Merck Serono S.A. (Switzerland)

OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." RESULTS: In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."

BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis. METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients). CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.)

Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.

Cardis, E., Vrijheid, M., Blettner, M., Gilbert, E., Hakama, M., Hill, C., Howe, G., Kaldor, J., Muirhead, C. R., Schubauer-Berigan, M., Yoshimura, T., Bermann, F., Cowper, G., Fix, J., Hacker, C., Heinmiller, B., Marshall, M., Thierry-Chef, I., Utterback, D., Ahn, Y-O., Amoros, E., Ashmore, P., Auvinen, A., Bae, J-M., Bernar, J. S., Biau, A., Combalot, E., Deboodt, P., Diez Sacristan, A., Eklöf, M., Engels, H., Engholm, G., Gulis, G., Habib, R. R., Holan, K., Hyvonen, H., Kerekes, A., Kurtinaitis, J., Malker, H., Martuzzi, M., Mastauskas, A., Monnet, A., Moser, M., Pearce, M. S., Richardson, D. B., Rodriguez-Artalejo, F., Rogel, A., Tardy, H., Telle-Lamberton, M., Turai, I., Usel, M. and Veress, K. The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Estimates of Radiation-Related Cancer Risks. Radiat. Res. 167, 396– 416 (2007).A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI <0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI −0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates.

