, Faculty of Science, Kumamoto University, Kumamoto (Japan); Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto (Japan)

    2016-07-29

    We have previously reported the co-localization of O-propargyl-puromycin (OP-Puro) with SUMO-2/3 and ubiquitin at promyelocytic leukemia-nuclear bodies (PML-NBs) in the presence of the proteasome inhibitor MG132, implying a role for the ubiquitin family in sequestering OP-puromycylated immature polypeptides to the nucleus during impaired proteasome activity. Here, we found that as expected puromycin induced SUMO-1/2/3 accumulation with ubiquitin at multiple nuclear foci in HeLa cells when co-exposed to MG132. Co-administration of puromycin and MG132 also facilitated redistribution of PML and the SUMO-targeted ubiquitin ligase RNF4 concurrently with SUMO-2/3. As removal of the drugs from the medium led to disappearance of the SUMO-2/3-ubiquitin nuclear foci, our findings indicated that nuclear assembly/disassembly of SUMO-2/3 and ubiquitin was pharmacologically manipulable, supporting our previous observation on OP-Puro, which predicted the ubiquitin family function in sequestrating aberrant proteins to the nucleus. -- Highlights: •Puromycin exhibits the O-propargyl-puromycin effect. •Puromycin induces SUMO redistribution upon proteasome inhibition. •Ubiquitin and RNF4 accumulate at PML-nuclear bodies with SUMO-2/3. •The ubiquitin family may function in nuclear sequestration of immature proteins.

  7. A systematic review and meta-analysis of diagnostic and prognostic serum biomarkers of colorectal cancer.

    Science.gov (United States)

    Liu, Zhongyu; Zhang, Yingchong; Niu, Yulong; Li, Ke; Liu, Xin; Chen, Huijuan; Gao, Chunfang

    2014-01-01

    Our systematic review summarizes the evidence concerning the accuracy of serum diagnostic and prognostic tests for colorectal cancer (CRC). The databases MEDLINE and EMBASE were searched iteratively to identify the relevant literature for serum markers of CRC published from 1950 to August 2012. The articles that provided adequate information to meet the requirements of the meta-analysis of diagnostic and prognostic markers were included. A 2-by-2 table of each diagnostic marker and its hazard ratio (HR) and the confidence interval (CI) of each prognostic marker was directly or indirectly extracted from the included papers, and the pooled sensitivity and specificity of the diagnostic marker and the pooled HR and the CI of the prognostic marker were subsequently calculated using the extracted data. In total, 104 papers related to the diagnostic markers and 49 papers related to the prognostic serum markers of CRC were collected, and only 19 of 92 diagnostic markers were investigated in more than two studies, whereas 21 out of 44 prognostic markers were included in two or more studies. All of the pooled sensitivities of the diagnostic markers with > = 3 repetitions were less than 50%, and the meta-analyses of the prognostic markers with more than 3 studies were performed, VEGF with highest (2.245, CI: 1.347-3.744) and MMP-7 with lowest (1.099, CI: 1.018-1.187)) pooled HRs are presented. The quality of studies addressing the diagnostic and prognostic accuracy of the tests was poor, and the results were highly heterogeneous. The poor characteristics indicate that these tests are of little value for clinical practice.

  8. GPU Accelerated Prognostics

    Science.gov (United States)

    Gorospe, George E., Jr.; Daigle, Matthew J.; Sankararaman, Shankar; Kulkarni, Chetan S.; Ng, Eley

    2017-01-01

    Prognostic methods enable operators and maintainers to predict the future performance for critical systems. However, these methods can be computationally expensive and may need to be performed each time new information about the system becomes available. In light of these computational requirements, we have investigated the application of graphics processing units (GPUs) as a computational platform for real-time prognostics. Recent advances in GPU technology have reduced cost and increased the computational capability of these highly parallel processing units, making them more attractive for the deployment of prognostic software. We present a survey of model-based prognostic algorithms with considerations for leveraging the parallel architecture of the GPU and a case study of GPU-accelerated battery prognostics with computational performance results.

  9. Validation of Human Papillomavirus as a Favourable Prognostic Marker and Analysis of CD8+Tumour-infiltrating Lymphocytes and Other Biomarkers in Cancer of Unknown Primary in the Head and Neck Region.

    Science.gov (United States)

    Sivars, Lars; Landin, David; Grün, Nathalie; Vlastos, Andrea; Marklund, Linda; Nordemar, Sushma; Ramqvist, Torbjörn; Munck-Wikland, Eva; Näsman, Anders; Dalianis, Tina

    2017-02-01

    Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed. A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8 + ) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC. HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8 + TIL counts indicated favourable prognosis. HPV status is useful for the management of patients with HNCUP and the role of CD8 + TILs should be further explored. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Promoters active in interphase are bookmarked during mitosis by ubiquitination.

    Science.gov (United States)

    Arora, Mansi; Zhang, Jie; Heine, George F; Ozer, Gulcin; Liu, Hui-wen; Huang, Kun; Parvin, Jeffrey D

    2012-11-01

    We analyzed modification of chromatin by ubiquitination in human cells and whether this mark changes through the cell cycle. HeLa cells were synchronized at different stages and regions of the genome with ubiquitinated chromatin were identified by affinity purification coupled with next-generation sequencing. During interphase, ubiquitin marked the chromatin on the transcribed regions of ∼70% of highly active genes and deposition of this mark was sensitive to transcriptional inhibition. Promoters of nearly half of the active genes were highly ubiquitinated specifically during mitosis. The ubiquitination at the coding regions in interphase but not at promoters during mitosis was enriched for ubH2B and dependent on the presence of RNF20. Ubiquitin labeling of both promoters during mitosis and transcribed regions during interphase, correlated with active histone marks H3K4me3 and H3K36me3 but not a repressive histone modification, H3K27me3. The high level of ubiquitination at the promoter chromatin during mitosis was transient and was removed within 2 h after the cells exited mitosis and entered the next cell cycle. These results reveal that the ubiquitination of promoter chromatin during mitosis is a bookmark identifying active genes during chromosomal condensation in mitosis, and we suggest that this process facilitates transcriptional reactivation post-mitosis.

  11. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II.

    Science.gov (United States)

    Starita, Lea M; Horwitz, Andrew A; Keogh, Michael-Christopher; Ishioka, Chikashi; Parvin, Jeffrey D; Chiba, Natsuko

    2005-07-01

    The breast- and ovarian-specific tumor suppressor BRCA1, when associated with BARD1, is an ubiquitin ligase. We have shown here that this heterodimer ubiquitinates a hyperphosphorylated form of Rpb1, the largest subunit of RNA polymerase II. Two major phosphorylation sites have been identified in the Rpb1 carboxyl terminal domain, serine 2 (Ser-2) or serine 5 (Ser-5) of the YSPTSPS heptapeptide repeat. Only the Ser-5 hyperphosphorylated form is ubiquitinated by BRCA1/BARD1. Overexpression of BRCA1 in cells stimulated the DNA damage-induced ubiquitination of Rpb1. Similar to the in vitro reaction, the stimulation of Rpb1 ubiquitination by BRCA1 in cells occurred only on those molecules hyperphosphorylated on Ser-5 of the heptapeptide repeat. In vitro, the carboxyl terminus of BRCA1 (amino acids 501-1863) was dispensable for the ubiquitination of hyperphosphorylated Rpb1. In cells, however, efficient Rpb1 ubiquitination required the carboxyl terminus of BRCA1, suggesting that interactions mediated by this region were essential in the complex milieu of the nucleus. These results link the BRCA1-dependent ubiquitination of the polymerase with DNA damage.

  12. A novel immunosuppressory peptide originating from the ubiquitin sequence.

    Science.gov (United States)

    Pasikowski, Paweł; Goździewicz, Tomasz; Stefanowicz, Piotr; Artym, Jolanta; Zimecki, Michał; Szewczuk, Zbigniew

    2011-12-01

    Ubiquitin is a conservative polypeptide present in every eukaryotic cell. Apart from its involvement in proteasomal degradation and other intracellular signal pathways, it was suggested to play an important role as the extracellular immunomodulator and antimicrobial agent. Moreover, ubiquitin-derived peptides were shown to express significant biological activities. Our previous studies showed a high immunosuppressive potency of the ubiquitin peptic hydrolysate in which we identified over 70 different peptides. The present work focuses on synthesizing the most abundant of these peptides and investigating their immunomodulatory potency. The peptide VKTLTGKTI possessed the highest immunosuppressory activity in AFC experiments, comparable to the previously described LEDGRTLSDY sequence (a previously discovered ubiquitin-derived peptide). Moreover, some of the investigated peptides expressed immunostimulatory effects. These findings support the idea that ubiquitin, together with products of its degradation, could represent a self-regulating immunoregulatory system. Peptide VKTLTGKTI was also tested for its activity to prolong the skin graft survival in mice. The results showed that the investigated peptide significantly extended the skin transplant rejection time, therefore it could be considered as a potential supplementary medicine in the post-transplantation therapy. Moreover, we synthesized two analogs of investigated peptides, first designed to mimic the non-linear epitope consisting of ubiquitin 16-21 and ubiquitin 52-57 fragments, and second designed to mimic the ubiquitin 5-13 hairpin. We also tested their immunosuppressory activity in in vitro experiments. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    Science.gov (United States)

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  14. KF-1 ubiquitin ligase: an anxiety suppressor

    Directory of Open Access Journals (Sweden)

    Tamotsu Hashimoto-Gotoh

    2009-05-01

    Full Text Available Anxiety is an instinct that may have developed to promote adaptive survival by evading unnecessary danger. However, excessive anxiety is disruptive and can be a basic disorder of other psychiatric diseases such as depression. The KF-1, a ubiquitin ligase located to the endoplasmic reticulum (ER, may prevent excessive anxiety; kf-1−/− mice exhibit selectively elevated anxiety-like behavior against light or heights. Thus, KF-1 may degrade some target proteins, responsible for promoting anxiety, through the ER-associated degradation pathway, similar to Parkin in Parkinson's disease (PD. Parkin, another ER-ubiquitin ligase, prevents the degeneration of dopaminergic neurons by degrading the target proteins responsible for PD. Molecular phylogenetic studies have revealed that the prototype of kf-1 appeared in the very early phase of animal evolution but was lost, unlike parkin, in the lineage leading up to Drosophila. Therefore, kf-1−/− mice, be a powerful tool for elucidating the molecular mechanisms involved in emotional regulation, and for screening novel anxiolytic/antidepressant compounds.

  15. COMMD1-mediated ubiquitination regulates CFTR trafficking.

    Directory of Open Access Journals (Sweden)

    Loïc Drévillon

    Full Text Available The CFTR (cystic fibrosis transmembrane conductance regulator protein is a large polytopic protein whose biogenesis is inefficient. To better understand the regulation of CFTR processing and trafficking, we conducted a genetic screen that identified COMMD1 as a new CFTR partner. COMMD1 is a protein associated with multiple cellular pathways, including the regulation of hepatic copper excretion, sodium uptake through interaction with ENaC (epithelial sodium channel and NF-kappaB signaling. In this study, we show that COMMD1 interacts with CFTR in cells expressing both proteins endogenously. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. In summary, our data demonstrate that CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane. Thus, increasing COMMD1 expression may provide an approach to simultaneously inhibit ENaC absorption and enhance CFTR trafficking, two major issues in cystic fibrosis.

  16. A unique deubiquitinase that deconjugates phosphoribosyl-linked protein ubiquitination

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Jiazhang; Yu, Kaiwen; Fei, Xiaowen; Liu, Yao; Nakayasu, Ernesto S.; Piehowski, Paul D.; Shaw, Jared B.; Puvar, Kedar; Das, Chittaranjan; Liu, Xiaoyun; Luo, Zhao-Qing

    2017-05-12

    Ubiquitination regulates many aspects of host immunity and thus is a common target for infectious agents. Recent studies revealed that members of the SidE effector family of the bacterial pathogen Legionella pneumophila attacked several small GTPases associated with the endoplasmic reticulum by a novel ubiquitination mechanism that does not require the E1 and E2 enzymes of the host ubiquitination machinery. Following ubiquitin activation by ADP- ribosylation via a mono-ADP-ribosylation motif, ADP-ribosylated ubiquitin is cleaved by a phosphodiesterasedomainwithinSdeA,whichisconcomitantwiththelinkof phosphoribosylated ubiquitin to serine residues in the substrate. Here we demonstrate that the activity of SidEs is regulated by SidJ, another effector encoded by a gene situated in the locus coding for three members of the SidE family (SdeC, SdeB and SdeA). SidJ functions to remove ubiquitin from SidEs-modified substrates by cleaving the phosphodiester bond that links phosphoribosylated ubiquitin to protein substrates. Further, the deubiquitinase activity of SidJ is essential for its role in L. pneumophila infection. Finally, the activity of SidJ is required for efficiently reducing the abundance of ubiquitinated Rab33b in infected cells within a few hours after bacterial uptake. Our results establish SidJ as a deubiquitinase that functions to impose temporal regulation of the activity of the SidE effectors. The identification of SidJ may shed light on future study of signaling cascades mediated by this unique ubiquitination that also potentially regulates cellular processes in eukaryotic cells.

  17. PKC-Dependent GlyT1 Ubiquitination Occurs Independent of Phosphorylation: Inespecificity in Lysine Selection for Ubiquitination.

    Directory of Open Access Journals (Sweden)

    Susana P Barrera

    Full Text Available Neurotransmitter transporter ubiquitination is emerging as the main mechanism for endocytosis and sorting of cargo into lysosomes. In this study, we demonstrate PKC-dependent ubiquitination of three different isoforms of the glycine transporter 1 (GlyT1. Incubation of cells expressing transporter with the PKC activator phorbol ester induced a dramatic, time-dependent increase in GlyT1 ubiquitination, followed by accumulation of GlyT1 in EEA1 positive early endosomes. This occurred via a mechanism that was abolished by inhibition of PKC. GlyT1 endocytosis was confirmed in both retinal sections and primary cultures of mouse amacrine neurons. Replacement of only all lysines in the N-and C-termini to arginines prevented ubiquitination and endocytosis, displaying redundancy in the mechanism of ubiquitination. Interestingly, a 40-50% reduction in glycine uptake was detected in phorbol-ester stimulated cells expressing the WT-GlyT1, whereas no significant change was for the mutant protein, demonstrating that endocytosis participates in the reduction of uptake. Consistent with previous findings for the dopamine transporter DAT, ubiquitination of GlyT1 tails functions as sorting signal to deliver transporter into the lysosome and removal of ubiquitination sites dramatically attenuated the rate of GlyT1 degradation. Finally, we showed for the first time that PKC-dependent GlyT1 phosphorylation was not affected by removal of ubiquitination sites, suggesting separate PKC-dependent signaling events for these posttranslational modifications.

  18. Stable Isotope Labeling Reveals Novel Insights Into Ubiquitin-Mediated Protein Aggregation With Age, Calorie Restriction, and Rapamycin Treatment.

    Science.gov (United States)

    Basisty, Nathan B; Liu, Yuxin; Reynolds, Jason; Karunadharma, Pabalu P; Dai, Dao-Fu; Fredrickson, Jeanne; Beyer, Richard P; MacCoss, Michael J; Rabinovitch, Peter S

    2017-08-18

    Accumulation of protein aggregates with age was first described in aged human tissue over 150 years ago and has since been described in virtually every human tissue. Ubiquitin modifications are a canonical marker of insoluble protein aggregates; however, the composition of most age-related inclusions remains relatively unknown. To examine the landscape of age-related protein aggregation in vivo, we performed an antibody-based pulldown of ubiquitinated proteins coupled with metabolic labeling and mass spectrometry on young and old mice on calorie restriction (CR), rapamycin (RP)-supplemented, and control diets. We show increased abundance of many ubiquitinated proteins in old mice and greater retention of preexisting (unlabeled) ubiquitinated proteins relative to their unmodified counterparts-fitting the expected profile of age-increased accumulation of long-lived aggregating proteins. Both CR and RP profoundly affected ubiquitinome composition, half-live, and the insolubility of proteins, consistent with their ability to mobilize these age-associated accumulations. Finally, confocal microscopy confirmed the aggregation of two of the top predicted aggregating proteins, keratins 8/18 and catalase, as well as their attenuation by CR and RP. Stable-isotope labeling is a powerful tool to gain novel insights into proteostasis mechanisms, including protein aggregation, and could be used to identify novel therapeutic targets in aging and protein aggregation diseases. © The Author 2017. 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.

