Oral Abstracts 7: RA ClinicalO37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or ΔmTSS ≤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMS—Provided Expert Advice, Undertaken Trials, AbbVie—AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartis—Research Grants, Consultation Fees. S.F., AbbVie—Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB—Research Grants, Consultation Fees. H.K., AbbVie—Employee, Stocks. S.R., AbbVie—Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB—Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharma—Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) ΔmTSS ≤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + ΔmTSS ≤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + ΔmTSS ≤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: ΔmTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

Assumption without representation: the unacknowledged abstraction from communities and social goods

We have not clearly acknowledged the abstraction from unpriceable “social goods” (derived from communities) which, different from private and public goods, simply disappear if it is attempted to market them. Separability from markets and economics has not been argued, much less established. Acknowledging communities would reinforce rather than undermine them, and thus facilitate the production of social goods. But it would also help economics by facilitating our understanding of – and response to – financial crises as well as environmental destruction and many social problems, and by reducing the alienation from economics often felt by students and the public

Spectrin oligomerization is cooperatively coupled to membrane assembly: A linkage targeted by many hereditary hemolytic anemias?

In the erythrocyte, ankyrin is the major adapter protein linking mutation of the linker sequences that join helices C and A in repeat tetramers of band 3 to the spectrin–actin cytoskeleton. This linkage units that intervene between the two functional sites, mutations that involves a direct interaction between ankyrin and the 14th–15th repeat presumably block repeat-to-repeat transfer of conformational informaunit of b-spectrin. The spectrin cytoskeleton itself is stabilized by tion; (ii) mutations in a-spectrin repeats 4 to 6 that disrupt the ability the self-association of spectrin heterodimers into tetramers and larger of this region to trans-regulate ankyrin binding by the adjacent boligomers, a process mediated by the 17th repeat unit of b-spectrin spectrin repeats 14–15; and (iii) exon-skipping mutations that shorten and a short NH2-terminal sequence in a-spectrin. The self-association a-spectrin and force repeats 4 to 6 to fall out-of-register with the of spectrin and its ankyrin-mediated membrane binding have generally ankyrin-binding motif in b-spectrin. Collectively, these results demonbeen considered independent events.We now demonstrate that spectrin strate a molecular mechanism whereby a membrane receptor can diself- association, the binding of spectrin to ankyrin, and the binding of rectly promote cytoskeletal assembly. q 2001 Academic Press ankyrin to the 43-kDa cytoplasmic domain of band 3 (cdb3) are coupled in a positively cooperative way. In solution, [125I]-labeled ankyrin was found by ND-PAGE3 to enhance the affinity of spectrin self-association by 10-fold. The reciprocal process was also true, in that spectrin tetramers and oligomers bound ankyrin with enhanced affinity relative to dimer spectrin. Saturation of the b-spectrin self-association site by INTRODUCTION an NH2-terminal 80-kDa a-spectrin peptide enhanced the affinity of spectrin dimer for ankyrin, indicating a direct relationship between ankyrin binding and the occupancy of the b-spectrin self-association During the process of erythroid maturation the cortical site. cdb3 accentuated these cooperative interactions. Several inherited spectrin mutations that cause hemolytic disease but that do not directly cytoskeleton is formed by interactions between ankyrin, destabilize the self-association or ankyrin-binding sites can be ex- band 3 (the membrane anion transporter 1, AE1), and specplained by these results. Three classes of mutations appear to disrupt trin (for reviews, see Lux and Palek, 1995; Morrow et al., cooperative coupling between self-association and ankyrin binding

The effect of elective sham dose escalation on the placebo response during an antimuscarinic trial for overactive bladder symptoms

We analyzed the effects of baseline symptom severity and placebo response magnitude on the decision to dose escalate in a 12-week, randomized, double-blind, flexible dose antimuscarinic trial of subjects with overactive bladder symptoms. Data from the placebo arm of the trial were used for this post hoc analysis. Subjects could elect dose escalation at week 2. Those in the placebo arm received sham escalation. Most placebo treated subjects who continued to week 2 elected dose escalation (75% or 325 of 435). Overactive bladder symptoms at baseline were similar between placebo escalators and nonescalators. Nonescalators showed a significantly larger placebo response than escalators, as measured by improvements in bladder diary end points and patient reported outcomes, and by the incidence rate of adverse events before and after sham escalation. These findings suggest that the decision to dose escalate among placebo treated subjects is independent of baseline symptom severity but may be influenced by the placebo response magnitude for efficacy assessment and adverse events. Placebo nonescalators showed a rapid, large placebo response while placebo escalators showed a smaller placebo response even after sham escalation. These observations may have important implications for the design and interpretation of flexible dose trials using a placebo contro

