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Lena Nordström Sandra Sernbo Patrik Eden Kirsten Grønbæk Arne Kolstad Riikka Räty Marja‐Liisa Karjalainen Christian Geisler Elisabeth Ralfkiær Christer Sundström Anna Laurell Jan Delabie Mats Ehinger Mats Jerkeman Sara Ek 《British journal of haematology》2014,166(1):98-108
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment‐related morbidity, additional parameters need to be evaluated to enable risk‐adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki‐67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating 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 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions. 相似文献
84.
Pei-Chung Lee Stephanie Elizabeth Zmina Charles Morgan Stopford Jonida Toska Arne Rietsch 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(19):E2027-E2036
Pathogenic Gram-negative bacteria use syringe-like type III secretion systems (T3SS) to inject effector proteins directly into targeted host cells. Effector secretion is triggered by host cell contact, and before contact is prevented by a set of conserved regulators. How these regulators interface with the T3SS apparatus to control secretion is unclear. We present evidence that the proton motive force (pmf) drives T3SS secretion in Pseudomonas aeruginosa, and that the cytoplasmic regulator PcrG interacts with distinct components of the T3SS apparatus to control two important aspects of effector secretion: (i) It coassembles with a second regulator (Pcr1) on the inner membrane T3SS component PcrD to prevent effectors from accessing the T3SS, and (ii) In conjunction with PscO, it controls protein secretion activity by modulating the ability of T3SS to convert pmf.Many Gram-negative bacterial pathogens rely on a type III secretion system (T3SS) to promote disease by directly injecting effector proteins into the cytoplasm of host cells. This apparatus consists of a base that spans the bacterial envelope and a needle that projects from the base and ends in a specialized tip structure. The bacterium secretes two translocator proteins via the T3SS, which insert into the host cell membrane to form a pore, through which effector proteins are then transferred (1, 2).One of the hallmarks of type III secretion is that export of effector proteins is triggered by host cell contact (3–5). The secretion apparatus is fully assembled before cell contact, but effector secretion is prevented through the concerted action of needle tip-associated proteins and regulators that control secretion from the bacterial cytoplasm.In most systems, the needle tip protein prevents premature effector secretion, most likely by allosterically constraining the T3SS in an effector secretion “off” conformation (6–10). PcrG, the needle tip protein chaperone, as well as PopN, a member of the YopN/MxiC family of proteins, control effector secretion from the bacterial cytoplasm in Pseudomonas aeruginosa. PcrG’s regulatory function is independent of its function in promoting the export of needle tip protein PcrV. Deletion of pcrG or pcrV results in partial deregulation of effector secretion, whereas removal of both genes results in high-level secretion of effectors (8). In some bacteria, the needle tip protein promotes its own export with the aid of a self-chaperoning domain, rather than with a separate export chaperone (11). Recent evidence suggests that in these systems, the needle tip protein itself also regulates effector secretion from the cytoplasm, in addition to its regulatory role at the T3SS needle tip (12). The mechanism of this regulation is unclear.YopN/MxiC family proteins, PopN in P. aeruginosa, are T3SS regulators that are exported once effector secretion is triggered (13–17). These proteins control effector secretion from the bacterial cytoplasm (18–20). P. aeruginosa PopN and the closely related YopN associate with three other proteins that are required to prevent premature effector secretion (21–23). For PopN, these three proteins are Pcr1, Pcr2, and PscB. Pcr2 and PscB form a heterodimeric export chaperone, and Pcr1 is thought to tether the PopN complex to the apparatus (23). The prevailing model for explaining how PopN and related regulators control effector secretion is that they partially insert and plug the secretion channel while being tethered to the T3SS, either directly via a C-terminal interaction or indirectly via a C-terminal–associated protein, i.e., Pcr1 in P. aeruginosa (19, 20). The apparatus component with which these regulators interact is unknown, however.Triggering of effector secretion results in the rapid injection of effector proteins into the host cell (4, 5). How this rapid burst of secretion is energized is a matter of some controversy. The flagellum, which also uses a type III secretion mechanism, uses the proton motive force (pmf) to catalyze the rapid export of flagellar subunits. In fact, secretion is possible in mutants lacking the flagellum-associated ATPase, FliI, if the associated regulatory protein, FliH, is eliminated as well (24–26). The pmf’s contribution to the rate of secretion relative to the ATPase has been questioned in the case of virulence-associated T3SS (27), where removal of the ATPase results in a complete block of secretion (28, 29) that is not alleviated by deletion of the associated FliH homolog (30).Here we present evidence that export via the P. aeruginosa T3SS is energized primarily by the pmf, thereby offering a unified model for how protein secretion is energized in all T3SSs. The cytoplasmic T3SS regulator PcrG controls both the access of effectors to the T3SS and, surprisingly, the secretion activity of the apparatus. These two functions are controlled by separate regions of PcrG. Control of secretion activity involves the central portion of PcrG as well as PscO, which regulate the pmf-dependent export of secretion substrates. Mutants that up-regulate translocator secretion without turning on effector export confirm that effector secretion is not blocked by physical obstruction of the secretion channel. Instead, access of effectors to the T3SS is controlled by the C terminus of PcrG in conjunction with the PopN complex through an interaction with the inner membrane T3SS component PcrD. This protein complex likely blocks an acceptor site for effectors. Thus, PcrG is a multifaceted protein that, along with its export chaperone function, serves as a brake and a switch to control effector secretion. 相似文献
85.