  19. Improving the Prognostic Ability through Better Use of Standard Clinical Data - The Nottingham Prognostic Index as an Example.

    Directory of Open Access Journals (Sweden)

    Klaus-Jürgen Winzer

    Full Text Available Prognostic factors and prognostic models play a key role in medical research and patient management. The Nottingham Prognostic Index (NPI is a well-established prognostic classification scheme for patients with breast cancer. In a very simple way, it combines the information from tumor size, lymph node stage and tumor grade. For the resulting index cutpoints are proposed to classify it into three to six groups with different prognosis. As not all prognostic information from the three and other standard factors is used, we will consider improvement of the prognostic ability using suitable analysis approaches.Reanalyzing overall survival data of 1560 patients from a clinical database by using multivariable fractional polynomials and further modern statistical methods we illustrate suitable multivariable modelling and methods to derive and assess the prognostic ability of an index. Using a REMARK type profile we summarize relevant steps of the analysis. Adding the information from hormonal receptor status and using the full information from the three NPI components, specifically concerning the number of positive lymph nodes, an extended NPI with improved prognostic ability is derived.The prognostic ability of even one of the best established prognostic index in medicine can be improved by using suitable statistical methodology to extract the full information from standard clinical data. This extended version of the NPI can serve as a benchmark to assess the added value of new information, ranging from a new single clinical marker to a derived index from omics data. An established benchmark would also help to harmonize the statistical analyses of such studies and protect against the propagation of many false promises concerning the prognostic value of new measurements. Statistical methods used are generally available and can be used for similar analyses in other diseases.

  20. Prognostics of Power MOSFET

    Data.gov (United States)

    National Aeronautics and Space Administration — This paper demonstrates how to apply prognostics to power MOSFETs (metal oxide field effect transistor). The methodology uses thermal cycling to age devices and...

  1. The Ubiquitin Ligase CHIP Prevents SirT6 Degradation through Noncanonical Ubiquitination

    Science.gov (United States)

    Ronnebaum, Sarah M.; Wu, Yaxu; McDonough, Holly

    2013-01-01

    The ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the sirtuin family member SirT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity. In CHIP-deficient cells, SirT6 protein half-life is substantially reduced due to increased proteasome-mediated degradation, but CHIP overexpression in these cells increases SirT6 protein expression without affecting SirT6 transcription. CHIP noncanonically ubiquitinates SirT6 at K170, which stabilizes SirT6 and prevents SirT6 canonical ubiquitination by other ubiquitin ligases. In CHIP-depleted cells, SirT6 K170 mutation increases SirT6 half-life and prevents proteasome-mediated degradation. The global decrease in SirT6 expression in the absence of CHIP is associated with decreased SirT6 promoter occupancy, which increases histone acetylation and promotes downstream gene transcription in CHIP-depleted cells. Cells lacking CHIP are hypersensitive to DNA-damaging agents, but DNA repair and cell viability are rescued by enforced expression of SirT6. The discovery of this CHIP-SirT6 interaction represents a novel protein-stabilizing mechanism and defines an intersection between protein quality control and epigenetic regulation to influence pathways that regulate the biology of aging. PMID:24043303

  2. E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

    Directory of Open Access Journals (Sweden)

    Arun Upadhyay

    2017-05-01

    Full Text Available Cells regularly synthesize new proteins to replace old or damaged proteins. Deposition of various aberrant proteins in specific brain regions leads to neurodegeneration and aging. The cellular protein quality control system develop various defense mechanisms against the accumulation of misfolded and aggregated proteins. The mechanisms underlying the selective recognition of specific crucial protein or misfolded proteins are majorly governed by quality control E3 ubiquitin ligases mediated through ubiquitin-proteasome system. Few known E3 ubiquitin ligases have shown prominent neurodevelopmental functions, but their interactions with different developmental proteins play critical roles in neurodevelopmental disorders. Several questions are yet to be understood properly. How E3 ubiquitin ligases determine the specificity and regulate degradation of a particular substrate involved in neuronal proliferation and differentiation is certainly the one, which needs detailed investigations. Another important question is how neurodevelopmental E3 ubiquitin ligases specifically differentiate between their versatile range of substrates and timing of their functional modulations during different phases of development. The premise of this article is to understand how few E3 ubiquitin ligases sense major molecular events, which are crucial for human brain development from its early embryonic stages to throughout adolescence period. A better understanding of these few E3 ubiquitin ligases and their interactions with other potential proteins will provide invaluable insight into disease mechanisms to approach toward therapeutic interventions.

  3. Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein

    Directory of Open Access Journals (Sweden)

    Barbara Mojsa

    2014-05-01

    Full Text Available Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17 and one deubiquitinase (e.g., USP9X, that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system.

  4. Enhanced detection of ubiquitin isopeptides using reductive methylation.

    Science.gov (United States)

    Chicooree, Navin; Connolly, Yvonne; Tan, Chong-Teik; Malliri, Angeliki; Li, Yaoyong; Smith, Duncan L; Griffiths, John R

    2013-03-01

    Identification of ubiquitination (Ub) sites is of great interest due to the critical roles that the modification plays in cellular regulation. Current methods using mass spectrometry rely upon tryptic isopeptide diglycine tag generation followed by database searching. We present a novel approach to ubiquitin detection based upon the dimethyl labeling of isopeptide N-termini glycines. Ubiquitinated proteins were digested with trypsin and the resulting peptide mixture was derivatized using formaldehyde-D2 solution and sodium cyanoborohydride. The dimethylated peptide mixtures were next separated by liquid chromatography and analyzed on a quadrupole-TOF based mass spectrometer. Diagnostic b2' and a1' ions released from the isopeptide N-terminus upon collision-induced dissociation (CID) were used to spectrally improve the identification of ubiquitinated isopeptides. Proof of principle was established by application to a ubiquitinated protein tryptic digest spiked into a six-protein mix digest background. Extracted ion chromatograms of the a1' and b2' diagnostic product ions from the diglycine tag resulted in a significant reduction in signal complexity and demonstrated a selectivity towards the identification of diglycine branched isopeptides. The method was further shown to be capable of identifying diglycine isopeptides resulting from in-gel tryptic digests of ubiquitin enriched material from a His-Ub transfected cell line. We envisage that these ions may be utilized in global ubiquitination studies with post-acquisition MS/MS (or MSe) data interrogation on high resolution hybrid mass spectrometers. ᅟ

  5. Palliative medicine review: prognostication.

    Science.gov (United States)

    Glare, Paul A; Sinclair, Christian T

    2008-01-01

    Prognostication, along with diagnosis and treatment, is a traditional core clinical skill of the physician. Many patients and families receiving palliative care want information about life expectancy to help plan realistically for their futures. Although underappreciated, prognosis is, or at least should be, part of every clinical decision. Despite this crucial role, expertise in the art and science of prognostication diminished during the twentieth century, due largely to the ascendancy of accurate diagnostic tests and effective therapies. Consequently, "Doctor, how long do I have?" is a question most physicians find unprepared to answer effectively. As we focus on palliative care in the twenty-first century, prognostication will need to be restored as a core clinical proficiency. The discipline of palliative medicine can provide leadership in this direction. This paper begins by discussing a framework for understanding prognosis and how its different domains might be applied to all patients with life limiting illness, although the main focus of the paper is predicting survival in patients with cancer. Examples of prognostic tools are provided, although the subjective assessment of prognosis remains important in the terminally ill. Other issues addressed include: the importance of prognostication in terms of clinical decision-making, discharge planning, and care planning; the impact of prognosis on hospice referrals and patient/family satisfaction; and physicians' willingness to prognosticate.

  6. Ubiquitin-conjugating enzyme UBE2C is highly expressed in breast microcalcification lesions.

    Science.gov (United States)

    Chou, Chen-Pin; Huang, Nan-Chieh; Jhuang, Shu-Jhen; Pan, Huay-Ben; Peng, Nan-Jing; Cheng, Jiin-Tsuey; Chen, Chian-Feng; Chen, Jih-Jung; Chang, Tsung-Hsien

    2014-01-01

    Ubiquitin-conjugating enzyme 2C (UBE2C) contributes to ubiquitin-mediated proteasome degradation of cell cycle progression in breast cancer. Microcalcification (MC) is the most common mammographic feature of early breast cancer. In this study, we evaluated whether UBE2C could be a tumor marker of early breast cancer with MC found on screening mammography. UBE2C protein and mRNA expression were measured in breast core biopsy pairs of MC and adjacent non-MC breast tissue from each subject. Immunohistochemistry revealed UBE2C positivity in 69.4% of MC samples and 77.6% negativity in non-MC samples (pbreast cancer cells with UBE2C knockdown; UBE2C knockdown downregulated cell proliferation and activated the cellular apoptosis pathway to inhibit cell colony formation. Furthermore, UBE2C expression was associated with that of carcinogenic genes human epidermal growth factor receptor type 2 (HER2), cellular c-Ki-ras2 proto-oncogene (KRAS), vascular endothelial growth factor (VEGF), CXC chemokine receptor 4 (CXCR4), C-C motif chemokine 5 (CCL5), neural precursor cell expressed, developmentally downregulated 9 (NEDD9) and Ras homolog family member C (RhoC). UBE2C may be a marker for diagnosis of nonpalpable breast lesions but not benign or malignant tumors in mammography core biopsies. Suppression of UBE2C may be a potential therapy target in breast cancer.

  7. P62/Ubiquitin IHC expression in gastrointestinal carcinomas

    Directory of Open Access Journals (Sweden)

    Amr eMohamed

    2015-03-01

    Full Text Available P62 and ubiquitin are small regulatory proteins demonstrated to have implications in the prognosis and survival of various malignancies including: hepatocellular, breast, ovarian, and some gastrointestinal carcinomas. Several trials studied the link of their activity to the extrinsic apoptosis pathway and showed that their autophagy modification has a critical stand point in tumorigenesis. These findings explain their vital role in controlling the process of cell death and survival. It has been shown recently that p62 and ubiquitin overexpression in different types of cancers, such as triple negative breast and ovarian cancers, have directly correlated with incidence of distant metastases. We aim to evaluate p62/ubiquitin expression in gastrointestinal carcinomas of gastric, colonic and pancreatic origin. In gastric carcinoma (45, positive p62 nuclear expression was noted in 53% and cytoplasmic in 57%, while positive ubiquitin was nuclear expressed in 80%, and cytoplasmic in 24%. In colon carcinoma (70, positive p62 nuclear expression was noted in 41% and cytoplasmic in 68.5%, while positive ubiquitin was nuclear in 57% and cytoplasmic in 42%. In pancreatic cancer, positive p62 nuclear expression was noted in 86% and cytoplasmic in 60%, while positive ubiquitin was nuclear in 100% and cytoplasmic in 80%. Normal gastric (6, colon (4 and pancreatic (4 tissues were negative for both P62 and ubiquitin (nuclear and cytoplasmic staining <20%. The results suggest that p62 and ubiquitin are highly expressed in nuclei and cytoplasm of gastric, colonic and pancreatic carcinomas. More studies are needed to correlate IHC expression of p62/ubiquitin with clinicopathologic parameters and overall survival in GI carcinomas.

  8. The prognostic relevance of estimates of proliferative activity in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, B V; Sørensen, Flemming Brandt; Knoop, A

    2003-01-01

    AIMS: Immunohistochemical estimates of cell proliferation evaluated with MIB-1 antibody have been suggested as prognostic indicators in different types of carcinoma. This study investigates whether MIB-1 scores add additional prognostic impact when evaluated together with classical clinicopatholo......AIMS: Immunohistochemical estimates of cell proliferation evaluated with MIB-1 antibody have been suggested as prognostic indicators in different types of carcinoma. This study investigates whether MIB-1 scores add additional prognostic impact when evaluated together with classical...... and number of mitoses included in the analysis, MIB-1 estimates showed no independent prognostic impact.CONCLUSIONS: High MIB-1 estimates did not add independent prognostic information at diagnosis when evaluated together with classical prognostic markers of early breast cancer....

  9. The prognostic relevance of estimates of proliferative activity in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, B V; Sørensen, Flemming Brandt; Knoop, A

    2003-01-01

    AIMS: Immunohistochemical estimates of cell proliferation evaluated with MIB-1 antibody have been suggested as prognostic indicators in different types of carcinoma. This study investigates whether MIB-1 scores add additional prognostic impact when evaluated together with classical clinicopatholo......AIMS: Immunohistochemical estimates of cell proliferation evaluated with MIB-1 antibody have been suggested as prognostic indicators in different types of carcinoma. This study investigates whether MIB-1 scores add additional prognostic impact when evaluated together with classical...... and number of mitoses included in the analysis, MIB-1 estimates showed no independent prognostic impact. CONCLUSIONS: High MIB-1 estimates did not add independent prognostic information at diagnosis when evaluated together with classical prognostic markers of early breast cancer....

  10. Newborn mouse lens proteome and its alteration by lysine 6 mutant ubiquitin

    Science.gov (United States)

    Ubiquitin is a tag that often initiates degradation of proteins by the proteasome in the ubiquitin proteasome system. Targeted expression of K6W mutant ubiquitin (K6W-Ub) in the lens results in defects in lens development and cataract formation, suggesting critical functions for ubiquitin in lens. T...

  11. Water Evaporation and Conformational Changes from Partially Solvated Ubiquitin

    Directory of Open Access Journals (Sweden)

    Saravana Prakash Thirumuruganandham

    2010-01-01

    Full Text Available Using molecular dynamics simulation, we study the evaporation of water molecules off partially solvated ubiquitin. The evaporation and cooling rates are determined for a molecule at the initial temperature of 300 K. The cooling rate is found to be around 3 K/ns, and decreases with water temperature in the course of the evaporation. The conformation changes are monitored by studying a variety of intermediate partially solvated ubiquitin structures. We find that ubiquitin shrinks with decreasing hydration shell and exposes more of its hydrophilic surface area to the surrounding.

  12. E3 ubiquitin ligases as drug targets and prognostic biomarkers in melanoma

    Directory of Open Access Journals (Sweden)

    Kristina Bielskienė

    2015-01-01

    E3 ligases are of interest as drug targets for their ability to regulate proteins stability and functions. Compared to the general proteasome inhibitor bortezomib, which blocks the entire protein degradation, drugs that target a particular E3 ligase are expected to have better selectivity with less associated toxicity. Components of different E3 ligases complexes (FBW7, MDM2, RBX1/ROC1, RBX2/ROC2, cullins and many others are known as oncogenes or tumor suppressors in melanomagenesis. These proteins participate in regulation of different cellular pathways and such important proteins in cancer development as p53 and Notch. In this review we summarized published data on the role of known E3 ligases in the development of melanoma and discuss the inhibitors of E3 ligases as a novel approach for the treatment of malignant melanomas.

  13. No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival.

    Science.gov (United States)

    Luo, Li; Orlow, Irene; Kanetsky, Peter A; Thomas, Nancy E; Fang, Shenying; Lee, Jeffrey E; Berwick, Marianne; Lee, Ji-Hyun

    2017-01-01

    The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma. The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD) SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF). We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM) and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF) method in addition to Cox proportional hazards models. The Harrell's C-index was used to compare the performance of model predictability. The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM), and the hospital-based MD Anderson study consisted of 1,804 CM patients. Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83) in the GEM study. Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively). The Cox model identified no significant associations after adjusting for multiplicity. Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.

  14. No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival.

    Directory of Open Access Journals (Sweden)

    Li Luo

    Full Text Available The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma. The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF. We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF method in addition to Cox proportional hazards models. The Harrell's C-index was used to compare the performance of model predictability. The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM, and the hospital-based MD Anderson study consisted of 1,804 CM patients. Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83 in the GEM study. Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively. The Cox model identified no significant associations after adjusting for multiplicity. Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.