Bax is a Bcl-2 family protein with proapoptotic activity, which has been shown to trigger cytochrome crelease from mitochondria both in vitro and in vivo. In control HeLa cells, Bax is present in the cytosol and weakly associated with mitochondria as a monomer with an apparent molecular mass of 20,000 Da. After treatment of the HeLa cells with the apoptosis inducer staurosporine or UV irradiation, Bax associated with mitochondria is present as two large molecular weight oligomers/complexes of 96,000 and 260,000 Da, which are integrated into the mitochondrial membrane. Bcl-2 prevents Bax oligomerization and insertion into the mitochondrial membrane. The outer mitochondrial membrane protein voltage-dependent anion channel and the inner mitochondrial membrane protein adenosine nucleotide translocator do not coelute with the large molecular weight Bax oligomers/complexes on gel filtration. Bax oligomerization appears to be required for its proapoptotic activity, and the Bax oligomer/complex might constitute the structural entirety of the cytochromec-conducting channel in the outer mitochondrial membrane. Bax is a Bcl-2 family protein with proapoptotic activity, which has been shown to trigger cytochrome crelease from mitochondria both in vitro and in vivo. In control HeLa cells, Bax is present in the cytosol and weakly associated with mitochondria as a monomer with an apparent molecular mass of 20,000 Da. After treatment of the HeLa cells with the apoptosis inducer staurosporine or UV irradiation, Bax associated with mitochondria is present as two large molecular weight oligomers/complexes of 96,000 and 260,000 Da, which are integrated into the mitochondrial membrane. Bcl-2 prevents Bax oligomerization and insertion into the mitochondrial membrane. The outer mitochondrial membrane protein voltage-dependent anion channel and the inner mitochondrial membrane protein adenosine nucleotide translocator do not coelute with the large molecular weight Bax oligomers/complexes on gel filtration. Bax oligomerization appears to be required for its proapoptotic activity, and the Bax oligomer/complex might constitute the structural entirety of the cytochromec-conducting channel in the outer mitochondrial membrane. Apoptosis is mediated through two major pathways, the death receptor pathway and the mitochondrial pathway (1Hengartner M.O. Nature. 2000; 407: 770-776Crossref PubMed Scopus (6296) Google Scholar). The mitochondrial pathway is controlled and regulated by the Bcl-2 family of proteins (2Yang E. Korsmeyer S.J. Blood. 1996; 88: 386-401Crossref PubMed Google Scholar, 3Green D.R. Reed J.C. Science. 1998; 281: 1309-1312Crossref PubMed Google Scholar, 4Kelekar A. Thompson C.B. 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The complex formation leads to caspase 9 activation followed by downstream activation of other caspases, ultimately leading to cell death. Mounting evidence points to Bax and other proapoptotic family members as the central regulators of the release of proteins from the mitochondrial intramembrane space. Overexpression of Bax in cells or the addition of purified recombinant Bax directly to isolated mitochondria triggers the release of cytochrome c (29Rosse T. Olivier R. Monney L. Rager M. Conus S. Fellay I. Jansen B. Borner C. Nature. 1998; 391: 496-499Crossref PubMed Scopus (799) Google Scholar, 30Eskes R. Antonsson B. Osen-Sand A. Montessuit S. Richter C. Sadoul R. Mazzei G. Nichols A. Martinou J.-C. J. Cell Biol. 1998; 143: 217-224Crossref PubMed Scopus (586) Google Scholar, L. D. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, E. Waterhouse N.J. T.G. Green D.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the through which Bax triggers the of the outer mitochondrial membrane is The of the Bax protein has been by M. Youle R.J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The Bax a to the overall of the two other Bcl-2 family proteins for which structural is the antiapoptotic protein and the BH3 protein M. H. D. Thompson C.B. Nature. 1996; PubMed Scopus Google Scholar, J.J. Li H. J. G. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Milliman C.L. Korsmeyer S.J. D. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The proteins contain central hydrophobic and by the proteins, the Bax is the that the C-terminal hydrophobic This domain forms a that the hydrophobic on the The of the Bcl-2 proteins are of and the and are proteins that function as membrane that of or Bax and other Bcl-2 family proteins have been shown to activity in membranes P. H. M. Thompson C.B. Nature. 1997; PubMed Scopus Google Scholar, M.O. S. M. Reed J. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, B. A.M. Montessuit S. S. Martinou I. L. A. J.-C. Mazzei G. K. Sadoul R. Martinou J.-C. Science. 1997; PubMed Scopus Google Scholar, A. Yin X.-M. K. M. Waksman G. Korsmeyer Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). have shown that in to recombinant Bax in trigger release from isolated mitochondria B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar). Bax shown to a channel large to the release of cytochrome c from M. Korsmeyer S.J. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar). in cells to the apoptosis inducer staurosporine or UV irradiation, Bax forms which with mitochondrial membrane The Bax are into the mitochondrial membrane. that in the of Bcl-2, Bax formation and insertion into the mitochondrial membrane is The from and and from gel anion nucleotide Bax from and from from from from from from and from from and from from protein from and the and from The a from M. T. 1994; PubMed Scopus Google Scholar). gel voltage-dependent anion channel adenosine nucleotide translocator mitochondrial acid recombinant Bax cells, HeLa cells, and a HeLa cell Bcl-2 S. I. Sadoul R. Martinou J.-C. Cell Death 1997; PubMed Scopus Google in with and Apoptosis by the cells in staurosporine for the cells UV and for cells in the of staurosporine or UV the of the the cells in by at for and in mitochondrial The cells in with by through a The through the and at for The and the in The The at for to and The at for This and at for to the cell The to the mitochondrial in and at for the mitochondrial in of and on of a of of on of of The at in a for at at the of and and in at mitochondria in of with caspase for at the of the the at for and the mitochondria with The mitochondrial in or on for and at for The to the mitochondrial the protein The mitochondrial in to a protein of and on for the of the the at The which proteins, and to a of The in on for and at for The which membrane proteins, at on a in and at a of by The with gel proteins from the The of the by that at the and the at After of and from the by The on and to The proteins with the as in the and the with the from Bax with and at the and the into the cells with the Bax The between and to the addition of of of the Bax and the cells for the of the the cells and mitochondria isolated by as isolated from cells to of mitochondrial protein with caspase in for at the of the the mitochondria by and in of The and to of and the for at The by the addition of to a of and for at The mitochondria by and by in for at The at for and the with of protein for at by and of and of protein and on for at by and with of The in and the on in a to membranes and by with and at for and with and as Bax with a at the in and purified as S. Mazzei G. E. Antonsson B. 1999; PubMed Scopus Google Scholar). by the in the for The purified protein in at with a at the and purified as S. Osen-Sand Nichols A. R. Montessuit S. S. K. Antonsson B. Martinou J. Cell Biol. 1999; PubMed Scopus Google Scholar). The purified in at by of with of caspase and of caspase and the for at of as by from caspase by to by into and at HeLa cells have been to the of Bax in apoptotic Apoptosis by the cells in the of staurosporine for or by UV with in HeLa cells, Bax both in the cytosol and associated with the mitochondria In apoptotic cells, Bax from the Although a in Bax associated with the mitochondria in the apoptotic cells, not for the Bax that Bax that is not to the mitochondria is in apoptotic cells, through A. Y. Reed J.C. 1998; 17: PubMed Scopus Google Scholar). the of Bax associated with mitochondria from control and apoptotic HeLa cells, mitochondrial proteins with as and The mitochondrial on gel and the from the by with an to the and an of their molecular and of their Bax from control or apoptotic HeLa cell mitochondria as a at to a molecular mass of 260,000 Bax in control apoptotic mitochondrial of other mitochondrial membrane proteins that have been to with including Bak, Bcl-XL, and with Bax as molecular weight in between mitochondrial from control and apoptotic cells the mitochondrial membrane protein with a in and a in The of the at has been reported to of Bax and other Bcl-2 family members Y.-T. Youle R.J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In a reported that to trigger oligomerization of Bax B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar). might have the oligomerization of Bax and other proteins from the mitochondrial in protein between control and apoptotic on the of to trigger Bax oligomerization that in to and effect on Bax B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar). Bax from mitochondria. shown in as as in Bax from the mitochondrial membrane of both control and apoptotic This is an important control to that not and a of Bax from the mitochondria. isolated by from control and apoptotic HeLa cells, proteins with as and and the mitochondrial on gel filtration. In the mitochondrial from control cells, Bax in This to a molecular mass of 20,000 Da, which is to the molecular mass of In in the mitochondrial from cells apoptosis been by staurosporine Bax as large in with molecular of 260,000 and 96,000 The of Bax in between and on the of cells that apoptosis at the of with a that the protein Bax not with for that the mitochondria isolated by by that the Bax associated with the the mitochondrial purified on a the of the The mitochondria the Bax in the mitochondrial from apoptotic cells, Bax present in both apoptotic and control mitochondrial In apoptosis by HeLa cells to UV oligomerization of Bax associated with the mitochondria. to mitochondrial from cells, two of Bax at and on gel isolated HeLa mitochondria with caspase for The from the mitochondria the Bax as mitochondria from or HeLa cells Thus, apoptosis by in Bax In addition to its with Bcl-2 family Bax has been reported to with other mitochondrial membrane with the outer mitochondrial membrane protein and the inner membrane protein both of the have been reported S. M. Y. Nature. 