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  • 1
  • 2
    Keywords: MORTALITY ; RISK ; HEART ; ASSOCIATION ; ARTERY-DISEASE ; CREATININE ; CKD ; CHRONIC KIDNEY-DISEASE ; EQUATION ; CYSTATIN C
    Abstract: Background The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. Methods We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4.2-19.0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. Findings The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0.0139 [95% CI 0.0105- 0.0174] for ACR and 0.0065 [0.0042-0.0088] for eGFR) and heart failure (0.0196 [0.0108-0.0284] and 0.0109 [0.0059-0.0159]) than for coronary disease (0.0048 [0.0029-0.0067] and 0.0036 [0.0019-0.0054]) and stroke (0.0105 [0.0058-0.0151]and 0.0036 [0.0004-0.0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0.0227 (0.0158-0.0296) after omission of eGFR and ACR compared with less than 0.007 for any single modifiable traditional predictor. Interpretation Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population.
    Type of Publication: Journal article published
    PubMed ID: 26028594
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  • 3
    Keywords: CELLS ; GROWTH-FACTOR ; SURVIVAL ; DIFFERENTIATION ; COMPLEX ; PHOSPHORYLATION ; PROTEIN-KINASE ; METASTASIS ; chemotherapy ; adenocarcinoma
    Abstract: Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P 〈 0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
    Type of Publication: Journal article published
    PubMed ID: 26137966
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  • 4
    Publication Date: 2012-07-06
    Description: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the 'oncometabolite' R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Masato -- Knobbe, Christiane B -- Munger, Joshua C -- Lind, Evan F -- Brenner, Dirk -- Brustle, Anne -- Harris, Isaac S -- Holmes, Roxanne -- Wakeham, Andrew -- Haight, Jillian -- You-Ten, Annick -- Li, Wanda Y -- Schalm, Stefanie -- Su, Shinsan M -- Virtanen, Carl -- Reifenberger, Guido -- Ohashi, Pamela S -- Barber, Dwayne L -- Figueroa, Maria E -- Melnick, Ari -- Zuniga-Pflucker, Juan-Carlos -- Mak, Tak W -- R01 AI081773/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 30;488(7413):656-9. doi: 10.1038/nature11323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763442" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Bone Marrow/pathology ; Cell Lineage ; CpG Islands/genetics ; DNA Methylation ; Disease Models, Animal ; Epigenesis, Genetic/*genetics ; Female ; Gene Knock-In Techniques ; Glioma/pathology ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Histones/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Leukemia, Myeloid, Acute/genetics ; Male ; Mice ; Mutant Proteins/genetics/*metabolism ; Mutation/*genetics ; Myeloid Cells/cytology/metabolism ; Spleen/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; tumor ; Germany ; KINASE ; GENERATION ; DEATH ; PROTEIN ; MICE ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; mechanisms ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; SUPPRESSION ; ALPHA ; CLEAVAGE ; TRANSGENIC MICE ; activation-induced cell death ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; BETA ; T-LYMPHOCYTES ; sensitization ; TCR ; KAPPA-B ; sensitivity ; SIGNALING COMPLEX ; IMMUNOLOGICAL SYNAPSE ; T lymphocytes ; CD95 ; signaling ; PROGRAM ; RE ; INCREASE ; IMMUNE-SYSTEM ; cell death ; ANTIGEN RECEPTORS ; HPK1 ; progenitor ; INDUCE ; NEGATIVE REGULATION ; SWITCH ; AICD ; CD28 COSTIMULATION ; HEMATOPOIETIC PROGENITOR KINASE-1 ; IKK ; KINASE-C-THETA
    Abstract: Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous I kappa B kinase (IKK) complex and is crucial for TCR-mediated NF kappa B activation. While full-length HPK1 enhances IKK beta phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF kappa B activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NF kappa B upon TCR restimulation by binding to IKK alpha and IKK beta. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NF kappa B, and propose that HPK1 is a life/death switch in T lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 16341093
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  • 6
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; Germany ; DEATH ; PROTEIN ; PROTEINS ; LINES ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; T-CELLS ; CELL-LINES ; VARIANTS ; UP-REGULATION ; NUMBER ; LINE ; cell lines ; REGULATOR ; SIGNALING COMPLEX DISC ; SIGNALING COMPLEX ; EFFECTOR ; CD95 APO-1/FAS ; CD95 ; HUMAN T-CELLS ; PROGRAM ; RE ; CASPASE-8 ; MEDIATED APOPTOSIS ; regulation ; CD95-MEDIATED APOPTOSIS ; SIGNALING COMPLEXES ; FLICE-INHIBITORY PROTEINS