  15. E2 enzyme inhibition by stabilization of a low affinity interface with ubiquitin

    Science.gov (United States)

    St-Cyr, Daniel J.; Ziemba, Amy; Garg, Pankaj; Plamondon, Serge; Auer, Manfred; Sidhu, Sachdev; Marinier, Anne; Kleiger, Gary; Tyers, Mike; Sicheri, Frank

    2014-01-01

    Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small molecule inhibitor of the E2 ubiquitin conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester, without overtly affecting the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities. PMID:24316736

  16. Prognostic stratification of ulcerated melanoma: not only the extent matters.

    Science.gov (United States)

    Bønnelykke-Behrndtz, Marie L; Schmidt, Henrik; Christensen, Ib J; Damsgaard, Tine E; Møller, Holger J; Bastholt, Lars; Nørgaard, Peter H; Steiniche, Torben

    2014-12-01

    For patients with melanoma, ulceration is an important prognostic marker and interestingly also a predictive marker for the response of adjuvant interferon. A consensual definition and accurate assessment of ulceration are therefore crucial for proper staging and clinical management. We evaluated the prognostic impact of the extent and type of ulceration and the epidermal involvement theoretically preceding it (consumption of epidermis and cleft formation) or seen subsequent to the inflammation (reepithelialization and reactive epidermal hyperplasia), aiming for better prognostic stratification of ulcerated lesions. From H&E-stained sections, the status (presence vs absence), extent (percentage of the total tumor length), and type (infiltrative vs attenuative) of ulceration and epidermal involvement were evaluated from 385 patients with cutaneous melanoma. The presence of ulceration (hazard ratio [HR], 1.83), an attenuative type of ulceration (HR, 3.02), and excessive ulceration (HR, 3.57) were independent predictors of poor melanoma-specific survival. Further subdivision of minimal/moderate ulceration showed independent prognostic value only for lesions with epidermal involvement of the surrounding epidermis (HR, 1.78). The extent and type of ulceration and involvement of the surrounding epidermis provided more accurate prognostic information than the mere absence or presence and may be useful markers allowing better stratification of ulcerated lesions. Copyright© by the American Society for Clinical Pathology.

  17. The Unique Morgue Ubiquitination Protein Is Conserved in a Diverse but Restricted Set of Invertebrates

    OpenAIRE

    Zhou, Ying; Carpenter, Zachary W.; Brennan, Gregory; Nambu, John R.

    2009-01-01

    Drosophila Morgue is a unique ubiquitination protein that facilitates programmed cell death and associates with DIAP1, a critical cell death inhibitor with E3 ubiquitin ligase activity. Morgue possesses a unique combination of functional domains typically associated with distinct types of ubiquitination enzymes. This includes an F box characteristic of the substrate-binding subunit in Skp, Cullin, and F box (SCF)-type ubiquitin E3 ligase complexes and a variant ubiquitin E2 conjugase domain w...

  18. A role for PCNA ubiquitination in immunoglobulin hypermutation.

    Directory of Open Access Journals (Sweden)

    Hiroshi Arakawa

    2006-11-01

    Full Text Available Proliferating cell nuclear antigen (PCNA is a DNA polymerase cofactor and regulator of replication-linked functions. Upon DNA damage, yeast and vertebrate PCNA is modified at the conserved lysine K164 by ubiquitin, which mediates error-prone replication across lesions via translesion polymerases. We investigated the role of PCNA ubiquitination in variants of the DT40 B cell line that are mutant in K164 of PCNA or in Rad18, which is involved in PCNA ubiquitination. Remarkably, the PCNA(K164R mutation not only renders cells sensitive to DNA-damaging agents, but also strongly reduces activation induced deaminase-dependent single-nucleotide substitutions in the immunoglobulin light-chain locus. This is the first evidence, to our knowledge, that vertebrates exploit the PCNA-ubiquitin pathway for immunoglobulin hypermutation, most likely through the recruitment of error-prone DNA polymerases.

  19. Regulation of G Protein-Coupled Receptors by Ubiquitination

    Directory of Open Access Journals (Sweden)

    Kamila Skieterska

    2017-04-01

    Full Text Available G protein-coupled receptors (GPCRs comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

  20. Ubiquitination of stalled ribosome triggers ribosome-associated quality control.

    Science.gov (United States)

    Matsuo, Yoshitaka; Ikeuchi, Ken; Saeki, Yasushi; Iwasaki, Shintaro; Schmidt, Christian; Udagawa, Tsuyoshi; Sato, Fumiya; Tsuchiya, Hikaru; Becker, Thomas; Tanaka, Keiji; Ingolia, Nicholas T; Beckmann, Roland; Inada, Toshifumi

    2017-07-31

    Translation arrest by polybasic sequences induces ribosome stalling, and the arrest product is degraded by the ribosome-mediated quality control (RQC) system. Here we report that ubiquitination of the 40S ribosomal protein uS10 by the E3 ubiquitin ligase Hel2 (or RQT1) is required for RQC. We identify a RQC-trigger (RQT) subcomplex composed of the RNA helicase-family protein Slh1/Rqt2, the ubiquitin-binding protein Cue3/Rqt3, and yKR023W/Rqt4 that is required for RQC. The defects in RQC of the RQT mutants correlate with sensitivity to anisomycin, which stalls ribosome at the rotated form. Cryo-electron microscopy analysis reveals that Hel2-bound ribosome are dominantly the rotated form with hybrid tRNAs. Ribosome profiling reveals that ribosomes stalled at the rotated state with specific pairs of codons at P-A sites serve as RQC substrates. Rqt1 specifically ubiquitinates these arrested ribosomes to target them to the RQT complex, allowing subsequent RQC reactions including dissociation of the stalled ribosome into subunits.Several protein quality control mechanisms are in place to trigger the rapid degradation of aberrant polypeptides and mRNAs. Here the authors describe a mechanism of ribosome-mediated quality control that involves the ubiquitination of ribosomal proteins by the E3 ubiquitin ligase Hel2/RQT1.

  1. Detection of ubiquitinated huntingtin species in intracellular aggregates

    Directory of Open Access Journals (Sweden)

    Katrin eJuenemann

    2015-01-01

    Full Text Available Protein conformation diseases, including polyglutamine diseases, result from the accumulation and aggregation of misfolded proteins. Huntington’s disease is one of nine diseases caused by an expanded polyglutamine repeat within the affected protein and is hallmarked by intracellular inclusion bodies composed of aggregated N-terminal huntingtin fragments and other sequestered proteins. Fluorescence microscopy and filter trap assay are conventional methods to study protein aggregates, but cannot be used to analyze the presence and levels of post-translational modifications of aggregated huntingtin such as ubiquitination. Ubiquitination of proteins can be a signal for degradation and intracellular localization, but also affects protein activity and protein-protein interactions. The function of ubiquitination relies on its mono- and polymeric isoforms attached to protein substrates. Studying the ubiquitination pattern of aggregated huntingtin fragments offers an important possibility to understand huntingtin degradation and aggregation processes within the cell. For the identification of aggregated huntingtin and its ubiquitinated species, solubilization of the cellular aggregates is mandatory. Here we describe methods to identify post-translational modifications such as ubiquitination of aggregated mutant huntingtin. This approach is specifically described for use with mammalian cell culture and is suitable to study other disease-related proteins prone to aggregate.

  2. Mechanisms of mono- and poly-ubiquitination: Ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine

    Directory of Open Access Journals (Sweden)

    Sadowski Martin

    2010-08-01

    Full Text Available Abstract Ubiquitination involves the attachment of ubiquitin to lysine residues on substrate proteins or itself, which can result in protein monoubiquitination or polyubiquitination. Ubiquitin attachment to different lysine residues can generate diverse substrate-ubiquitin structures, targeting proteins to different fates. The mechanisms of lysine selection are not well understood. Ubiquitination by the largest group of E3 ligases, the RING-family E3 s, is catalyzed through co-operation between the non-catalytic ubiquitin-ligase (E3 and the ubiquitin-conjugating enzyme (E2, where the RING E3 binds the substrate and the E2 catalyzes ubiquitin transfer. Previous studies suggest that ubiquitination sites are selected by E3-mediated positioning of the lysine toward the E2 active site. Ultimately, at a catalytic level, ubiquitination of lysine residues within the substrate or ubiquitin occurs by nucleophilic attack of the lysine residue on the thioester bond linking the E2 catalytic cysteine to ubiquitin. One of the best studied RING E3/E2 complexes is the Skp1/Cul1/F box protein complex, SCFCdc4, and its cognate E2, Cdc34, which target the CDK inhibitor Sic1 for K48-linked polyubiquitination, leading to its proteasomal degradation. Our recent studies of this model system demonstrated that residues surrounding Sic1 lysines or lysine 48 in ubiquitin are critical for ubiquitination. This sequence-dependence is linked to evolutionarily conserved key residues in the catalytic region of Cdc34 and can determine if Sic1 is mono- or poly-ubiquitinated. Our studies indicate that amino acid determinants in the Cdc34 catalytic region and their compatibility to those surrounding acceptor lysine residues play important roles in lysine selection. This may represent a general mechanism in directing the mode of ubiquitination in E2 s.

  3. Androgen receptor expression as a prognostic and predictive ...

    African Journals Online (AJOL)

    Fatma Zakaria

    2015-10-30

    Oct 30, 2015 ... clinical and histo-morphological factors of all patients were assessed. The steroid hormones status including (ER, PR,. Her.2, AR and KI-67) was evaluated by immunohistochem- istry (IHC). The aim of this study focused on predictive and prognostic value of AR expression as a hormonal marker in TNBC.

  4. Diagnostic and prognostic value of circulating tumor cells in female ...

    African Journals Online (AJOL)

    Aim: The aim of the current study is to detect CTCs in the blood of breast cancer females by the expression of Mammoglobin and Mucin-1 to evaluate their potential as diagnostic and prognostic markers of breast cancer and predictors of metastasis. Subjects and methods: The study involved 50 patients and thirty controls.

  5. Genetic Prognostic Factors and Follow-up in Uveal Melanoma

    NARCIS (Netherlands)

    T. van den Bosch (Thomas)

    2012-01-01

    textabstractAn important part of oncological research is to identify prognostic factors and predict which patients are at risk for (early) metastasis. This thesis aims to describe the known genetic alterations in uveal melanoma and define new chromosomal regions and markers involved with (micro-)

  6. The regulation of DNA damage tolerance by Ubiquitin and Ubiquitin-like modifiers

    Directory of Open Access Journals (Sweden)

    Lina Cipolla

    2016-06-01

    Full Text Available DNA replication is an extremely complex process that needs to be executed in a highly accurate manner in order to propagate the genome. This task requires the coordination of a number of enzymatic activities and it is incredibly fragile and prone to arrest after DNA damage. DNA damage tolerance provides a last line of defense that allows completion of DNA replication in presence of an unrepaired template. One of such mechanisms is called Post Replication Repair (PRR and it is used by the cells to bypass highly distorted templates caused by damaged bases. PRR is extremely important for the cellular life and performs the bypass of the damage both in an error free and in an error prone manner. In light of these two possible outcomes, PRR needs to be tightly regulated and controlled in order to prevent accumulation of mutations leading ultimately to genome instability. Post-translational modifications provide the framework for this regulation and Ubiquitylation and SUMOylation of PRR proteins play a pivotal role in choosing which pathway to activate, controlling the different outcomes of damage bypass. PCNA (Proliferating Cell Nuclear Antigen, the DNA clamp for replicative polymerases, plays a central role in the regulation of damage tolerance and its modification by Ubiquitin and SUMO controls both the error free and error prone branches of PRR. Furthermore, a significant number of polymerases involved in the bypass of DNA damage possess domains that can bind post-translational modifications and they are themselves target for ubiquitylation. In this review, we will focus on how Ubiquitin and Ubiquitin-like modifications can regulate the DNA damage tolerance systems and how they are capable of controlling the recruitment of different proteins to the replication fork.

  7. Prognostics of Power MOSFET

    Science.gov (United States)

    Celaya, Jose Ramon; Saxena, Abhinav; Vashchenko, Vladislay; Saha, Sankalita; Goebel, Kai Frank

    2011-01-01

    This paper demonstrates how to apply prognostics to power MOSFETs (metal oxide field effect transistor). The methodology uses thermal cycling to age devices and Gaussian process regression to perform prognostics. The approach is validated with experiments on 100V power MOSFETs. The failure mechanism for the stress conditions is determined to be die-attachment degradation. Change in ON-state resistance is used as a precursor of failure due to its dependence on junction temperature. The experimental data is augmented with a finite element analysis simulation that is based on a two-transistor model. The simulation assists in the interpretation of the degradation phenomena and SOA (safe operation area) change.

  8. The Fanconi anemia pathway and ubiquitin

    Directory of Open Access Journals (Sweden)

    Taniguchi Toshiyasu

    2007-11-01

    Full Text Available Abstract Fanconi anemia (FA is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. To date, 12 FA gene products have been identified, which cooperate in a common DNA damage-activated signaling pathway regulating DNA repair (the FA pathway. Eight FA proteins form a nuclear complex harboring E3 ubiquitin ligase activity (the FA core complex that, in response to DNA damage, mediates the monoubiquitylation of the FA protein FANCD2. Monoubiquitylated FANCD2 colocalizes in nuclear foci with proteins involved in DNA repair, including BRCA1, FANCD1/BRCA2, FANCN/PALB2 and RAD51. All these factors are required for cellular resistance to DNA crosslinking agents. The inactivation of the FA pathway has also been observed in a wide variety of human cancers and is implicated in the sensitivity of cancer cells to DNA crosslinking agents. Drugs that inhibit the FA pathway may be useful chemosensitizers in the treatment of cancer. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com.

  9. Marcadores moleculares no câncer de pulmão: papel prognóstico e sua relação com o tabagismo Molecular markers in lung cancer: prognostic role and relationship to smoking

    Directory of Open Access Journals (Sweden)

    Ricardo Luiz de Menezes Duarte

    2006-02-01

    regarding prognostic value or therapeutic efficacy. Treatment strategies to cure lung cancer should focus on these early genetic lesions in order to promote their repair or to eliminate these lung cancer cells.

  10. Neutrophils as a prognostic factor in the systemic treatment of Ovarian Cancer

    DEFF Research Database (Denmark)

    Henriksen, Jon Røikjær; Dahl Steffensen, Karina

    research protocol. Performance status (PS), FIGO stage, tumour grade, residual tumour, baseline neutrophils, first nadir neutrophils and LDH were analysed in comparison to overall survival (OS). Results: Patients with low vs medium vs high level of baseline neutrophils (cut-offs: 4.7 and 6.5) showed median...... prognostic marker in multivariate analysis comparing low vs high baseline neutrophils (HR: 1.97) ( 95% CI: 1.18-3.30)(P=0.009). Other independent prognostic markers were FIGO stage, residual tumour and performance status. Conclusions: Baseline neutrophil blood count was found to be an independent prognostic...

  11. Risk stratification of intermediate-risk acute myeloid leukemia: Integrative analysis of a multitude of gene mutation and gene expression markers

    NARCIS (Netherlands)

    V. Rockova (Veronika); S. Abbas (Saman); B.J. Wouters (Bas); C.A.J. Erpelinck (Claudia); H.B. Beverloo (Berna); H.R. Delwel (Ruud); W.L.J. van Putten (Wim); B. Löwenberg (Bob); P.J.M. Valk (Peter)

    2011-01-01

    textabstractNumerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a

  12. Prognostic factors in oligodendrogliomas

    DEFF Research Database (Denmark)

    Westergaard, L; Gjerris, F; Klinken, L

    1997-01-01

    An outcome analysis was performed on 96 patients with pure cerebral oligodendrogliomas operated in the 30-year period 1962 to 1991. The most important predictive prognostic factors were youth and no neurological deficit, demonstrated as a median survival for the group younger than 20 years of 17...

  13. Dimeric analogs of immunosuppressive decapeptide fragment of ubiquitin.

    Science.gov (United States)

    Kluczyk, Alicja; Cydzik, Marzena; Biernat, Monika; Bąchor, Remigiusz; Pasikowski, Paweł; Stefanowicz, Piotr; Artym, Jolanta; Zimecki, Michał; Szewczuk, Zbigniew

    2012-07-01

    Our previous studies revealed that ubiquitin and its decapeptide fragment with the LEDGRTLSDY sequence, located on the exposed molecule loop, strongly suppressed the immune response. This suggested that the loop may serve as a functional epitope of ubiquitin molecule and that a possible mechanism of biological action of the synthesized peptides is associated with interfering in interactions of ubiquitin with other molecules. Ubiquitin is known to exist in oligomeric forms, which can interact with various oligomeric receptors. We designed and synthesized new dimeric analogs of the ubiquitin fragment, to probe whether dimeric peptides may have higher affinity towards the ubiquitin receptors responsible for immunosuppression, which are believed to form oligomeric structures. Three dimerization strategies, N-terminus to N-terminus, C-terminus to C-terminus, and N-terminus to C-terminus (head-to-tail) via PEG derivatives were used to synthesize the dimeric peptides on solid support. In the course of our research, we developed a new and straightforward procedure of dimerization where α-amino groups of the C-terminal lysine residues of two peptide fragments were linked by PEG spacer directly on solid support. The effect of dimeric analogs on the immunological response was tested in the AFC in vitro experiment. The immunological tests showed that the head-to-tail dimerization caused a more profound increase in the biological activity than other tested dimerization methods. Our results suggest that such orientation of peptide components may correspond to orientation of the hypothetic ubiquitin receptors responsible for the immunomodulatory activity. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

  14. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study

    DEFF Research Database (Denmark)

    Nordström, Lena; Sernbo, Sandra; Eden, Patrik

    2014-01-01

    an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11...