1999; PubMed Scopus Google Scholar, I. C. Susin S.A. S. Reed J.C. Kroemer G. Science. 1998; 281: PubMed Scopus Google Scholar). the Bax these proteins, the from the gel for Bak, Bcl-XL, and major of in and present a molecular weight which forms of in the between control and apoptotic cells Thus, the Bax are not present in the mitochondrial membrane of cells, between and the Bax are a large with a major in for Bak, between control and apoptotic cells the Bax as a at in the mitochondrial from both control and apoptotic the Bax at between the control and apoptotic mitochondrial that is of the Bax from mitochondria of apoptotic The of recombinant Bax from the gel two at and This that recombinant Bax forms two of It appears that the be a of the In the mitochondrial from apoptotic HeLa cells, two Bax the at and the at and The Bax from apoptotic mitochondrial at molecular with the recombinant This in apparent molecular weight might that in the mitochondrial membrane the Bax with as the of the Bax Bax to and in of Bax the cells in the of the caspase to cells from and for by that the Bax both in the cytosol and the mitochondria isolated from and cells, membrane proteins with and the on gel filtration. the cytosol from the cells, and the on gel filtration. In the mitochondrial from cells and in the cytosol from cells, Bax in the mitochondrial from cells Bax to in staurosporine or HeLa cells The of Bax in the with the not the to and that the proteins of the the of the mitochondria from the cells for the of Although the of the proteins low, in the Bax the of the Bax on isolated mitochondria from the cells as and Bax with and the on with and in Bax with to and the with that the Bax from mitochondria of apoptotic cells are of Bax and are not Bax in complex with other Bax not in the cytosol It has been shown that in Bax the is not and not S. Osen-Sand Nichols A. R. Montessuit S. S. K. Antonsson B. Martinou J. Cell Biol. 1999; PubMed Scopus Google not the Bax in the The molecular of the in the mitochondrial and the of Bax in the to Bax and Although molecular weight can be the molecular be in of the between a Bax and to a complex with an protein of of mitochondrial from cells by gel on from cells and cells with and Bax isolated and with proteins by at for of the of protein on a in and at a of of and by and with The from the mitochondrial in addition by and the to and and the to and The cytosol from cells with and as the mitochondrial with have shown that treatment of isolated HeLa mitochondria in the insertion of Bax into the outer mitochondrial membrane R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google Scholar). the in Bax required for into the mitochondrial membrane mitochondria from control and apoptotic cells with which proteins to the proteins integrated into the membrane associated with the membrane After the and the membrane by the by R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google that in control cells Bax to the mitochondrial in the apoptotic cells of the protein into the membrane 9 and integrated into the membrane in both control and apoptotic the membrane protein to be integrated into the membrane in both shown in mitochondria from apoptotic cells both and the of the of shown in 9 Bax present as the of Bax in the mitochondrial in the control cells and is a of protein that not HeLa cell Bcl-2 is to apoptosis S. I. Sadoul R. Martinou J.-C. Cell Death 1997; PubMed Scopus Google Scholar). these cells with staurosporine for and Bax associated with the mitochondria of and control control and cells Bax Bax in mitochondria isolated from cells Bcl-2 in in both control and in the of Bak, Bcl-XL, and between control and apoptotic Bax been into the mitochondrial membrane in the cells, the isolated mitochondria with in the Bax to the mitochondrial Bax in the membrane of Bcl-2 to be into the mitochondrial membranes from both control and cells 9 The release of cytochrome c from mitochondria has been shown to a in many apoptotic signaling cascades through the activation of the downstream (28Li P. Nijhawan D. Budihardjo I. Srinivasula S.M. Ahmad M. Alnemri E.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6261) Google Scholar). to Bax as a trigger of cytochrome crelease (29Rosse T. Olivier R. Monney L. Rager M. Conus S. Fellay I. Jansen B. Borner C. Nature. 1998; 391: 496-499Crossref PubMed Scopus (799) Google Scholar, 30Eskes R. Antonsson B. Osen-Sand A. Montessuit S. Richter C. Sadoul R. Mazzei G. Nichols A. Martinou J.-C. J. Cell Biol. 1998; 143: 217-224Crossref PubMed Scopus (586) Google Scholar, L. D. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). on the of protein to in have been that Bax to a cytochrome Bax oligomerization and insertion in the outer mitochondrial membrane in a channel or by Bax to or Thompson C.B. Nat. Cell Biol. 1999; PubMed Scopus Google J.-C. S. Antonsson B. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar). Thus, at the molecular Bax triggers cytochrome c gel and the formation of molecular weight Bax in mitochondrial membranes of apoptotic of Bax in mitochondrial followed by and have the of the of Bax R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google A. Jockel J. Korsmeyer EMBO J. 1998; 17: PubMed Scopus Google Scholar). The of Bax to for the to the formation of Bax between formation of large Bax and apoptosis by gel of membrane proteins with The of is the protein and complex be by the A. K. PubMed Scopus Google Scholar, A. in and Scholar). and Youle Y.-T. Youle R.J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google have reported that Bax from cells that on the to which they in Bax shown in a by M. Youle R.J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the by M. Youle R.J. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google from the formation of large Bax In with these that not to trigger oligomerization of recombinant Bax B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar). Bcl-2 and not in the of including B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar, S. T. Fellay I. I. T. Borner C. EMBO J. 2000; PubMed Scopus Google Scholar). as mitochondrial membrane proteins from control and apoptotic cells with Bax on gel as a molecular weight In proteins including Bak, Bcl-XL, and a major of the that has been reported to with with Bax in a to a molecular mass of 260,000 Da. the mitochondrial membrane protein not coelute with the that the not a protein or a of the mitochondrial membrane. The that not trigger oligomerization of recombinant and Bax that a to Bax oligomerization in mitochondria that mitochondrial Bax from control cells as a monomer on gel the protein from mitochondria of apoptotic cells as large molecular weight which in two major to of 260,000 and 96,000 Da. This Bax in mitochondrial from HeLa cells apoptosis by staurosporine or UV that the addition of caspase Bid, a Bax to mitochondria isolated from HeLa cells to trigger the formation of large molecular weight Bax that oligomerization of Bax and its to large be a to apoptotic The Bax in the mitochondrial and they in the cytosol, that they at or within the outer mitochondrial membrane. the that these large Bax of mitochondria into the outer mitochondrial their This be with that Bax from the cytosol to mitochondria apoptosis Y.-T. Youle R.J. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, C.L. A. Youle R.J. J. Cell Biol. 1997; PubMed Scopus Google Scholar, A. M. R. K. Korsmeyer S.J. J. Cell Biol. 1998; 143: PubMed Scopus Google and that of Bax is by its insertion in the mitochondrial membrane A. Jockel J. Korsmeyer EMBO J. 1998; 17: PubMed Scopus Google Scholar). in the the to trigger cytochrome c release from that Bax are not the that Bax is to trigger the release of from The of the cytochromec-conducting Bax to be a M. Korsmeyer S.J. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar). that in cells that are to apoptosis S. I. Sadoul R. Martinou J.-C. Cell Death 1997; PubMed Scopus Google Bax oligomerization not This is with that Bcl-2 prevents the of which its activation and membrane insertion S. Osen-Sand Nichols A. R. Montessuit S. S. K. Antonsson B. Martinou J. Cell Biol. 1999; PubMed Scopus Google Scholar, R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google Scholar). In the cells, Bcl-2 both in the cytosol and in the mitochondrial membrane. It is which of these two Bcl-2 prevents the that Bax have shown that of isolated in the of to channel activity in and are to trigger cytochrome crelease from mitochondria B. Montessuit S. S. R. Martinou J.-C. J. 2000; PubMed Scopus Google Scholar). is from E. membranes with is as these channel activity, that is with the of Bax activity not from E. membranes with or by gel two of and The molecular mass of the Bax from mitochondrial membranes with the a in the of Bax the or an with other mitochondrial In gel to the mitochondrial membrane for the of other Bcl-2 family members Bcl-XL, as well as for and that with and in This is with that that with to in the complex an of M. S. J. 1998; PubMed Scopus Google Scholar, K. A. D. J. 1998; PubMed Scopus Google Scholar). is the in the of between and do not the the that these proteins within in to S. M. Y. Nature. 1999; PubMed Scopus Google Scholar, I. C. Susin S.A. S. Reed J.C. Kroemer G. Science. 1998; 281: PubMed Scopus Google have been to by R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google or by and not that within between Bax and or Bax and be or that of these proteins with other at It is important to in to the of Bak, Bcl-XL, Bcl-2, and do not proteins to be of large molecular weight between Bcl-2 and or and have been reported S. M. Y. Nature. 1999; PubMed Scopus Google G.J. L. J. C. J. Cell Biol. 1999; PubMed Scopus Google Scholar, M. H. D. M. Thompson C.B. Science. 1997; PubMed Scopus Google Scholar). The of Bcl-2 with and of with is with these not between the In have the formation of two molecular weight Bax in mitochondrial membranes of cells The formation of these Bax a of including a in Bax by or other proteins S. Osen-Sand Nichols A. R. Montessuit S. S. K. Antonsson B. Martinou J. Cell Biol. 1999; PubMed Scopus Google and insertion into the outer mitochondrial membrane R. S. Antonsson B. Martinou J.-C. Cell. Biol. 2000; PubMed Scopus Google Scholar). 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After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1-induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1-CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms.