    Abstract: c-FLIPs (c-FLICE inhibitory proteins) play an essential role in regulation of death receptor-induced apoptosis. Multiple splice variants of c-FLIP have been described on the mRNA level; so far only two of them, c-FLIPL and c-FLIPS, had been found to be expressed at the protein level. In this report, we reveal the endogenous expression of a third isoform of c-FLIP. We demonstrate its presence in a number of T and B cell lines as well as in primary human T cells. We identified this isoform as c-FLIPR, a death effector domain-only splice variant previously identified on the mRNA level. Importantly, c-FLIPR is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex upon CD95 stimulation. Several properties of c-FLIPR are similar to c-FLIPS: both isoforms have a short half-life, a similar pattern of expression during activation of primary human T cells, and are strongly induced in T cells upon CD3/CD28 costimulation. Taken together, our data demonstrate endogenous expression of c-FLIPR and similar roles of c-FLIPR and c-FLIPS isoforms in death receptor-mediated apoptosis
    Type of Publication: Journal article published
    PubMed ID: 15701649
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; Germany ; DEATH ; PROTEIN ; PROTEINS ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; INDUCTION ; INITIATION ; MOLECULAR-CLONING ; FLICE ; OLIGOMERIZATION ; SIGNALING COMPLEX ; CD95 ; COMPLEX DISC ; GEL-ELECTROPHORESIS ; signaling ; RE ; CAP3 ; MOUSE CASPASE-8
    Abstract: Formation of the CD95 (APO-1/Fas) death inducing signaling complex (DISC) plays a central role in CD95 signaling. Previously, CD95 DISC composition was analyzed by two-dimensional gel electrophoresis and four major cytotoxicity-associated proteins (CAP1-4) were found. CAP1 and CAP2 were defined to be unmodified and phosphorylated FADD, respectively. CAP4 was identified as procaspase-8a. CAP3, however, has remained elusive. In this study, we demonstrate that CAP3 is an intermediate of procaspase-8 processing. CAP3 is generated within seconds of DISC formation and subsequently processed to the prodomain of procaspase-8a that is known as p26 (CAP5). These findings lead to new insights into the mechanism of procaspase-8 processing and apoptosis initiation
    Type of Publication: Journal article published
    PubMed ID: 16179941
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; Germany ; KINASE ; PATHWAY ; DEATH ; PROTEIN ; PROTEINS ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; DENDRITIC CELLS ; T-CELLS ; BINDING ; CLEAVAGE ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; signaling ; MALIGNANT-CELLS ; RE ; FAS ; CASPASE ACTIVATION ; C-FLIP ; IKK ; death receptor ; FLICE-INHIBITORY PROTEINS ; LONG FORM ; RECEPTOR-INDUCED APOPTOSIS
    Abstract: c-FLIP proteins (isoforms: c-FLIPL, c-FLIPS, and c-FLIPR) play an essential role in the regulation of death receptor - induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor kappa B (NF-kappa B) activity by interacting with the I kappa B kinase (IKK) complex via the IKK gamma subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-kappa B activation and life/death decisions in lymphocytes and DCs
    Type of Publication: Journal article published
    PubMed ID: 16682493
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  • 9
    Keywords: APOPTOSIS ; CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; RNA ; MICE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; FAMILY ; primary ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; MEMBER ; MEMBERS ; TRANSGENIC MICE ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; Bcl-2 ; molecular ; MOLECULAR-BASIS ; RE ; FAMILIES ; LIFE ; LEVEL ; cell death ; ANTIGEN RECEPTORS ; progenitor ; SUPPRESSOR ; FAS LIGAND ; AICD ; HEMATOPOIETIC PROGENITOR KINASE-1 ; USA ; B-LYMPHOCYTES ; FATE ; FRAGMENT ; FAMILY-MEMBER BIM ; B-CELL ; KINASE-1 ; EXPANSION ; caspase-3 ; block ; B cells ; BCL-2 FAMILY ; COMPLEMENT ; FULL-LENGTH ; MEDIATED CLEAVAGE ; SMALL INTERFERING RNA
    Abstract: Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 17712048
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  • 10
    Keywords: APOPTOSIS ; CELL ; T-CELL ; LYMPHOMA ; resistance ; sensitivity ; USA
    Type of Publication: Journal article published
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