  15. Marker chromosomes.

    Science.gov (United States)

    Rao, Kiran Prabhaker; Belogolovkin, Victoria

    2013-04-01

    Marker chromosomes are a morphologically heterogeneous group of structurally abnormal chromosomes that pose a significant challenge in prenatal diagnosis. Phenotypes associated with marker chromosomes are highly variable and range from normal to severely abnormal. Clinical outcomes are very difficult to predict when marker chromosomes are detected prenatally. In this review, we outline the classification, etiology, cytogenetic characterization, and clinical consequences of marker chromosomes, as well as practical approaches to prenatal diagnosis and genetic counseling.

  16. Using prognostic models in CLL to personalize approach to clinical care: Are we there yet?

    Science.gov (United States)

    Mina, Alain; Sandoval Sus, Jose; Sleiman, Elsa; Pinilla-Ibarz, Javier; Awan, Farrukh T; Kharfan-Dabaja, Mohamed A

    2017-10-28

    Four decades ago, two staging systems were developed to help stratify CLL into different prognostic categories. These systems, the Rai and the Binet staging, depended entirely on abnormal exam findings and evidence of anemia and thrombocytopenia. Better understanding of biologic, genetic, and molecular characteristics of CLL have contributed to better appreciating its clinical heterogeneity. New prognostic models, the GCLLSG prognostic index and the CLL-IPI, emerged. They incorporate biologic and genetic information related to CLL and are capable of predicting survival outcomes and cases anticipated to need therapy earlier in the disease course. Accordingly, these newer models are helping develop better informed surveillance strategies and ultimately tailor treatment intensity according to presence (or lack thereof) of certain prognostic markers. This represents a step towards personalizing care of CLL patients. We anticipate that as more prognostic factors continue to be identified, the GCLLSG prognostic index and CLL-IPI models will undergo further revisions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. The SCF ubiquitin ligase Slimb controls Nerfin-1 turnover in Drosophila.

    Science.gov (United States)

    Lin, Xiaohui; Wang, Feng; Li, Yuanpei; Zhai, Chaojun; Wang, Guiping; Zhang, Xiaoting; Gao, Yang; Yi, Tao; Sun, Dan; Wu, Shian

    2018-01-01

    The C2H2 type zinc-finger transcription factor Nerfin-1 expresses dominantly in Drosophila nervous system and plays an important role in early axon guidance decisions and preventing neurons dedifferentiation. Recently, increasing reports indicated that INSM1 (homologue to nerfin-1 in mammals) is a useful marker for prognosis of neuroendocrine tumors. The dynamic expression of Nerfin-1 is regulated post-transcriptionally by multiple microRNAs; however, its post-translational regulation is still unclear. Here we showed that the protein turnover of Nerfin-1 is regulated by Slimb, the substrate adaptor of SCFSlimb ubiquitin ligase complex. Mechanistically, Slimb associates with Nerfin-1 and promotes it ubiquitination and degradation in Drosophila S2R+ cells. Furthermore, we determined that the C-terminal half of Nerfin-1 (Nerfin-1CT) is required for its binding to Slimb. Genetic epistasis assays showed that Slimb misexpression antagonizes, while knock-down enhances the activity of Nerfin-1CT in Drosophila eyes. Our data revealed a new link to understand the underlying mechanism for Nerfin-1 turnover in post-translational level, and provided useful insights in animal development and disease treatment by manipulating the activity of Slimb and Nerfin-1. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3β phosphorylation.

    Science.gov (United States)

    Liu, Ningning; Chai, Renjie; Liu, Bin; Zhang, Zhenhui; Zhang, Shuangwei; Zhang, Jingzhi; Liao, Yuning; Cai, Jianyu; Xia, Xiaohong; Li, Aiqun; Liu, Jinbao; Huang, Hongbiao; Liu, Shiming

    2016-09-23

    Cardiac hypertrophy, a compensatory response to various stimuli in the heart, independently predicts cardiovascular ailments and related deaths. Increasing evidence indicates ubiquitin-proteasome signaling contributes to cardiac hypertrophy regulation. Here, we identified ubiquitin-specific protease 14 (USP14), a 19S proteasome associated deubiquitinase (DUB), as a novel target for cardiac hypertrophy therapy via inhibition of the GSK-3β pathway. Indeed, USP14 expression was increased in an animal model of abdominal aorta constriction. In an angiotensin II (AngII) induced primary neonatal rat cardiomyocyte hypertrophy model, USP14 expression was increased in a time-dependent manner, and reduced USP14 deubiquitinase activity or USP14 knockdown resulted in lower expression levels of the myocardial hypertrophy specific marker β-MHC, and subsequent decreased GSK-3β phosphorylation. In conclusion, USP14 mediates the development of cardiac hypertrophy by promoting GSK-3β phosphorylation, suggesting that USP14 might represent a novel therapeutic target for cardiac hypertrophy treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Prognostic factors and scoring system for survival in colonic perforation.

    Science.gov (United States)

    Komatsu, Shuhei; Shimomatsuya, Takumi; Nakajima, Masayuki; Amaya, Hirokazu; Kobuchi, Taketsune; Shiraishi, Susumu; Konishi, Sayuri; Ono, Susumu; Maruhashi, Kazuhiro

    2005-01-01

    No ideal and generally accepted prognostic factors and scoring systems exist to determine the prognosis of peritonitis associated with colonic perforation. This study was designed to investigate prognostic factors and evaluate the various scoring systems to allow identification of high-risk patients. Between 1996 and 2003, excluding iatrogenic and trauma cases, 26 consecutive patients underwent emergency operations for colorectal perforation and were selected for this retrospective study. Several clinical factors were analyzed as possible predictive factors, and APACHE II, SOFA, MPI, and MOF scores were calculated. The overall mortality was 26.9%. Compared with the survivors, non-survivors were found more frequently in Hinchey's stage III-IV, a low preoperative marker of pH, base excess (BE), and a low postoperative marker of white blood cell count, PaO2/FiO2 ratio, and renal output (24h). According to the logistic regression model, BE was a significant independent variable. Concerning the prognostic scoring systems, an APACHE II score of 19, a SOFA score of 8, an MPI score of 30, and an MOF score of 7 or more were significantly related to poor prognosis. Preoperative BE and postoperative white blood cell count were reliable prognostic factors and early classification using prognostic scoring systems at specific points in the disease process are useful to improve our understanding of the problems involved.

  20. Roles of protein ubiquitination and degradation kinetics in biological oscillations.

    Directory of Open Access Journals (Sweden)

    Lida Xu

    Full Text Available Protein ubiquitination and degradation play important roles in many biological functions and are associated with many human diseases. It is well known that for biochemical oscillations to occur, proper degradation rates of the participating proteins are needed. In most mathematical models of biochemical reactions, linear degradation kinetics has been used. However, the degradation kinetics in real systems may be nonlinear, and how nonlinear degradation kinetics affects biological oscillations are not well understood. In this study, we first develop a biochemical reaction model of protein ubiquitination and degradation and calculate the degradation rate against the concentration of the free substrate. We show that the protein degradation kinetics mainly follows the Michaelis-Menten formulation with a time delay caused by ubiquitination and deubiquitination. We then study analytically how the Michaelis-Menten degradation kinetics affects the instabilities that lead to oscillations using three generic oscillation models: 1 a positive feedback mediated oscillator; 2 a positive-plus-negative feedback mediated oscillator; and 3 a negative feedback mediated oscillator. In all three cases, nonlinear degradation kinetics promotes oscillations, especially for the negative feedback mediated oscillator, resulting in much larger oscillation amplitudes and slower frequencies than those observed with linear kinetics. However, the time delay due to protein ubiquitination and deubiquitination generally suppresses oscillations, reducing the amplitude and increasing the frequency of the oscillations. These theoretical analyses provide mechanistic insights into the effects of specific proteins in the ubiquitination-proteasome system on biological oscillations.

  1. Prognostic stratification of colorectal cancer patients: current perspectives

    Directory of Open Access Journals (Sweden)

    Schneider NI

    2014-07-01

    Full Text Available Nora I Schneider, Cord LangnerInstitute of Pathology, Medical University of Graz, Graz, AustriaAbstract: Tumor staging according to the American Joint Committee on Cancer/Union for International Cancer Control tumor, node, metastasis (TNM system is currently regarded as the standard for staging of patients with colorectal cancer. This system provides the strongest prognostic information for patients with early stage disease and those with advanced disease. For patients with intermediate levels of disease, it is less able to predict disease outcome. Therefore, additional prognostic markers are needed to improve the management of affected patients. Ideal markers are readily assessable on hematoxylin and eosin-stained tumor slides, and in this way are easily applicable worldwide. This review summarizes the histological features of colorectal cancer that can be used for prognostic stratification. Specifically, we refer to the different histological variants of colorectal cancer that have been identified, each of these variants carrying distinct prognostic significance. Established markers of adverse outcomes are lymphatic and venous invasion, as well as perineural invasion, but underreporting still occurs in the routine setting. Tumor budding and tumor necrosis are recent advances that may help to identify patients at high risk for recurrence. The prognostic significance of the antitumor inflammatory response has been known for quite a long time, but a lack of standardization prevented its application in routine pathology. However, scales to assess intra- and peritumoral inflammation have recently emerged, and can be expected to strengthen the prognostic significance of the pathology report.Keywords: colorectal cancer, lymphatic invasion, blood-vessel invasion, perineural invasion, tumor budding, tumor necrosis

  2. Significance analysis of prognostic signatures.

    Directory of Open Access Journals (Sweden)

    Andrew H Beck

    Full Text Available A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that "random" gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically

  3. Increased gibberellin contents contribute to accelerated growth and development of transgenic tobacco overexpressing a wheat ubiquitin gene.

    Science.gov (United States)

    Wang, Guo-Kun; Zhang, Meng; Gong, Jiang-Feng; Guo, Qi-Fang; Feng, Ya-Nan; Wang, Wei

    2012-12-01

    Overexpressing TaUb2 promoted stem growth and resulted in early flowering in transgenic tobacco plants. Ubiquitin are involved in the production, metabolism and proper function of gibberellin. The ubiquitin-26S proteasome system (UPS), in which ubiquitin (Ub) functions as a marker, is a post-translational regulatory system that plays a prominent role in various biological processes. To investigate the impact of different Ub levels on plant growth and development, transgenic tobacco (Nicotiana tabacum L.) plants were engineered to express an Ub gene (TaUb2) from wheat (Triticum aestivum L.) under the control of cauliflower mosaic virus 35S promoter. Transgenic tobacco plants overexpressing TaUb2 demonstrated an accelerated growth rate at early stage and an early flowering phenotype in development. The preceding expression of MADS-box genes also corresponded to the accelerated developmental phenotypes of the transgenic tobacco plants compared to that of wild-type (WT). Total gibberellin (GA) and active GA contents in transgenic tobacco plants were higher than those in WT at the corresponding developmental stages, and some GA metabolism genes were upregulated. Treatment with GA(3) conferred a similarly accelerated grown rate in WT plants to that of transgenic tobacco plants, while growth was inhibited when transgenic tobacco plants were treated with a GA biosynthesis inhibitor. Thus, the results suggest that Ub are involved in the production, metabolism and proper function of GA, which is important in the regulation of plant growth and development.

  4. New prognostic biomarkers in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Aneta Szudy-Szczyrek

    2016-01-01

    Full Text Available Multiple myeloma is a malignant neoplastic disease, characterized by uncontrolled proliferation and accumulation of plasma cells in the bone marrow, which is usually connected with production of a monoclonal protein. It is the second most common hematologic malignancy. It constitutes approximately 1% of all cancers and 10% of hematological malignancies. Despite the huge progress that has been made in the treatment of multiple myeloma in the past 30 years including the introduction of new immunomodulatory drugs and proteasome inhibitors, it is still an incurable disease. According to current data, the five-year survival rate is 45%. Multiple myeloma is a very heterogeneous disease with a very diverse clinical course, which is expressed by differences in effectiveness of therapeutic strategies and ability to develop chemoresistance. This diversity implies the need to define risk stratification factors that would help to create personalized and optimized therapy and thereby improve treatment outcomes. Prognostic markers that aim to objectively evaluate the risk of a poor outcome, relapse and the patient’s overall outcome are useful for this purpose. The existing, widely used prognostic classifications, such as the Salmon-Durie classification or ISS, do not allow for individualization of treatment. As a result of the development of diagnostic techniques, especially cytogenetics and molecular biology, we were able to discover a lot of new, more sensitive and specific prognostic factors. The paper presents recent reports on the role of molecular, cytogenetic and biochemical alterations in pathogenesis and prognosis of the disease.

  5. Use of Biotinylated Ubiquitin for Analysis of Rat Brain Mitochondrial Proteome and Interactome

    Directory of Open Access Journals (Sweden)

    Marina V. Medvedeva

    2012-09-01

    Full Text Available Applicability of in vitro biotinylated ubiquitin for evaluation of endogenous ubiquitin conjugation and analysis of ubiquitin-associated protein-protein interactions has been investigated. Incubation of rat brain mitochondria with biotinylated ubiquitin followed by affinity chromatography on avidin-agarose, intensive washing, tryptic digestion of proteins bound to the affinity sorbent and their mass spectrometry analysis resulted in reliable identification of 50 proteins belonging to mitochondrial and extramitochondrial compartments. Since all these proteins were bound to avidin-agarose only after preincubation of the mitochondrial fraction with biotinylated ubiquitin, they could therefore be referred to as specifically bound proteins. A search for specific ubiquitination signature masses revealed several extramitochondrial and intramitochondrial ubiquitinated proteins representing about 20% of total number of proteins bound to avidin-agarose. The interactome analysis suggests that the identified non-ubiquitinated proteins obviously form tight complexes either with ubiquitinated proteins or with their partners and/or mitochondrial membrane components. Results of the present study demonstrate that the use of biotinylated ubiquitin may be considered as the method of choice for in vitro evaluation of endogenous ubiquitin-conjugating machinery in particular subcellular organelles and changes in ubiquitin/organelle associated interactomes. This may be useful for evaluation of changes in interactomes induced by protein ubiquitination under norm and various brain pathologies.

  6. Use of biotinylated ubiquitin for analysis of rat brain mitochondrial proteome and interactome.

    Science.gov (United States)

    Buneeva, Olga A; Medvedeva, Marina V; Kopylov, Arthur T; Zgoda, Victor G; Medvedev, Alexei E

    2012-01-01

    Applicability of in vitro biotinylated ubiquitin for evaluation of endogenous ubiquitin conjugation and analysis of ubiquitin-associated protein-protein interactions has been investigated. Incubation of rat brain mitochondria with biotinylated ubiquitin followed by affinity chromatography on avidin-agarose, intensive washing, tryptic digestion of proteins bound to the affinity sorbent and their mass spectrometry analysis resulted in reliable identification of 50 proteins belonging to mitochondrial and extramitochondrial compartments. Since all these proteins were bound to avidin-agarose only after preincubation of the mitochondrial fraction with biotinylated ubiquitin, they could therefore be referred to as specifically bound proteins. A search for specific ubiquitination signature masses revealed several extramitochondrial and intramitochondrial ubiquitinated proteins representing about 20% of total number of proteins bound to avidin-agarose. The interactome analysis suggests that the identified non-ubiquitinated proteins obviously form tight complexes either with ubiquitinated proteins or with their partners and/or mitochondrial membrane components. Results of the present study demonstrate that the use of biotinylated ubiquitin may be considered as the method of choice for in vitro evaluation of endogenous ubiquitin-conjugating machinery in particular subcellular organelles and changes in ubiquitin/organelle associated interactomes. This may be useful for evaluation of changes in interactomes induced by protein ubiquitination under norm and various brain pathologies.