Transforming Growth Factor Beta Induces Caspase 3-Independent Cleavage of AlphaII-Spectrin (Alpha-Fodrin) Coincident with Apoptosis

Transforming growth factor β (TGF-β) is a potent growth inhibitor and inducer of cell death in B-lymphocytes and is essential for immune regulation and maintenance of self-tolerance. In this report the mouse immature B cell line, WEHI 231, was used to examine the mechanisms involved in TGF-β-mediated apoptosis. Induction of apoptosis is detected as early as 8 h after TGF-β administration. Coincident with the onset of apoptosis, the cytoskeletal actin-binding protein, αII-spectrin (α-fodrin) is cleaved into 150-, 115-, and 110-kDa fragments. The broad spectrum caspase inhibitor (Boc-D-fmk (BD-fmk)) completely abolished TGF-β-induced apoptosis and αII-spectrin cleavage. Caspase 3, although present in WEH1 231 cells, was not activated by TGF-β, nor was its substrate, poly(ADP-ribose) polymerase. These results identify αII-spectrin as a novel substrate that is cleaved during TGF-β-induced apoptosis. Our data provide the first evidence of calpain and caspase 3-independent cleavage of αII-spectrin during apoptosis and suggests that TGF-β induces apoptosis and αII-spectrin cleavage via a potentially novel caspase. This report also provides the first direct evidence of caspase 3 activation in WEH1 231 cells and indicates that at least two distinct apoptotic pathways exist

Colgante circular con umbo pendiente de un aro cerrado - salv0006_ar

Proyectos del Plan Nacional I+D+I con referencias PB94-0129, PB97-1132, BHA 2002-00138, HUM 2006-06250/HISTProyectos de la CAM con referencias 06/0020/1997, 06/0094/1998, 06/0090/2000, 06/0043/2001Programa Consolider-Ingenio 2010 con sigla CSD2007-00058NoMuseo Arqueológico Nacional (Madrid)Salvacañete (Cuenca)Colgante circular con umbo pendiente de un aro cerrad

Transforming Growth Factor Beta Induces Caspase 3-Independent Cleavage of AlphaII-Spectrin (Alpha-Fodrin) Coincident with Apoptosis

Transforming growth factor β (TGF-β) is a potent growth inhibitor and inducer of cell death in B-lymphocytes and is essential for immune regulation and maintenance of self-tolerance. In this report the mouse immature B cell line, WEHI 231, was used to examine the mechanisms involved in TGF-β-mediated apoptosis. Induction of apoptosis is detected as early as 8 h after TGF-β administration. Coincident with the onset of apoptosis, the cytoskeletal actin-binding protein, αII-spectrin (α-fodrin) is cleaved into 150-, 115-, and 110-kDa fragments. The broad spectrum caspase inhibitor (Boc-D-fmk (BD-fmk)) completely abolished TGF-β-induced apoptosis and αII-spectrin cleavage. Caspase 3, although present in WEH1 231 cells, was not activated by TGF-β, nor was its substrate, poly(ADP-ribose) polymerase. These results identify αII-spectrin as a novel substrate that is cleaved during TGF-β-induced apoptosis. Our data provide the first evidence of calpain and caspase 3-independent cleavage of αII-spectrin during apoptosis and suggests that TGF-β induces apoptosis and αII-spectrin cleavage via a potentially novel caspase. This report also provides the first direct evidence of caspase 3 activation in WEH1 231 cells and indicates that at least two distinct apoptotic pathways exist

Identification of the Primary Caspase 3 Cleavage Site in alpha II-Spectrin during Apoptosis

Alpha II-spectrin is one of the major proteins responsible for maintaining the cytoskeletal integrity of the cell. The caspase 3-mediated cleavage of alpha II-spectrin during apoptotic cell death may play an important role in altering membrane stability and the formation of apoptotic bodies. In this study, we identified the primary caspase 3 cleavage site in alpha II-spectrin. We found that the transcriptional inhibitor, actinomycin D, induced caspase 3 activation and that caspase 3 activation is coincident with the cleavage of alpha II-spectrin protein at a primary cleavage site. Deletion analysis and site directed mutagenesis identified the primary cleavage site in alpha II spectrin at amino acid 1185 (DETD). The primary caspase 3 cleavage site in alpha II spectrin is conserved in immature and mature B cells. Our results indicate that alpha II-spectrin is initially cleaved at a caspase 3 consensus site and this primary event likely alters the structural conformation of the protein exposing subsequent cleavage sites and altering cytoskeletal integrity. Identification of the primary cleavage site for caspase 3 may help to elucidate the role of alpha II-spectrin in membrane stability and apoptosis as well as provide new insights into alpha II-spectrin autoantibody formation associated with the autoimmune disease, Sjögren\u27s syndrome