OBJECTIVES: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. DESIGN: Multinational retrospective cohort study of cancer mortality. SETTING: Cohorts of workers in the nuclear industry in 15 countries. PARTICIPANTS: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. MAIN OUTCOME MEASUREMENTS: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. RESULTS: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. CONCLUSIONS: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.

The chemokine receptors CCR2 and CCR5 play important roles in the recruitment of monocytes/macrophages and T cells. To better understand the role of both receptors in murine models of inflammatory diseases and to recognize potential problems when correlating these data to humans, we have generated mAbs against murine CCR2 and CCR5. In mice CCR2 is homogeneously expressed on monocytes and on 2--15% of T cells, closely resembling the expression pattern in humans. In contrast to humans, murine NK cells are highly CCR5 positive. In addition, CCR5 is expressed on 3--10% of CD4 and 10--40% of CD8-positive T cells and is weakly detectable on monocytes. Using a model of immune complex nephritis, we examined the effects of inflammation on chemokine receptor expression and found a 10-fold enrichment of CCR5(+) and CCR2(+) T cells in the inflamed kidneys. The activity of various chemokines and the antagonistic properties of the mAbs were measured by ligand-induced internalization of CCR2 and CCR5 on primary leukocytes. The Ab MC-21 (anti-CCR2) reduced the activity of murine monocyte chemotactic protein 1 by 95%, whereas the Ab MC-68 (anti-CCR5) blocked over 99% of the macrophage-inflammatory protein 1alpha and RANTES activity. MC-21 and MC-68 efficiently blocked the ligand binding to CCR2 and CCR5 with an IC(50) of 0.09 and 0.6--1.0 microg/ml, respectively. In good correlation to these in vitro data, MC-21 almost completely prevented the influx of monocytes in thioglycollate-induced peritonitis. Therefore, both Abs appear as useful reagents to further study the role of CCR2 and CCR5 in murine disease models.