  7. In silico analysis of ubiquitin/ubiquitin-like modifiers and their conjugating enzymes in Entamoeba species.

    Science.gov (United States)

    Arya, Shweta; Sharma, Gaurav; Gupta, Preeti; Tiwari, Swati

    2012-07-01

    Covalent modification of proteins by ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) regulates many cellular functions in eukaryotes. These modifications are likely to be associated with pathogenesis, growth, and development of many protozoan parasites but molecular details about this pathway are unavailable for most protozoa. This study presents an analysis of the Ub pathway in three members of the Entamoeba species. Using bioinformatics tools we have identified all Ub and Ubl genes along with their corresponding activating, conjugating, and ligating enzymes (E1, E2s, and E3s) in three Entamoeba species, Entamoeba histolytica, Entamoeba dispar, and Entamoeba invadens. Phylogenetic trees were established for the identified E2s and RING finger E3s using maximum-likelihood method to infer the relationship among these proteins. In silico co-domain analysis of RING finger E3s implicates these proteins in a variety of functions. Several known and putative regulatory motifs were identified in the upstream regions of RING finger domain containing E3 genes. All E2 and E3 genes were analyzed in genomic context in E. histolytica and E. dispar. Most E2s and E3s were in syntenic positions in the two genomes. Association of these genes with transposable elements (TEs) was compared between E. histolytica and E. dispar. A closer association was found between RING finger E3s with TEs in E. histolytica. In summary, our analyses suggests that the complexity of the Ub pathway in Entamoeba species is close to that observed in higher eukaryotes. This study provides important data for further understanding the role of Ub pathway in the biology of these organisms.

  8. Ubiquitin-conjugating enzyme UBE2C is highly expressed in breast microcalcification lesions.

    Directory of Open Access Journals (Sweden)

    Chen-Pin Chou

    Full Text Available Ubiquitin-conjugating enzyme 2C (UBE2C contributes to ubiquitin-mediated proteasome degradation of cell cycle progression in breast cancer. Microcalcification (MC is the most common mammographic feature of early breast cancer. In this study, we evaluated whether UBE2C could be a tumor marker of early breast cancer with MC found on screening mammography. UBE2C protein and mRNA expression were measured in breast core biopsy pairs of MC and adjacent non-MC breast tissue from each subject. Immunohistochemistry revealed UBE2C positivity in 69.4% of MC samples and 77.6% negativity in non-MC samples (p<0.0001. On RT-qPCR, 56.1% of malignant MC lesion samples showed high mRNA level of UBE2C and 80% of benign MC lesion samples showed a low level of UBE2C (p = 0.1766. We investigated the carcinogenic role of UBE2C in MCF-7 breast cancer cells with UBE2C knockdown; UBE2C knockdown downregulated cell proliferation and activated the cellular apoptosis pathway to inhibit cell colony formation. Furthermore, UBE2C expression was associated with that of carcinogenic genes human epidermal growth factor receptor type 2 (HER2, cellular c-Ki-ras2 proto-oncogene (KRAS, vascular endothelial growth factor (VEGF, CXC chemokine receptor 4 (CXCR4, C-C motif chemokine 5 (CCL5, neural precursor cell expressed, developmentally downregulated 9 (NEDD9 and Ras homolog family member C (RhoC. UBE2C may be a marker for diagnosis of nonpalpable breast lesions but not benign or malignant tumors in mammography core biopsies. Suppression of UBE2C may be a potential therapy target in breast cancer.

  9. Patented small molecule inhibitors in the ubiquitin proteasome system

    Directory of Open Access Journals (Sweden)

    Colland Frédéric

    2007-11-01

    Full Text Available Abstract Deregulation of the ubiquitin proteasome system (UPS has been implicated in the pathogenesis of many human diseases, including cancer and neurodegenerative disorders. The recent approval of the proteasome inhibitor Velcade® (bortezomib for the treatment of multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. We review here new patented proteasome inhibitors and patented small molecule inhibitors targeting more specific UPS components, such as E3 ubiquitin ligases and deubiquitylating enzymes. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com.

  10. Substrates of the BRCA1-dependent ubiquitin ligase.

    Science.gov (United States)

    Starita, Lea M; Parvin, Jeffrey D

    2006-02-01

    Discovering the precise function of the breast and ovarian specific tumor suppressor, BRCA1, has proven to be quite complicated. It has been determined that BRCA1, together with BARD1, comprise an E3 ubiquitin ligase. Since it is now known that BRCA1 is an enzyme, the challenge for BRCA1 research is to learn how this enzymatic activity functions in normal breast and ovarian cells in order to suppress cancerous transformation. This review will survey the known ubiquitination substrates of BRCA1 and suggest how these reactions may influence the genomic stability and proliferation of breast cells.

  11. Functional assessment of ubiquitin-depended processes under microgravity conditions

    Science.gov (United States)

    Zhabereva, Anastasia; Shenkman, Boris S.; Gainullin, Murat; Gurev, Eugeny; Kondratieva, Ekaterina; Kopylov, Arthur

    Ubiquitylation, a widespread and important posttranslational modification of eukaryotic proteins, controls a multitude of critical cellular processes, both in normal and pathological conditions. The present work aims to study involvement of ubiquitin-dependent regulation in adaptive response to the external stimuli. Experiments were carried out on C57BL/6 mice. The microgravity state under conditions of real spaceflight on the biosatellite “BION-M1” was used as a model of stress impact. Additionally, number of control series including the vivarium control and experiments in Ground-based analog were also studied. The aggregate of endogenously ubiquitylated proteins was selected as specific feature of ubiquitin-dependent processes. Dynamic changes of modification pattern were characterized in liver tissue by combination of some methods, particularly by specific isolation of explicit protein pool, followed by immunodetection and/or mass spectrometry-based identification. The main approach includes specific extraction of proteins, modified by multiubiquitin chains of different length and topology. For this purpose two techniques were applied: 1) immunoprecipitation with antibodies against ubiquitin and/or multiubiquitin chains; 2) pull-down using synthetic protein construct termed Tandem Ubiquitin Binding Entities (TUBE, LifeSensors). TUBE represents fusion protein, composed of well characterized ubiquitin-binding domains, and thereby allows specific high-affinity binding and extraction of ubiquitylated proteins. Resulting protein fractions were analyzed by immunoblotting with antibodies against different types of multiubiquitin chains. Using this method we mapped endogenously modified proteins involved in two different types of ubiquitin-dependent processes, namely catabolic and non-catabolic ubiquitylation, in liver tissues, obtained from both control as well as experimental groups of animals, mentioned above. Then, isolated fractions of ubiquitylated proteins

  12. Prognostic Gene Expression Profiles in Breast Cancer

    DEFF Research Database (Denmark)

    Sørensen, Kristina Pilekær

    Each year approximately 4,800 Danish women are diagnosed with breast cancer. Several clinical and pathological factors are used as prognostic and predictive markers to categorize the patients into groups of high or low risk. Around 90% of all patients are allocated to the high risk group and offe......Each year approximately 4,800 Danish women are diagnosed with breast cancer. Several clinical and pathological factors are used as prognostic and predictive markers to categorize the patients into groups of high or low risk. Around 90% of all patients are allocated to the high risk group...... and offered systemic adjuvant therapy, and 50% of these patients receive chemotherapy. However, approximately 25-30% of the lymph node negative and 50% of the lymph node positive high risk patients would experience recurrence if left untreated with systemic adjuvant therapy. Consequently, considerable......, hormone receptor status, histological grade, age of patient at diagnosis, and year of surgery. All patients included in the study had not received any kind of systemic adjuvant therapy; hence, the study results were not influenced by treatment response. We compared lncRNA expression in metastatic and non...

  13. Opposite prognostic roles of HIF1β and HIF2β expressions in bone metastatic clear cell renal cell cancer

    DEFF Research Database (Denmark)

    Szendroi, Attila; Szász, A. Marcell; Kardos, Magdolna

    2016-01-01

    BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1β/HIF2β and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2β was lower in mRCC both at mRNA...

  14. Interplays between Sumoylation, SUMO-Targeted Ubiquitin Ligases, and the Ubiquitin-Adaptor Protein Ufd1 in Fission Yeast

    DEFF Research Database (Denmark)

    Køhler, Julie Bonne

    their conformation or interactions with other macromolecules. Though, whereas the downstream consequence of ubiquitin conjugation is often protein degradation, the functional outcomes of sumoylation are less unifiable. A class of ubiquitin E3 ligases able to target sumoylated proteins for degradation by the 26S...... proteasome mediates direct cross-talk between the two modification systems. By contributing to the dynamic turnover of SUMO conjugated species these SUMO-targeted ubiquitin ligases (STUbLs) fulfills essential roles in both yeast and man. However, the specific sumoylated proteins affected by STUbL activity...... and the specific molecular interactions and sequence of events linking sumoylation, ubiquitylation and substrate degradation, has been largely uncovered. Using the fission yeast model organism I here present evidence for a role of the Ufd1 (ubiquitinfusion degradation 1) protein, and by extension of the Cdc48-Ufd1...

  15. Tumour marker expression in blood and lymphatic vessels of human ...

    African Journals Online (AJOL)

    The behaviour of tumours cannot be effectively assessed on histological tissue sections only, hence, specific bi-ological markers were used to predict tumour behaviour. The biological markers at the same time must provide prognostic information, necessary for the treatment of patients. The immunostaining of antibodies ...

  16. Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research

    NARCIS (Netherlands)

    Burbach, J.P.H.; Kurk, S.A.; Cpebergh van den Braak, R.R.; Dik, V.K.; May, A.M.; Meijer, G.A.; Punt, C.J.A.; Vink, G.R.; Los, M.; Hoogerbrugge, N.; Huijgens, P.C.; Ijzermans, J.N.; Kuipers, E.J.; Noo, M.E. de; Pennings, J.P.; Velden, A.M. van der; Verhoef, C.; Siersema, P.D.; Oijen, M.G. van; Verkooijen, H.M.; Koopman, M.

    2016-01-01

    BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor.

  17. Prospective Dutch colorectal cancer cohort : an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research

    NARCIS (Netherlands)

    Burbach, J P M|info:eu-repo/dai/nl/413994627; Kurk, S A|info:eu-repo/dai/nl/413919730; Coebergh van den Braak, R R J; Dik, V K; May, A M|info:eu-repo/dai/nl/304818658; Meijer, G. A.; Punt, C J A; Vink, G R; Los, M; Hoogerbrugge, N; Huijgens, P C; Ijzermans, J N M; Kuipers, E J; de Noo, M E; Pennings, J P; van der Velden, A M T; Verhoef, C; Siersema, P D|info:eu-repo/dai/nl/110603826; van Oijen, M G H; Verkooijen, H M|info:eu-repo/dai/nl/213707705; Koopman, M|info:eu-repo/dai/nl/298209640

    2016-01-01

    BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor.

  18. Valor da enolase específica do neurônio como indicador de prognóstico pós-parada cardiorrespiratória Serum neuron-specific enolase as a prognostic marker after a cardiac arrest

    Directory of Open Access Journals (Sweden)

    Tatiana H. Rech

    2006-12-01

    complication after a cardiac arrest. Many studies are trying to find prognostic markers that can be associated with outcomes in patients surviving a cardiac arrest. Biochemical markers of neuronal injury seem to be promising in this scenario. Therefore, NSE levels have been studied in patients after a cardiac arrest and high enzyme levels suggest more extensive brain damage and are associated with unfavorable clinical outcomes. CONCLUSIONS: Outcome after a cardiac arrest is mostly determined by the degree of hypoxic brain damage and early determinations of serum NSE level can be a valuable ancillary method for assessing outcome in these patients.

  19. Qualitative ubiquitome unveils the potential significances of protein lysine ubiquitination in hyphal growth of Aspergillus nidulans.

    Science.gov (United States)

    Chu, Xin-Ling; Feng, Ming-Guang; Ying, Sheng-Hua

    2016-02-01

    Protein ubiquitination is an evolutionarily conserved post-translational modification process in eukaryotes, and it plays an important role in many biological processes. Aspergillus nidulans, a model filamentous fungus, contributes to our understanding of cellular physiology, metabolism and genetics, but its ubiquitination is not completely revealed. In this study, the ubiquitination sites in the proteome of A. nidulans were identified using a highly sensitive mass spectrometry combined with immuno-affinity enrichment of the ubiquitinated peptides. The 4816 ubiquitination sites were identified in 1913 ubiquitinated proteins, accounting for 18.1% of total proteins in A. nidulans. Bioinformatic analysis suggested that the ubiquitinated proteins associated with a number of biological functions and displayed various sub-cellular localisations. Meanwhile, seven motifs were revealed from the ubiquitinated peptides, and significantly over-presented in the different pathways. Comparison of the enriched functional catalogues indicated that the ubiquitination functions divergently during growth of A. nidulans and Saccharomyces cerevisiae. Additionally, the proteins in A. nidulans-specific sub-category (cell growth/morphogenesis) were subjected to the protein interaction analysis which demonstrated that ubiquitination is involved in the comprehensive protein interactions. This study presents a first proteomic view of ubiquitination in the filamentous fungus, and provides an initial framework for exploring the physiological roles of ubiquitination in A. nidulans.

  20. Selectivity of E2-E3 interactions in the human ubiquitin system

    NARCIS (Netherlands)

    van Wijk, S.J.L.

    2010-01-01

    Highly selective interactions between ubiquitin-conjugating enzymes and RING-type E3 ligases are crucial for the adequate and efficient action of ubiquitin and ubiquitin-like pathways. Within these cascades, E2 enzymes provide a connecting link between activation and the final covalent conjugation,

  1. Ubiquitination independent of E1 and E2 enzymes by bacterial effectors

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Jiazhang; Sheedlo, Michael J.; Yu, Kaiwen; Tan, Yunhao; Nakayasu, Ernesto S.; Das, Chittaranjan; Liu, Xiaoyun; Luo, Zhao-Qing

    2016-04-06

    Signaling by ubiquitination regulates virtually every cellular process in eukaryotes. Covalent attachment of ubiquitin to a substrate is catalyzed by the E1, E2 and E3 three-enzyme cascade 1, which links the C terminus of ubiquitin via an isopeptide bond mostly to the ε-amino group of a lysine of the substrate. Given the essential roles of ubiquitination in the regulation of the immune system, it is not surprising that the ubiquitination network is a common target for diverse infectious agents 2. For example, many bacterial pathogens exploit ubiquitin signaling using virulence factors that function as E3 ligases, deubiquitinases 3 or as enzymes that directly attack ubiquitin 4. The bacterial pathogen Legionella pneumophila utilizes approximately 300 effectors that modulate diverse host processes to create a niche permissive for its replication in phagocytes 5. Here we demonstrate that members of the SidE effector family (SidEs) of L. pneumophila ubiquitinate multiple Rab small GTPases associated with the endoplasmic reticulum (ER). Moreover, we show that these proteins are capable of catalyzing ubiquitination without the need for the E1 and E2 enzymes. The E1/E2-independent ubiquitination catalyzed by these enzymes requires NAD but not ATP and Mg2+. A putative mono ADP-ribosyltransferase (mART) motif critical for the ubiquitination activity is also essential for the role of SidEs in intracellular bacterial replication in a protozoan host. These results establish that ubiquitination can be catalyzed by a single enzyme.

  2. RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response

    DEFF Research Database (Denmark)

    Poulsen, Sara L; Hansen, Rebecca K; Wagner, Sebastian A

    2013-01-01

    Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), pro...

  3. Serum markers of liver fibrosis

    DEFF Research Database (Denmark)

    Veidal, Sanne Skovgård; Bay-Jensen, Anne-Christine; Tougas, Gervais

    2010-01-01

    BACKGROUND: Fibrosis is a central histological feature of chronic liver diseases and is characterized by the accumulation and reorganization of the extracellular matrix. The gold standard for assessment of fibrosis is histological evaluation of a percutaneous liver biopsy. Albeit a considerable......-epitopes, may be targeted for novel biochemical marker development in fibrosis. We used the recently proposed BIPED system (Burden of disease, Investigative, Prognostic, Efficacy and Diagnostic) to characterise present serological markers. METHODS: Pubmed was search for keywords; Liver fibrosis, neo......, a systematic use of the neo-epitope approach, i.e. the quantification of peptide epitopes generated from enzymatic cleavage of proteins during extracellular remodeling, may prove productive in the quest to find new markers of liver fibrosis....