Irina Pader Rajib Sengupta Marcus Cebula Jianqiang Xu Jon O. Lundberg Arne Holmgren Katarina Johansson Elias S. J. Arnér 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(19):6964-6969
Thioredoxin-related protein of 14 kDa (TRP14, also called TXNDC17 for thioredoxin domain containing 17, or TXNL5 for thioredoxin-like 5) is an evolutionarily well-conserved member of the thioredoxin (Trx)-fold protein family that lacks activity with classical Trx1 substrates. However, we discovered here that human TRP14 has a high enzymatic activity in reduction of l-cystine, where the catalytic efficiency (2,217 min−1⋅µM−1) coupled to Trx reductase 1 (TrxR1) using NADPH was fivefold higher compared with Trx1 (418 min−1⋅µM−1). Moreover, the l-cystine reduction with TRP14 was in contrast to that of Trx1 fully maintained in the presence of a protein disulfide substrate of Trx1 such as insulin, suggesting that TRP14 is a more dedicated l-cystine reductase compared with Trx1. We also found that TRP14 is an efficient S-denitrosylase with similar efficiency as Trx1 in catalyzing TrxR1-dependent denitrosylation of S-nitrosylated glutathione or of HEK293 cell-derived S-nitrosoproteins. Consequently, nitrosylated and thereby inactivated caspase 3 or cathepsin B could be reactivated through either Trx1- or TRP14-catalyzed denitrosylation reactions. TRP14 was also, in contrast to Trx1, completely resistant to inactivation by high concentrations of hydrogen peroxide. The oxidoreductase activities of TRP14 thereby complement those of Trx1 and must therefore be considered for the full understanding of enzymatic control of cellular thiols and nitrosothiols.The redox or nitrosylation state of reactive cysteine (Cys) residues in proteins can affect a multitude of intracellular events, either beneficial or harmful, depending upon biological context (1, 2). Two major cellular systems that control the redox states of Cys residues are the thioredoxin (Trx) and the glutathione (GSH) systems. The Trx system includes isoforms of Trx, Trx reductase (TrxR), and NADPH together with several Trx-dependent enzymes and proteins (3). The GSH/GSH disulfide redox couple is kept reduced by the NADPH-dependent activity of GSH reductase (GR) and donates electrons to isoforms of glutaredoxin (Grx) and other GSH-dependent enzymes (4).In addition to Trx, many proteins have a Trx fold and a Trx-like active-site sequence. One such protein is thioredoxin-related protein of 14 kDa (TRP14, also known as TXNDC17 or TXNL5), which is an evolutionarily well-conserved cytosolic and widely expressed Trx-fold protein that can be reduced by TrxR1 (5). Its crystal structure, compared with Trx1, shows additional structural features in the active site, thereby explaining its lack of activity with most classical Trx1 protein disulfide substrates including ribonucleotide reductase, insulin, peroxiredoxins, or methionine sulfoxide reductase (5–7). TRP14 was suggested to have evolved to exert specific signaling roles in cells and was identified as a modulator of TNFα/NFκB signaling pathways through interactions with the dynein light chain LC8 protein (6, 8). We previously found that treatment of cells with cisplatin triggered the formation of covalent cross-links between TrxR1 and either Trx1 or TRP14, which suggests that TRP14 is tightly linked to TrxR1 within the cellular context (9). Recently, we also found that TRP14 is able to reactivate oxidized phosphotyrosine phosphatase 1B, thereby indeed implicating specific functions in modulation of cellular signaling pathways (10).In addition to having general protein disulfide reductase activities, Trx1 is also a denitrosylase for a broad spectrum of nitrosoproteins and nitrosothiols (11, 12). Substrates include S-nitrosocaspase 3 (13, 14), S-nitrosocaspase 8 (15), S-nitrosoglutathione (GSNO) (16, 17), and S-nitrosocysteine (l-CysSNO) (12). Nitrosylation and denitrosylation reactions provide a regulatory mechanism for protein function and are thereby also involved in a variety of cellular signal transduction pathways. For example, S-nitrosylation of caspases can inhibit their activity and thus regulate apoptosis in resting cells (18, 19). A full understanding of NO homeostasis and its pathways is of medical importance because an aberrant formation of nitrosylated proteins has been implicated in a variety of diseases. However, protein denitrosylation is a hitherto less studied part in NO-mediated signaling (20, 21). In addition to Trx1, another enzyme mediating cellular denitrosylation reactions is GSNO reductase (GSNOR). GSNOR is the same enzyme as class III alcohol dehydrogenase, mainly