BACKGROUND Chances of achieving parenthood are high for couples who undergo fertility treatment. However, many choose to discontinue before conceiving. A systematic review was conducted to investigate patients' stated reasons for and predictors of discontinuation at five fertility treatment stages. METHODS Six databases were systematically searched. Search-terms referred to fertility treatment and discontinuation. Studies reporting on patients' stated reasons for or predictors of treatment discontinuation were included. A list of all reasons for discontinuation presented in each study was made, different categories of reasons were defined and the percentage of selections of each category was calculated. For each predictor, it was noted how many studies investigated it and how many found a positive and/or negative association with discontinuation. RESULTS The review included 22 studies that sampled 21 453 patients from eight countries. The most selected reasons for discontinuation were: postponement of treatment (39.18%, postponement of treatment or unknown 19.17%), physical and psychological burden (19.07%, psychological burden 14%, physical burden 6.32%), relational and personal problems (16.67%, personal reasons 9.27%, relational problems 8.83%), treatment rejection (13.23%) and organizational (11.68%) and clinic (7.71%) problems. Some reasons were common across stages (e.g. psychological burden). Others were stage-specific (e.g. treatment rejection during workup). None of the predictors reported were consistently associated with discontinuation. CONCLUSIONS Much longitudinal and theory led research is required to explain discontinuation. Meanwhile, treatment burden should be addressed by better care organization and support for patients. Patients should be well informed, have the opportunity to discuss values and worries about treatment and receive advice to decide about continuing treatment.

Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.

PURPOSE: To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS: Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS: Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION: There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell-specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell-driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F-deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F-deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease.

PURPOSE: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS: Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION: The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis. PATIENTS AND METHODS: Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. RESULTS: Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program. CONCLUSION: Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.

Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug's anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.

OBJECTIVES: Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. METHODS: In this double-blind, placebo-controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks. Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively. RESULTS: Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo. Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009). Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels. Most treatment-emergent adverse events were mild or moderate. CONCLUSIONS: There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit. TRIAL REGISTRATION NUMBER: EudraCT: 2007-003698-13; NCT00624338.

Replacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because of the known rapid recovery of pituitary function after antagonist cessation. This randomized two-center study was performed to compare nonsupplemented luteal phase characteristics after three different strategies for inducing final oocyte maturation. Forty patients underwent ovarian stimulation using recombinant (r-)FSH (150 IU/d, fixed) combined with a GnRH antagonist (antide; 1 mg/d) during the late follicular phase. When at least one follicle above 18 mm was observed, patients were randomized to induce oocyte maturation by a single injection of either r-human (h)CG (250 microg) (n = 11), r-LH (1 mg) (n = 13), or GnRH agonist (triptorelin; 0.2 mg) (n = 15). Retrieved oocytes were fertilized by either IVF or intracytoplasmatic sperm injection, depending on sperm quality. Embryo transfer was performed 3-4 d after oocyte retrieval. No luteal support was provided. Serum concentrations of FSH, LH, estradiol (E(2)), progesterone (P), and hCG were assessed at fixed intervals during the follicular and luteal phase. The median duration of the luteal phase was 13, 10, and 9 d for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.005). The median area under the curve per day (from 4 d post randomization until the onset of menses) for LH was 0.50, 2.34, and 1.07 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P = 0.001). The median area under the curve per day for P was 269 vs. 41 and 16 for the r-hCG, the r-LH, and the GnRH agonist group, respectively (P < 0.001). Low pregnancy rates (overall, 7.5%; range, 0-18% per started cycle) were observed in all groups. In conclusion, the nonsupplemented luteal phase was insufficient in all three groups. In the patients receiving r-hCG, the luteal phase was less disturbed, compared with both other groups, presumably because of prolonged clearance of hCG from the circulation and the resulting extended support of the corpus luteum. Despite high P and E(2) concentrations during the early luteal phase in all three groups, luteolysis started prematurely, presumably because of excessive negative steroid feedback resulting in suppressed pituitary LH release. Hence, support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment.