  4. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer

    DEFF Research Database (Denmark)

    Knudsen, Mie Grunnet; Sorensen, J B

    2012-01-01

    The use of CEA as a prognostic and predictive marker in patients with lung cancer is widely debated. The aim of this review was to evaluate the results from studies made on this subject. Using the search words "CEA", "tumor markers in lung cancer", "prognostic significance", "diagnostic...... and risk of death measured over time. No studies found CEA levels useful as a diagnostic marker for lung cancer. With regard to NSCLC the level of CEA measured in tumor tissue in NSCLC patients, were not of prognostic, diagnostic or predictive significance for OS or recurrence after treatment. In one study...... significance" and "predictive significance", a search was carried out on PubMed. Exclusion criteria was articles never published in English, articles before 1981 and articles evaluating tumor markers in lung cancer not involving CEA. Initially 217 articles were found, and 34 were left after selecting those...

  5. Ubiquitin expression in coeliac disease | Yeboah | Journal of the ...

    African Journals Online (AJOL)

    Biopsy-sections of the small intestine of established coeliac patients were investigated by immunoperoxidase procedures, using monoclonal antibodies to detect the presence of ubiquitin, a heat shock protein, to find out the role, if any, of this protein in the pathogenesis of coeliac disease. Sections from each case stained ...

  6. Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury.

    Science.gov (United States)

    Bhattacharya, Sabyasachi; Katlinski, Kanstantsin V; Reichert, Maximilian; Takano, Shigetsugu; Brice, Angela; Zhao, Bin; Yu, Qiujing; Zheng, Hui; Carbone, Christopher J; Katlinskaya, Yuliya V; Leu, N Adrian; McCorkell, Kelly A; Srinivasan, Satish; Girondo, Melanie; Rui, Hallgeir; May, Michael J; Avadhani, Narayan G; Rustgi, Anil K; Fuchs, Serge Y

    2014-03-01

    Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN effects in vitro. The significance of this paradoxical regulation is unknown. Presented here results demonstrate that inability to stimulate IFNAR1 ubiquitination in the Ifnar1(SA) knock-in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1(SA) mice (or their bone marrow-receiving wild type animals) display persistent immune infiltration of inflamed tissues, extensive damage and gravely inadequate tissue regeneration. Pharmacologic stimulation of IFNAR1 ubiquitination is protective against from toxic hepatitis and fulminant generalized inflammation in wild type but not Ifnar1(SA) mice. These results suggest that endogenous mechanisms that trigger IFNAR1 ubiquitination for limiting the inflammation-induced tissue damage can be purposely mimicked for therapeutic benefits.

  7. What history tells us XLI. Ubiquitin and proteolysis

    Indian Academy of Sciences (India)

    Keywords. Biochemistry vs. molecular biology; energy dependence; lysosome; nucleosome; proteolysis; ubiquitin. Abstract. Author Affiliations. MICHEL MORANGE1. Centre Cavaillès, République des Savoirs: Lettres, Sciences, Philosophie USR 3608, Ecole Normale Supérieure, 29 Rue d'Ulm, 75230, Paris Cedex 05, ...

  8. UbiGate: a synthetic biology toolbox to analyse ubiquitination.

    Science.gov (United States)

    Kowarschik, Kathrin; Hoehenwarter, Wolfgang; Marillonnet, Sylvestre; Trujillo, Marco

    2018-03-01

    Ubiquitination is mediated by an enzymatic cascade that results in the modification of substrate proteins, redefining their fate. This post-translational modification is involved in most cellular processes, yet its analysis faces manifold obstacles due to its complex and ubiquitous nature. Reconstitution of the ubiquitination cascade in bacterial systems circumvents several of these problems and was shown to faithfully recapitulate the process. Here, we present UbiGate - a synthetic biology toolbox, together with an inducible bacterial expression system - to enable the straightforward reconstitution of the ubiquitination cascades of different organisms in Escherichia coli by 'Golden Gate' cloning. This inclusive toolbox uses a hierarchical modular cloning system to assemble complex DNA molecules encoding the multiple genetic elements of the ubiquitination cascade in a predefined order, to generate polycistronic operons for expression. We demonstrate the efficiency of UbiGate in generating a variety of expression elements to reconstitute autoubiquitination by different E3 ligases and the modification of their substrates, as well as its usefulness for dissecting the process in a time- and cost-effective manner. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

  9. Prognostic factors in oligodendrogliomas

    DEFF Research Database (Denmark)

    Westergaard, L; Gjerris, F; Klinken, L

    1997-01-01

    .5 years and for the group older than 60 years of 13 months. The group without neurological deficits had a 5-years survival of 43 per cent while the group with deficits had a 5-years survival of 5 per cent. The 5-years survival for oligodendroglioma of grade II was 46 per cent and for grade III 10 per cent......An outcome analysis was performed on 96 patients with pure cerebral oligodendrogliomas operated in the 30-year period 1962 to 1991. The most important predictive prognostic factors were youth and no neurological deficit, demonstrated as a median survival for the group younger than 20 years of 17...

  10. MOLECULAR MARKERS FOR METASTATIC PROSTATE ADENOCARCINOMA

    Directory of Open Access Journals (Sweden)

    I. S. Kunin

    2012-01-01

    Full Text Available The search of molecular markers of metastasing and prognosis in prostate cancer remains an urgent task. In this study, we investigated the relationship of gene expression heparanase-1 (HPSE1 and D-glucuronil C5-epimerase (GLCE with early disease relapse and metastasis of a 2,5−3 years after diagnosis. It was shown that the ratio of the expression levels of genes HPSE1/GLCE > 1 may serve as a prognostic relapse marker and trends of the tumour to metastasis. The data obtained suggest to use this option as a molecular marker for the diagnostics of metastatic process and the disease prognosis.

  11. Ubiquitin regulates GGA3-mediated degradation of BACE1.

    Science.gov (United States)

    Kang, Eugene L; Cameron, Andrew N; Piazza, Fabrizio; Walker, Kendall R; Tesco, Giuseppina

    2010-07-30

    BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1) is a membrane-tethered member of the aspartyl proteases, essential for the production of beta-amyloid, a toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. The BACE1 C-terminal fragment contains a DXXLL motif that has been shown to bind the VHS (VPS27, Hrs, and STAM) domain of GGA1-3 (Golgi-localized gamma-ear-containing ARF-binding proteins). GGAs are trafficking molecules involved in the transport of proteins containing the DXXLL signal from the Golgi complex to endosomes. Moreover, GGAs bind ubiquitin and traffic synthetic and endosomal ubiquitinated cargoes to lysosomes. We have previously shown that depletion of GGA3 results in increased BACE1 levels and activity because of impaired lysosomal degradation. Here, we report that the accumulation of BACE1 is rescued by the ectopic expression of GGA3 in H4 neuroglioma cells depleted of GGA3. Accordingly, the overexpression of GGA3 reduces the levels of BACE1 and beta-amyloid. We then established that mutations in the GGA3 VPS27, Hrs, and STAM domain (N91A) or in BACE1 di-leucine motif (L499A/L500A), able to abrogate their binding, did not affect the ability of ectopically expressed GGA3 to rescue BACE1 accumulation in cells depleted of GGA3. Instead, we found that BACE1 is ubiquitinated at lysine 501 and is mainly monoubiquitinated and Lys-63-linked polyubiquitinated. Finally, a GGA3 mutant with reduced ability to bind ubiquitin (GGA3L276A) was unable to regulate BACE1 levels both in rescue and overexpression experiments. These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery.

  12. Ubiquitin Regulates GGA3-mediated Degradation of BACE1*

    Science.gov (United States)

    Kang, Eugene L.; Cameron, Andrew N.; Piazza, Fabrizio; Walker, Kendall R.; Tesco, Giuseppina

    2010-01-01

    BACE1 (β-site amyloid precursor protein-cleaving enzyme 1) is a membrane-tethered member of the aspartyl proteases, essential for the production of β-amyloid, a toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. The BACE1 C-terminal fragment contains a DXXLL motif that has been shown to bind the VHS (VPS27, Hrs, and STAM) domain of GGA1–3 (Golgi-localized γ-ear-containing ARF-binding proteins). GGAs are trafficking molecules involved in the transport of proteins containing the DXXLL signal from the Golgi complex to endosomes. Moreover, GGAs bind ubiquitin and traffic synthetic and endosomal ubiquitinated cargoes to lysosomes. We have previously shown that depletion of GGA3 results in increased BACE1 levels and activity because of impaired lysosomal degradation. Here, we report that the accumulation of BACE1 is rescued by the ectopic expression of GGA3 in H4 neuroglioma cells depleted of GGA3. Accordingly, the overexpression of GGA3 reduces the levels of BACE1 and β-amyloid. We then established that mutations in the GGA3 VPS27, Hrs, and STAM domain (N91A) or in BACE1 di-leucine motif (L499A/L500A), able to abrogate their binding, did not affect the ability of ectopically expressed GGA3 to rescue BACE1 accumulation in cells depleted of GGA3. Instead, we found that BACE1 is ubiquitinated at lysine 501 and is mainly monoubiquitinated and Lys-63-linked polyubiquitinated. Finally, a GGA3 mutant with reduced ability to bind ubiquitin (GGA3L276A) was unable to regulate BACE1 levels both in rescue and overexpression experiments. These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery. PMID:20484053

  13. Regulation of Hh/Gli signaling by dual ubiquitin pathways.

    Science.gov (United States)

    Jiang, Jin

    2006-11-01

    The Hedgehog (Hh) signaling pathway governs cell growth and patterning in animal development. Malfunction of several pathway components, including the key transcriptional effector Ci/Gli proteins, leads to a variety of human disorders including several malignancies. Ci/Gli activity is controlled by multi-layered regulatory mechanisms, the most prominent of which is the ubiquitin-mediated proteolysis. In the absence of Hh, Ci/Gli is proteolytically processed into a truncated form that functions as a transcriptional repressor of the Hh pathway. Ci processing is mediated by an SCF (Skip1/Cul1/F-box protein) ubiquitin ligase in which the F-box protein Slimb/beta-TRCP bridges Ci to the ubiquitin ligase. Recent studies in Drosophila and mammalian cultured cells have demonstrated that sequential phosphorylation of Ci/Gli by PKA, GSK3, and CKI creates multiple docking sites that can recruit SCF(Slimb/beta-TRCP), which then promotes Ci/Gli ubiquitination followed by proteasome-mediated processing. Recently, an E3 ubiquitin ligase consisting of the BTB (Broad Complex, Tramtrack, and Bric a Brac) protein HIB (Hh induced MATH and BTB protein) and Cullin 3 (Cul3) has been identified that acts in a negative feedback loop to fine-tune Hh signaling responses by degrading full length Ci. In eye imaginal discs where Hh signals coordinate cell proliferation and differentiation, HIB is highly expressed in the differentiating cells to prevent aberrant Hh signaling activity and ensure normal eye development. Tissue- and developmental stage-specific expression of HIB and its homologs in vertebrates may provide a conserved mechanism for ensuring precision in spatial and temporal control of Hh signaling.

  14. Characterization of ubiquitination dependent dynamics in growth factor receptor signaling by quantitative proteomics

    DEFF Research Database (Denmark)

    Akimov, Vyacheslav; Rigbolt, Kristoffer T G; Nielsen, Mogens M

    2011-01-01

    Protein ubiquitination is a dynamic reversible post-translational modification that plays a key role in the regulation of numerous cellular processes including signal transduction, endocytosis, cell cycle control, DNA repair and gene transcription. The conjugation of the small protein ubiquitin...... as ubiquitination-dependent events in signaling pathways. In addition to a detailed seven time-point profile of EGFR ubiquitination over 30 minutes of ligand stimulation, our data determined prominent involvement of Lysine-63 ubiquitin branching in EGF signaling. Furthermore, we found two centrosomal proteins, PCM1...

  15. The Angelman Syndrome-associated ubiquitin ligase Ube3A regulates synapse development by ubiquitinating Arc

    Science.gov (United States)

    Greer, Paul L.; Hanayama, Rikinari; Bloodgood, Brenda L.; Mardinly, Alan R.; Lipton, David M.; Flavell, Steven W.; Kim, Tae-Kyung; Griffith, Eric C.; Waldon, Zachary; Maehr, Rene; Ploegh, Hidde L.; Chowdhury, Shoaib; Worley, Paul F.; Steen, Judith; Greenberg, Michael E.

    2010-01-01

    Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development, and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA sub-type of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possible other ASDs. PMID:20211139

  16. Prognostic factors in lupus nephritis

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Starklint, Henrik; Halberg, Poul

    2006-01-01

    To evaluate the prognostic significance of clinical and renal biopsy findings in an unselected cohort of patients with systemic lupus erythematosus (SLE) and nephritis.......To evaluate the prognostic significance of clinical and renal biopsy findings in an unselected cohort of patients with systemic lupus erythematosus (SLE) and nephritis....

  17. Requirements Specifications for Prognostics: An Overview

    Data.gov (United States)

    National Aeronautics and Space Administration — With recent advancements in prognostics methodologies there has been a significant interest in maturing Prognostics and Health Management (PHM) to increase its...

  18. On Applying the Prognostic Performance Metrics

    Data.gov (United States)

    National Aeronautics and Space Administration — Prognostics performance evaluation has gained significant attention in the past few years. *As prognostics technology matures and more sophisticated methods for...

  19. Metrics for Offline Evaluation of Prognostic Performance

    Data.gov (United States)

    National Aeronautics and Space Administration — Prognostic performance evaluation has gained significant attention in the past few years.*Currently, prognostics concepts lack standard definitions and suffer from...

  20. Microalbuminúria é um marcador prognóstico independente em pacientes com insuficiência cardíaca crônica Microalbuminuria es un marcador pronóstico independiente en pacientes con insuficiencia cardíaca crónica Microalbuminuria is an independent prognostic marker in patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Humberto Villacorta

    2012-01-01

    prospectivamente incluidos. La edad media fue de 63,7 ± 12,2 y 37 (40,7% eran del sexo masculino. La media de fracción de eyección del ventrículo izquierdo (FEVI fue de 52,5 ± 17,5%. Pacientes en diálisis fueron excluidos. La Concentración de Albúmina Urinaria (CAU fue determinada en primera muestra de orina de la mañana. El tiempo transcurrido hasta el primer evento (internación por IC, consulta en el departamento de emergencia por IC o muerte cardiovascular fue definido como endpoint. El seguimiento medio fue de 11 ± 6,1 meses. RESULTADOS: En el momento de la inclusión en el estudio, 38 (41,3% pacientes tenían microalbuminuria y ningún paciente tuvo albuminuria evidente. Pacientes con microalbuminuria presentaron menor fracción de eyección ventricular izquierda que el resto de los individuos (47,9 ± 18,5 vs. 54,5 ± 17,7%, p = 0,08. La CAU presentó mayor en pacientes con eventos (mediana 59,8 vs. 18 mg/L, p = 0,0005. La sobrevida libre de eventos fue menor en los pacientes con microalbuminuria cuando fueron comparados con albuminuria normal (p BACKGROUND: Microalbuminuria has been described as a risk factor for progressive cardiovascular and renal diseases. Little is known about its prognostic value in patients (pts with established heart failure (HF. OBJECTIVE: To assess the role of microalbuminuria as a prognostic marker in patients with chronic HF receiving standard medication. METHODS: From January 2008 through September 2009, 92 pts with chronic HF, were prospectively included. Mean age was 63.7±12.2 and 37 (40.7% were male. Mean left ventricular ejection fraction (LVEF was 52.5±17.5%. Pts under dialysis were excluded. Urinary albumin concentration (UAC was determined in first morning spot sample of urine. Time to first event (HF hospitalization, emergency department visit for HF or cardiovascular death was defined as endpoint. Mean follow-up was 11±6.1 months. RESULTS: At the time of inclusion in the study, 38 (41.3% pts had microalbuminuria and no

  1. Tumor markers in breast cancer- European Group on Tumor Markers recommendations

    DEFF Research Database (Denmark)

    Molina, Rafael; Barak, Vivian; van Dalen, Arie

    2005-01-01

    in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin (trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node...