catalyzing denitrosylation of GSNO using NADH as an electron donor (22, 23). In addition, S-denitrosylation activities are supported by protein disulfide isomerase (PDI) (24), carbonyl reductase 1 (25), and lipoic acid (17).The high intracellular concentrations of GSH are also important in NO metabolism because of facilitated formation of GSNO by reaction of GSH with NO or by denitrosylation of cellular nitrosothiols (20, 26). Because the synthesis of GSH depends upon availability, cellular uptake and reduction of sulfur-containing precursors such as l-cystine, l-cystine homeostasis is also important for GSH functions (27). l-Cystine is taken up into cells using different transport systems, e.g., the oxidative stress-inducible cystine/glutamate antiporter (system ) (28). The mechanism behind the reduction of l-cystine still has not been fully elucidated, but has been implicated to include GSH itself or also TrxR1-dependent systems (29).In the present study, we wanted to further characterize the enzymatic properties of TRP14, which revealed that the protein is at least as efficient as Trx1 in supporting reduction of specific redox substrates, such as l-cystine. In that assay, TRP14 is a fivefold better substrate for TrxR1 than Trx1 itself and, furthermore, more dedicated as its activity is not diminished in the presence of other Trx1 substrates that are not reduced by TRP14. Furthermore, we discovered that TRP14 is yet another cytosolic oxidoreductase that can catalyze S-denitrosylation reactions. 相似文献
86.
Christian Samsonsen Arne Reimers Geir Bråthen Grethe Helde Eylert Brodtkorb 《Epilepsia》2014,55(11):e125-e128
The aim was to assess the clinical relevance of antiepileptic drug (AED) nonadherence by means of therapeutic drug concentration monitoring (TDM). Two hundred eighty‐two consecutive patients with epilepsy acutely admitted to hospital for seizures were included. Nonadherence was defined as having a serum concentration/dose ratio at admission of <75% of the patient's own control value (probable nonadherence: 50–75%; definite: <50%). Nonadherence was identified in 39% of patients (definite 24%; probable 15%). It was significantly more common in patients with generalized seizures compared to those with focal onset seizures, and in patients <30 years compared to older patients. When specifically asked, 44% of nonadherent patients claimed regular intake. Nonadherence is a major cause of seizure breakthrough in patients with epilepsy, particularly in young adults. Many patients seem to be unaware of missed drug intake. Prompt measurements of AED serum concentrations should be available as part of the emergency care for patients acutely hospitalized for seizures to permit this issue to be thoroughly addressed prior to discharge. 相似文献
87.
Else-Marie Bladbjerg Thomas M. Larsen Anette Due Jørgen Jespersen Steen Stender Arne Astrup 《Thrombosis research》2014
Diet is important in the prevention of cardiovascular disease, and it has been suggested that a high-MUFA diet is more cardioprotective than a low-fat diet. We hypothesised that the postprandial thrombotic risk profile is improved most favourably by a high-MUFA diet compared with a low-fat diet. This was tested in a parallel intervention trial on overweight individuals (aged 28.4 (SD 4.7) years) randomly assigned to a MUFA-diet (35-45% of energy as fat; > 20% as MUFA, n = 21) or a low-fat (LF) diet (20-30% of energy as fat, n = 22) for 6 months after a weight loss of ~ 10%. All foods were provided free of charge from a purpose-built supermarket. Meal tests designed after the same principles were performed before and after the dietary intervention, and blood samples were collected at 8.00 h (fasting), 12.00 h, and 18.00 h and analysed for factor VII coagulant activity (FVII:C), activated FVII, fibrinogen, prothrombin fragment 1 + 2 (F1 + 2), D-dimer, plasminogen activator inhibitor (PAI:Ag), and thrombin activatable fibrinolysis inhibitor. There were significant postprandial increases in F1 + 2 and D-dimer before and after dietary intervention, with significantly lower values after 6 months. No significant differences were observed between the postprandial changes induced by the two diets. The postprandial decrease in FVII:C and PAI:Ag did not differ before and after intervention, irrespective of the diets. Our findings suggest postprandial coagulation activation in overweight subjects with more pronounced acute than long-term effects. We observed similar effects of the MUFA diet and the LF diet on the postprandial prothrombotic risk profile. 相似文献
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