STUDY QUESTION: How good is fertility knowledge and what are treatment beliefs in an international sample of men and women currently trying to conceive? SUMMARY ANSWER: The study population had a modest level of fertility knowledge and held positive and negative views of treatment. WHAT IS KNOWN ALREADY: Few studies have examined general fertility treatment attitudes but studies of specific interventions show that attitudes are related to characteristics of the patient, doctor and context. Further, research shows that fertility knowledge is poor. However, the majority of these studies have examined the prevalence of infertility, the optimal fertile period and/or age-related infertility in women, in university students and/or people from high-resource countries making it difficult to generalize findings. STUDY DESIGN, SIZE, DURATION: A cross-sectional sample completed the International Fertility Decision-making Study (IFDMS) over a 9-month period, online or via social research panels and in fertility clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were 10 045 people (8355 women, 1690 men) who were on average 31.8 years old, had been trying to conceive for 2.8 years with 53.9% university educated. From a total of 79 countries, sample size was >100 in 18 countries. All 79 countries were assigned to either a very high Human Development Index (VH HDI) or a not very high HDI (NVH HDI). The IFDMS was a 45-min, 64-item English survey translated into 12 languages. The inclusion criteria were the age between 18 and 50 years and currently trying to conceive for at least 6 months. Fertility knowledge was assessed using a 13-item correct/incorrect scale concerned with risk factors, misconceptions and basic fertility facts (range: 0-100% correct). Treatment beliefs were assessed with positive and negative statements about fertility treatment rated on a five-point agree/disagree response scale. MAIN RESULTS AND THE ROLE OF CHANCE: Average correct score for Fertility Knowledge was 56.9%, with greater knowledge significantly related to female gender, university education, paid employment, VH HDI and prior medical consultation for infertility (all P < 0.001). The mean agreement scores for treatment beliefs showed that agreement for positive items (safety, efficacy) was correlated with agreement for negative items (short/long-term physical/emotional effects) (P > 0.001). People who had given birth/fathered a child, been trying to conceive for less than 12 months, who had never consulted for a fertility problem and who lived in a country with an NVH HDI agreed less with negative beliefs. HDI, duration of trying to conceive and help-seeking were also correlates of higher positive beliefs, alongside younger age, living in an urban area and having stepchildren. Greater fertility knowledge was associated with stronger agreement on negative treatment beliefs items (P < 0.001) but was unrelated to positive treatment beliefs items. LIMITATIONS, REASONS FOR CAUTION: There was volunteer bias insofar as more women, people of higher education and people with fertility problems (i.e. met criteria for infertility, had consulted a medical doctor, had conceived with fertility treatment) participated and this was true in VH and NVH HDI countries. The bias may mean that people in this sample had better fertility knowledge and less favourable treatment beliefs than is the case in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Educational interventions should be directed at improving knowledge of fertility health. Future prospective research should be aimed at investigating how fertility knowledge and treatment beliefs affect childbearing and help-seeking decision-making.

OBJECTIVE: To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand. METHODS: This phase Ib, double-blind, placebo-controlled, dose-escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1-4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1-4) or 9 weeks (cohorts 5 and 6). Patients with mild-to-moderate SLE were enrolled. RESULTS: Biologic activity of atacicept was demonstrated by dose-dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated-dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection-site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept. CONCLUSION: Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.

Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.