  2. (SSR) markers

    African Journals Online (AJOL)

    uwerhiavwe

    Variability was observed for six ... rapid increase in climate change, so there is need to develop high yielding ... the past decade including assessment of genetic diversity in maize ... The SSR gel images and marker data were processed using.

  3. Prognostic protein markers for triple negative breast cancer

    NARCIS (Netherlands)

    A. Umar (Arzu); N.Q. Liu (Ning Qing); R.B.H. Braakman (René)

    2010-01-01

    textabstractBreast cancer is the most commonly diagnosed malignancy in women in the Western world, with 13,000 new patients each year in the Netherlands alone. Extensive research on gene expression profiling has shown that breast cancer is a mixture of biologically different disease entities,

  4. Diet-sensitive prognostic markers for cardiovascular and renal disease

    NARCIS (Netherlands)

    Riphagen, Ineke Jowanna

    2016-01-01

    Diet plays a relevant role in the development and progression of lifestyle-related diseases like hypertension and type 2 diabetes and the subsequent risk of cardiovascular and renal disease. Riphagen used several diet-sensitive biomarkers to further explore the effects of diet on cardiovascular and

  5. Mast Cells as a Potential Prognostic Marker in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Gianluigi Taverna

    2013-01-01

    Full Text Available Despite years of intensive investigation that has been made in understanding prostate cancer, it remains one of the major men’s health issues and the leading cause of death worldwide. It is now ascertained that prostate cancer emerges from multiple spontaneous and/or inherited alterations that induce changes in expression patterns of genes and proteins that function in complex networks controlling critical cellular events. It is now accepted that several innate and adaptive immune cells, including T- and B-lymphocytes, macrophages, natural killer cells, dendritic cells, neutrophils, eosinophils, and mast cells (MCs, infiltrate the prostate cancer. All of these cells are irregularly scattered within the tumor and loaded with an assorted array of cytokines, chemokines, and inflammatory and cytotoxic mediators. This complex framework reflects the diversity in tumor biology and tumor-host interactions. MCs are well-established effector cells in Immunoglobulin-E (Ig-E associated immune responses and potent effector cells of the innate immune system; however, their clinical significance in prostate cancer is still debated. Here, these controversies are summarized, focusing on the implications of these findings in understanding the roles of MCs in primary prostate cancer.

  6. Circulating nucleic acids as a diagnostic and prognostic marker in ...

    African Journals Online (AJOL)

    Elevated levels of circulating nucleic acids have been found in a variety of benign and malignant pathological conditions. The ability to detect and quantitate specific DNA, RNA and micro-RNA sequences in serum/ plasma has opened up the possibilities of non-invasive diagnosis and monitoring of diseases. Circulating ...

  7. Prognostic and predictive markers for the new immunotherapies.

    Science.gov (United States)

    Mahoney, Kathleen M; Atkins, Michael B

    2014-11-01

    Blocking the programmed cell death 1 (PD-1) pathway with monoclonal antibodies has shown promising antitumor responses in clinical trials, with less toxicity than has been seen with prior immune therapies such as interleukin 2 and ipilimumab. Pembrolizumab, an anti-PD-1 antibody, recently gained US Food and Drug Administration (FDA) accelerated approval for the treatment of patients with ipilimumab-refractory melanoma, while nivolumab, another anti-PD-1 antibody, and MPDL3280A, an anti-programmed cell death 1 ligand (PD-L1) antibody, have been granted FDA "breakthrough designation" for treatment of subsets of patients with refractory Hodgkin lymphoma and metastatic bladder cancer, respectively. Encouraging antitumor activity has also been seen with these agents in patients with other malignancies, including non-small-cell lung cancer and head and neck cancer, tumors not previously thought to be immune-responsive. PD-L1 expression has emerged as a potential predictive biomarker for PD-1-directed therapy. Multiple, distinct, companion assays for PD-L1 positivity have been developed, but there is as yet no comparison, standardization, or prospective validation of these assays. PD-L1 expression on tumor cells and/or the tumor-immune infiltrate is likely only part of the predictive model necessary for selecting patients predisposed to respond to monotherapy. Additional predictive biomarkers are necessary to identify patients most likely to benefit from PD-1-based combination therapy, since tumor cell PD-L1 expression appears to have limited predictive value in this setting.

  8. Prognostic Markers in Pancreatic Cancer: the tumor and its environment

    NARCIS (Netherlands)

    J. van der Zee (Jill)

    2012-01-01

    textabstractIncidence Pancreatic cancer is not one of the most common types of cancer; however it is most certainly one of the most devastating types, ranking fourth in the list of cancer related deaths with a 5-year survival of only 6%. In 2010 there were an estimated 43.140 new cases whereas

  9. Cell surface carbohydrates as prognostic markers in human carcinomas

    DEFF Research Database (Denmark)

    Dabelsteen, Erik

    1996-01-01

    Tumour development is usually associated with changes in cell surface carbohydrates. These are often divided into changes related to terminal carbohydrate structures, which include incomplete synthesis and modification of normally existing carbohydrates, and changes in the carbohydrate core...... structure. The latter includes chain elongation of both glycolipids and proteins, increased branching of carbohydrates in N-linked glycoproteins, and blocked synthesis of carbohydrates in O-linked mucin-like glycoproteins. In mature organisms, expression of distinct carbohydrates is restricted to specific...... cell types; within a given tissue, variation in expression may be related to cell maturation. Tumour-associated carbohydrate structures often reflect a certain stage of cellular development; most of these moieties are structures normally found in other adult or embryonic tissues. There is no unique...

  10. Leukocytosis as a prognostic marker in the development of fetal ...

    African Journals Online (AJOL)

    2013-10-24

    Oct 24, 2013 ... FIRS is characterized by increase of IL-6 level in fetal blood plasma (]11 pg/ml) and the presence of umbilical cord inflammation (funisi- tis) (6, 7). FIRS may cause heavy damage in the fetus and newborns, as well as respiratory distress syndrome, neonatal sepsis, pneumonia, bronchial-pulmonary dys-.

  11. Malignant Pleural Mesothelioma Prognostic Marker: A Review of ...

    African Journals Online (AJOL)

    Erah

    extracellular matrix were positive for osteopontin. Osteopontin expression was observed in ... vesicles. In the LS (long-term survival) group, the distribution of HScore values of osteopontin expression varied from 5 to 250 (median, 50), whereas in the SS (short term survival) group, HScore values varied from 30 to 297.

  12. APNG as a prognostic marker in patients with glioblastoma

    DEFF Research Database (Denmark)

    Fosmark, Sigurd; Hellwege, Sofie; Dahlrot, Rikke H

    2017-01-01

    -tumor cells were excluded using an IHC/qIHC double-staining. For verification, APNG was measured by a quantitative double-immunofluorescence (IF) assay. As validation APNG mRNA expression was evaluated using independent TCGA data. RESULTS: Using qIHC, high levels of APNG were associated with better overall...... of GBMs was taken into account by excluding APNG expression in non-tumor cells from the analysis. METHODS: APNG expression was evaluated using automated image analysis and a novel quantitative immunohistochemical (IHC) assay (qIHC), where APNG protein expression was evaluated through countable dots. Non...

  13. Coagulopathy as prognostic marker in acute traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Gaurav Chhabra

    2013-01-01

    Full Text Available Context: Coagulopathy frequently occurs following traumatic brain injury (TBI and usually occurs 6-72 hour post-trauma. The incidence and the probable risk factors for development of coagulopathy and poor outcome following TBI are largely unknown and vary considerably. Aims: To assess the incidence and probable risk factors for development of coagulopathy and to identify the risk factors for poor outcome in terms of median survival time following TBI. Materials and Methods: In this prospective study over two years, patients of isolated moderate and severe traumatic brain injury (GCS≤12 admitted to trauma center had coagulation profile (PT, APTT, thrombin time, fibrinogen and D-dimer, arterial lactate and ABG analysis done on day of admission and on day three. Coagulopathy was defined as prothrombin time (PT or/and activated partial thromboplastin time (APTT more than 1.5 times the normal control. Incidence of in-hospital mortality was assessed in all cases. Statistical Analysis: A stepwise logistic regression analysis was performed to identify risk factors for coagulopathy and mortality in these patients. Results: A total of 208 patients were enrolled in the study. The mean age was 32 ± 12 years and mean GCS was 7.1 ± 2.8. Coagulopathy was present in 46% ( n = 96 of patients. Risk factors for development of coagulopathy were found out to be severity of head injury (OR: 2.81, elevated D-dimer (OR: 3.43, low hemoglobin (OR: 3.13, and effaced cisterns in the CT scan (OR: 2.72. Presence of coagulopathy (OR: 2.97 and severity of head injury (OR: 5.70 strongly predicted poor outcome, and were associated with a decreased median survival time. Conclusions: There is a high incidence of coagulopathy following TBI. The presence of coagulopathy as well as of severity of TBI are strong predictors of in-hospital mortality in these patients.

  14. Identification of Novel Prognostic Genetic Marker in Prostate Cancer

    Science.gov (United States)

    2001-08-01

    investigating the molecular basis of laterality of the human cerebral hemispheres . Gene dosage changes in patients with Klinefelter’s syndrome (karyotype...aberrations were detected in the form of chromosomal gain. Overall, the commonest aberration was gain of chromosome 8, followed by gains of...10q24 material to two three CaP cell lines. When comparing breakpoint sites on chromosome 5q, forming a derivative chro- regions of DU145 and PC-3

  15. Estudo citofotométrico da expressão do marcador tumoral Fator VIII e fatores prognósticos no adenocarcinoma gástrico Cytophotometric study of the expression of the tumoral marker Factor VIII and prognostic factors in gastrci adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Mary Tossa Nakamura

    2007-12-01

    ção III ou IV apresentaram índice de marcagem maiores do que aqueles com Bormann I ou II, porém sem correlação com a profundidade de invasão tumoral, grau de diferenciação, envolvimento nodal e padrão histológico. CONCLUSÕES: O presente estudo identificou e marcou 95,24% das amostras para o Fator VIII. Em relação aos fatores prognósticos não houve correlação significativa exceto entre o Fator VIII e a classificação de Bormann no qual o tipo III ou IV foi maior que o tipo I ou II.INTRODUCTION: Regarding gastric cancer, the incidence, diagnosis and therapeutic options showed improvement in the last decades, but prognosis remains gloomy, specially due the fact that most patients, already diagnosed present advanced tumors, metastatic and not liable to be surgically resected. Molecular biology is an area in science, which can give the answer to many questions and current scientific facts show that the this should be through detection of tumoral markers. The great advances in informatics refined cell image analysis by image cytophotometry makes it possible to study cell proliferation and angiogenesis in various tumor processes using immunohistochemistry and several markers. At present, studies are conducted to demonstrate the prognostic value of their expressions, however, in gastric adenocarcinoma the results have been divergent and studies are scarce. AIM: To identify and quantify the expression of cell proliferation markers using Ki-67 and of angiogenesis with Factor VIII in gastric adenocarcinoma using cytophotometry, and compare their expressions with factors such as Bormanns´ classification, tumor invasion depth, degree of differentiation, nodal involvement, histologic pattern and age. METHODS: Twenty-one patients with gastric adenocarcinoma identified between 1998 and 2006 were studied. Ki-67 and Factor VIII expressions were performed using immunohistochemistry with clone MIB-1 primary antibodies, monoclonal for Ki-67 and policlonal for Factor VIII

  16. Proteína C-reativa: marcador inflamatório com valor prognóstico em pacientes com insuficiência cardíaca descompensada C-reactive protein: an inflammatory marker with prognostic value in patients with decompensated heart failure

    Directory of Open Access Journals (Sweden)

    Humberto Villacorta

    2007-05-01

    Full Text Available FUNDAMENTO: A inflamação vem sendo implicada na fisiopatologia de uma série de doenças cardiovasculares. A proteína C-reativa (PCR titulada é um marcador de inflamação de fácil obtenção na sala de emergência. OBJETIVO: Estudar o valor prognóstico da PCR em pacientes admitidos por insuficiência cardíaca (IC descompensada. MÉTODOS: Coorte prospectiva de 119 pacientes com IC descompensada, atendidos na sala de emergência, com média de idade de 74 ± 11 anos, dos quais 76 (64% eram do sexo masculino. Todos estavam em classe funcional III ou IV da New York Heart Association. A dosagem da PCR foi realizada por ocasião da admissão na sala de emergência, pelo método de nefelometria. Os pacientes foram acompanhados, após a alta hospitalar, por um tempo médio de 12 ± 9,7 meses e o desfecho analisado foi a mortalidade cardiovascular. RESULTADOS: Houve 44 (36,9% óbitos, todos por causa cardiovascular. Indivíduos com PCR > 3 mg/dl apresentaram maior mortalidade que indivíduos com valores inferiores a esse (p=0,018. A análise multivariada pelo modelo proporcional de Cox destacou como fator independente para prognóstico mais importante a PCR (razão de chances de 0,0916 [intervalo de confiança de 95% = 0,0341 a 0,1490] para aumentos de uma unidade na PCR. CONCLUSÃO: A PCR é um preditor independente de mortalidade cardiovascular em pacientes com IC descompensada, indicando que a inflamação representa componente importante na fisiopatologia da doença.BACKGROUND: Inflammation has been implicated in the pathophysiology of a series of cardiovascular diseases. C-reactive protein (CRP is a marker of inflammation easily obtained in the emergency room. OBJECTIVE: To study the prognostic value of CRP in patients admitted for acute decompensated heart failure (ADHF. METHODS: A prospective cohort of 119 patients with ADHF treated in the emergency room. Mean age was 74±11 years and 76 (64% of patients were male. All were New York Heart

  17. The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor A Gene in Colorectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Torben F., E-mail: torben.hansen@slb.regionsyddanmark.dk; Spindler, Karen-Lise G. [Department of Oncology, Vejle Hospital, Vejle (Denmark); Andersen, Rikke F. [Department of Biochemistry, Vejle Hospital, Vejle (Denmark); Lindebjerg, Jan [Department of Clinical Pathology, Vejle Hospital, Vejle (Denmark); Kølvraa, Steen [Department of Clinical Genetics, Vejle Hospital, Vejle (Denmark); Brandslund, Ivan [Department of Biochemistry, Vejle Hospital, Vejle (Denmark); Jakobsen, Anders [Department of Oncology, Vejle Hospital, Vejle (Denmark)

    2010-06-28

    New prognostic markers in patients with colorectal cancer (CRC) are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene has been proposed. The objective of the present study was to investigate the prognostic importance of haplotypes in the VEGF-A gene in patients with CRC. The study included 486 patients surgically resected for stage II and III CRC, divided into two independent cohorts. Three SNPs in the VEGF-A gene were analyzed by polymerase chain reaction. Haplotypes were estimated using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible for this effect, was present in approximately 30% of the patients and demonstrated a significant relationship with poor survival, and it remained an independent prognostic marker after multivariate analysis, hazard ratio 2.46 (95% confidence interval 1.49–4.06), p < 0.001. Validation was provided by consistent findings in a second and independent cohort. Haplotype combinations call for further investigation.

  18. The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor A Gene in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Torben F. Hansen

    2010-06-01

    Full Text Available New prognostic markers in patients with colorectal cancer (CRC are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs in the vascular endothelial growth factor A (VEGF-A gene has been proposed. The objective of the present study was to investigate the prognostic importance of haplotypes in the VEGF-A gene in patients with CRC. The study included 486 patients surgically resected for stage II and III CRC, divided into two independent cohorts. Three SNPs in the VEGF-A gene were analyzed by polymerase chain reaction. Haplotypes were estimated using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible for this effect, was present in approximately 30% of the patients and demonstrated a significant relationship with poor survival, and it remained an independent prognostic marker after multivariate analysis, hazard ratio 2.46 (95% confidence interval 1.49–4.06, p < 0.001. Validation was provided by consistent findings in a second and independent cohort. Haplotype combinations call for further investigation.

  19. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

    Science.gov (United States)

    Glessner, Joseph T; Wang, Kai; Cai, Guiqing; Korvatska, Olena; Kim, Cecilia E; Wood, Shawn; Zhang, Haitao; Estes, Annette; Brune, Camille W; Bradfield, Jonathan P; Imielinski, Marcin; Frackelton, Edward C; Reichert, Jennifer; Crawford, Emily L; Munson, Jeffrey; Sleiman, Patrick M A; Chiavacci, Rosetta; Annaiah, Kiran; Thomas, Kelly; Hou, Cuiping; Glaberson, Wendy; Flory, James; Otieno, Frederick; Garris, Maria; Soorya, Latha; Klei, Lambertus; Piven, Joseph; Meyer, Kacie J; Anagnostou, Evdokia; Sakurai, Takeshi; Game, Rachel M; Rudd, Danielle S; Zurawiecki, Danielle; McDougle, Christopher J; Davis, Lea K; Miller, Judith; Posey, David J; Michaels, Shana; Kolevzon, Alexander; Silverman, Jeremy M; Bernier, Raphael; Levy, Susan E; Schultz, Robert T; Dawson, Geraldine; Owley, Thomas; McMahon, William M; Wassink, Thomas H; Sweeney, John A; Nurnberger, John I; Coon, Hilary; Sutcliffe, James S; Minshew, Nancy J; Grant, Struan F A; Bucan, Maja; Cook, Edwin H; Buxbaum, Joseph D; Devlin, Bernie; Schellenberg, Gerard D; Hakonarson, Hakon

    2009-05-28

    Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

  20. Using the Ubiquitin-modified Proteome to Monitor Distinct and Spatially Restricted Protein Homeostasis Dysfunction.

    Science.gov (United States)

    Gendron, Joshua M; Webb, Kristofor; Yang, Bing; Rising, Lisa; Zuzow, Nathan; Bennett, Eric J

    2016-08-01

    Protein homeostasis dysfunction has been implicated in the development and progression of aging related human pathologies. There is a need for the establishment of quantitative methods to evaluate global protein homoeostasis function. As the ubiquitin (ub) proteasome system plays a key role in regulating protein homeostasis, we applied quantitative proteomic methods to evaluate the sensitivity of site-specific ubiquitylation events as markers for protein homeostasis dysfunction. Here, we demonstrate that the ub-modified proteome can exceed the sensitivity of engineered fluorescent reporters as a marker for proteasome dysfunction and can provide unique signatures for distinct proteome challenges which is not possible with engineered reporters. We demonstrate that combining ub-proteomics with subcellular fractionation can effectively separate degradative and regulatory ubiquitylation events on distinct protein populations. Using a recently developed potent inhibitor of the critical protein homeostasis factor p97/VCP, we demonstrate that distinct insults to protein homeostasis function can elicit robust and largely unique alterations to the ub-modified proteome. Taken together, we demonstrate that proteomic approaches to monitor the ub-modified proteome can be used to evaluate global protein homeostasis and can be used to monitor distinct functional outcomes for spatially separated protein populations. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase

    Science.gov (United States)

    Gatti, Marco; Pinato, Sabrina; Maspero, Elena; Soffientini, Paolo; Polo, Simona; Penengo, Lorenza

    2012-01-01

    Ubiquitination of histones plays a critical role in the regulation of several processes within the nucleus, including maintenance of genome stability and transcriptional regulation. The only known ubiquitination site on histones is represented by a conserved Lys residue located at the C terminus of the protein. Here, we describe a novel ubiquitin mark at the N-terminal tail of histone H2As consisting of two Lys residues at positions 13 and 15 (K13/K15). This “bidentate” site is a target of the DNA damage response (DDR) ubiquitin ligases RNF8 and RNF168. Histone mutants lacking the K13/K15 site impair RNF168- and DNA damage-dependent ubiquitination. Conversely, inactivation of the canonical C-terminal site prevents the constitutive monoubiquitination of histone H2As but does not abolish the ubiquitination induced by RNF168. A ubiquitination-defective mutant is obtained by inactivating both the N- and the C-terminal sites, suggesting that these are unique, non-redundant acceptors of ubiquitination on histone H2As. This unprecedented result implies that RNF168 generates a qualitatively different Ub mark on chromatin. PMID:22713238

  2. Role of the Ubiquitin Proteasome System in Regulating Skin Pigmentation

    Directory of Open Access Journals (Sweden)

    Hideya Ando

    2009-10-01

    Full Text Available Pigmentation of the skin, hair and eyes is regulated by tyrosinase, the critical rate-limiting enzyme in melanin synthesis by melanocytes. Tyrosinase is degraded endogenously, at least in part, by the ubiquitin proteasome system (UPS. Several types of inherited hypopigmentary diseases, such as oculocutaneous albinism and Hermansky-Pudlak syndrome, involve the aberrant processing and/or trafficking of tyrosinase and its subsequent degradation which can occur due to the quality-control machinery. Studies on carbohydrate modifications have revealed that tyrosinase in the endoplasmic reticulum (ER is proteolyzed via ER-associated protein degradation and that tyrosinase degradation can also occur following its complete maturation in the Golgi. Among intrinsic factors that regulate the UPS, fatty acids have been shown to modulate tyrosinase degradation in contrasting manners through increased or decreased amounts of ubiquitinated tyrosinase that leads to its accelerated or decelerated degradation by proteasomes.

  3. Direct observation of silver nanoparticle-ubiquitin corona formation

    CERN Document Server

    Ding, Feng; Choudhary, Poonam; Chen, Ran; Brown, Jared M; Ke, Pu Chun

    2012-01-01

    Upon entering physiological environments, nanoparticles readily assume the form of a nanoparticle-protein corona that dictates their biological identity. Understanding the structure and dynamics of nanoparticle-protein corona is essential for predicting the fate, transport, and toxicity of nanomaterials in living systems and for enabling the vast applications of nanomedicine. We combined multiscale molecular dynamics simulations and complementary experiments to characterize the silver nanoparticle-ubiquitin corona formation. Specifically, ubiquitins competed with citrates for the nanoparticle surface and bound to the particle in a specific manner. Under a high protein/nanoparticle stoichiometry, ubiquitions formed a multi-layer corona on the particle surface. The binding exhibited an unusual stretched-exponential behavior, suggesting a rich kinetics originated from protein-protein, protein-citrate, and protein-nanoparticle interactions. Furthermore, the binding destabilized the {\\alpha}-helices while increasi...

  4. [Effects of transporter Agp1p ubiquitination on nitrogen utilization in Saccharomyces cerevisiae].

    Science.gov (United States)

    Li, Yingyu; Lv, Yongkun; Zhou, Jingwen; Du, Guocheng; Chen, Jian

    2015-05-04

    The purpose of this work is to studythe effects of ubiquitination of key nitrogen transporter Agp1p on nitrogen utilization in Saccharomyces cerevisiae. The ubiquitination detection vector to examine the ubiquitination process of Agp1p was constructed based on the bimolecular fluorescence complementation technology. The site-directed mutagenesis on the potential ubiquitination sites were performed to verify the effect on its ubiquitination regulation and nitrogen utilization. Agp1p can be ubiquitinated on the medium with glutamine, arginine, proline or ammonium. The fluorescence levels of mutant strains were down-regulated compared to the wild type strain. The quadruple mutant Agp1pK11-14-98-112R achieved the lowest level among all strains. The ubiuitination process could be significantly repressed by removing the potential ubiquitination residues. Furthermore, flask-shaking experiments with nineamino acids or urea as sole nitrogen source showed that the effect of nitrogen utilization efficiencyinthe quadruple mutant was the highest. Ubiquitination was involved in the regulation of Agp1p. Site-directed mutagenesis of potential ubiquitination sites of the transporter could significantly affect the nitrogen utilization process by altering the ubiquitination process.

  5. Ubiquitination of inducible nitric oxide synthase is required for its degradation

    Science.gov (United States)

    Kolodziejski, Pawel J.; Musial, Aleksandra; Koo, Ja-Seok; Eissa, N. Tony

    2002-01-01

    Inducible nitric oxide synthase (iNOS) is responsible for nitric oxide (NO) synthesis from l-arginine in response to inflammatory mediators. We have previously shown that iNOS is degraded through the 26S proteasome. Targeting of proteins for proteasomal degradation may or may not require their covalent linkage to multiubiquitin chains (ubiquitination). In addition, ubiquitination of a protein can serve functions other than signaling proteolysis. In this context, it is not known whether iNOS is subject to ubiquitination or whether ubiquitination is required for its degradation. In this study, we show that iNOS, expressed in HEK293 cells or induced in primary bronchial epithelial cells, A549 cells, or murine macrophages, is subject to ubiquitination. To investigate whether iNOS ubiquitination is required for its degradation, HEK293T cells were cotransfected with plasmids containing cDNAs of human iNOS and of the dominant negative ubiquitin mutant K48R. Disruption of ubiquitination by K48R ubiquitin resulted in inhibition of iNOS degradation. ts20 is a mutant cell line that contains a thermolabile ubiquitin-activating enzyme (E1) that is inactivated at elevated temperature, preventing ubiquitination. Incubation of ts20 cells, stably expressing human iNOS, at the nonpermissive temperature (40°C) resulted in inhibition of iNOS degradation and marked accumulation of iNOS. These studies indicate that iNOS is subject to ubiquitination and that ubiquitination is required for its degradation. PMID:12221289

  6. The ubiquitin pathway is required for innate immunity in Arabidopsis.

    Science.gov (United States)

    Goritschnig, Sandra; Zhang, Yuelin; Li, Xin

    2007-02-01

    Plant defences require a multitude of tightly regulated resistance responses. In Arabidopsis, the unique gain-of-function mutant suppressor of npr1-1 constitutive 1 (snc1) carries a point mutation in a Resistance (R)-gene, resulting in constitutive activation of defence responses without interaction with pathogens. This has allowed us to identify various downstream signalling components essential in multiple defence pathways. One mutant that suppresses snc1-mediated constitutive resistance is modifier of snc1 5 (mos5), which carries a 15-bp deletion in UBA1, one of two ubiquitin-activating enzyme genes in Arabidopsis. A mutation in UBA2 does not suppress snc1, suggesting that these two genes are not equally required in Arabidopsis disease resistance. On the other hand, a mos5 uba2 double mutant is lethal, implying partial redundancy of the two homologues. Apart from affecting snc1-mediated resistance, mos5 also exhibits enhanced disease susceptibility to a virulent pathogen and is impaired in response to infection with avirulent bacteria carrying the protease elicitor AvrRpt2. The mos5 mutation in the C-terminus of UBA1 might affect binding affinity of the downstream ubiquitin-conjugating enzymes, thus perturbing ubiquitination of target proteins. Furthermore, SGT1b and RAR1, which are necessary for resistance conferred by the SNC1-related R-genes RPP4 and RPP5, are dispensable in snc1-mediated resistance. Our data reveal the definite requirement for the ubiquitination pathway in the activation and downstream signalling of several R-proteins.

  7. Viral Mimicry to Usurp Ubiquitin and SUMO Host Pathways

    Directory of Open Access Journals (Sweden)

    Peter Wimmer

    2015-08-01

    Full Text Available Posttranslational modifications (PTMs of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub and small ubiquitin-like modifier (SUMO moieties. These modifications are widely used by eukaryotic cells to control the functional repertoire of proteins. Over the last decade, it became apparent that the repertoire of ubiquitiylation and SUMOylation regulating various biological functions is not restricted to eukaryotic cells, but is also a feature of human virus families, used to extensively exploit complex host-cell networks and homeostasis. Intriguingly, besides binding to host SUMO/Ub control proteins and interfering with the respective enzymatic cascade, many viral proteins mimic key regulatory factors to usurp this host machinery and promote efficient viral outcomes. Advanced detection methods and functional studies of ubiquitiylation and SUMOylation during virus-host interplay have revealed that human viruses have evolved a large arsenal of strategies to exploit these specific PTM processes. In this review, we highlight the known viral analogs orchestrating ubiquitin and SUMO conjugation events to subvert and utilize basic enzymatic pathways.

  8. Ubiquitin C-Terminal Hydrolase L1 in Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jennifer Hurst-Kennedy

    2012-01-01

    Full Text Available Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1, aka PGP9.5 is an abundant, neuronal deubiquitinating enzyme that has also been suggested to possess E3 ubiquitin-protein ligase activity and/or stabilize ubiquitin monomers in vivo. Recent evidence implicates dysregulation of UCH-L1 in the pathogenesis and progression of human cancers. Although typically only expressed in neurons, high levels of UCH-L1 have been found in many nonneuronal tumors, including breast, colorectal, and pancreatic carcinomas. UCH-L1 has also been implicated in the regulation of metastasis and cell growth during the progression of nonsmall cell lung carcinoma, colorectal cancer, and lymphoma. Together these studies suggest UCH-L1 has a potent oncogenic role and drives tumor development. Conversely, others have observed promoter methylation-mediated silencing of UCH-L1 in certain tumor subtypes, suggesting a potential tumor suppressor role for UCH-L1. In this paper, we provide an overview of the evidence supporting the involvement of UCH-L1 in tumor development and discuss the potential mechanisms of action of UCH-L1 in oncogenesis.

  9. Towards Prognostics for Electronics Components

    Data.gov (United States)

    National Aeronautics and Space Administration — Electronics components have an increasingly critical role in avionics systems and in the development of future aircraft systems. Prognostics of such components is...

  10. Standardizing Research Methods for Prognostics

    Data.gov (United States)

    National Aeronautics and Space Administration — Prognostics and health management (PHM) is a maturing system engineering discipline. As with most maturing disciplines, PHM does not yet have a universally accepted...

  11. Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment.

    Science.gov (United States)

    Maynard, Christa J; Böttcher, Claudia; Ortega, Zaira; Smith, Ruben; Florea, Bogdan I; Díaz-Hernández, Miguel; Brundin, Patrik; Overkleeft, Hermen S; Li, Jia-Yi; Lucas, Jose J; Dantuma, Nico P

    2009-08-18

    Aggregation-prone proteins have been suggested to overwhelm and impair the ubiquitin/proteasome system (UPS) in polyglutamine (polyQ) disorders, such as Huntington's disease (HD). Overexpression of an N-terminal fragment of mutant huntingtin (N-mutHtt), an aggregation-prone polyQ protein responsible for HD, obstructs the UPS in cellular models. Furthermore, based on the accumulation of polyubiquitin conjugates in brains of R6/2 mice, which express human N-mutHtt and are one of the most severe polyQ disorder models, it has been proposed that UPS dysfunction is a consistent feature of this pathology, occurring in both in vitro and in vivo models. Here, we have exploited transgenic mice that ubiquitously express a ubiquitin fusion degradation proteasome substrate to directly assess the functionality of the UPS in R6/2 mice or the slower onset R6/1 mice. Although expression of N-mutHtt caused a general inhibition of the UPS in PC12 cells, we did not observe an increase in the levels of proteasome reporter substrate in the brains of R6/2 and R6/1 mice. We show that the increase in ubiquitin conjugates in R6/2 mice can be primarily attributed to an accumulation of large ubiquitin conjugates that are different from the conjugates observed upon UPS inhibition. Together our data show that polyubiquitylated proteins accumulate in R6/2 brain despite a largely operative UPS, and suggest that neurons are able to avoid or compensate for the inhibitory effects of N-mutHtt.

  12. Prognostic relevance of Centromere protein H expression in esophageal carcinoma

    Science.gov (United States)

    Guo, Xian-Zhi; Zhang, Ge; Wang, Jun-Ye; Liu, Wan-Li; Wang, Fang; Dong, Ju-Qin; Xu, Li-Hua; Cao, Jing-Yan; Song, Li-Bing; Zeng, Mu-Sheng

    2008-01-01

    Background Many kinetochore proteins have been shown to be associated with human cancers. The aim of the present study was to clarify the expression of Centromere protein H (CENP-H), one of the fundamental components of the human active kinetochore, in esophageal carcinoma and its correlation with clinicopathological features. Methods We examined the expression of CENP-H in immortalized esophageal epithelial cells as well as in esophageal carcinoma cells, and in 12 cases of esophageal carcinoma tissues and the paired normal esophageal tissues by RT-PCR and Western blot analysis. In addition, we analyzed CENP-H protein expression in 177 clinicopathologically characterized esophageal carcinoma cases by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations. Results The level of CENP-H mRNA and protein were higher in the immortalized cells, cancer cell lines and most cancer tissues than in normal control tissues. Immunohistochemistry showed that CENP-H was expressed in 127 of 171 ESCC cases (74.3%) and in 3 of 6 esophageal adenocarcinoma cases (50%). Statistical analysis of ESCC cases showed that there was a significant difference of CENP-H expression in patients categorized according to gender (P = 0.013)