Merck Serono S.p.A. (Italy)

OBJECTIVE: To update the American College of Rheumatology (ACR) 2000 recommendations for hip and knee osteoarthritis (OA) and develop new recommendations for hand OA. METHODS: A list of pharmacologic and nonpharmacologic modalities commonly used to manage knee, hip, and hand OA as well as clinical scenarios representing patients with symptomatic hand, hip, and knee OA were generated. Systematic evidence-based literature reviews were conducted by a working group at the Institute of Population Health, University of Ottawa, and updated by ACR staff to include additions to bibliographic databases through December 31, 2010. The Grading of Recommendations Assessment, Development and Evaluation approach, a formal process to rate scientific evidence and to develop recommendations that are as evidence based as possible, was used by a Technical Expert Panel comprised of various stakeholders to formulate the recommendations for the use of nonpharmacologic and pharmacologic modalities for OA of the hand, hip, and knee. RESULTS: Both “strong” and “conditional” recommendations were made for OA management. Modalities conditionally recommended for the management of hand OA include instruction in joint protection techniques, provision of assistive devices, use of thermal modalities and trapeziometacarpal joint splints, and use of oral and topical nonsteroidal antiinflammatory drugs (NSAIDs), tramadol, and topical capsaicin. Nonpharmacologic modalities strongly recommended for the management of knee OA were aerobic, aquatic, and/or resistance exercises as well as weight loss for overweight patients. Nonpharmacologic modalities conditionally recommended for knee OA included medial wedge insoles for valgus knee OA, subtalar strapped lateral insoles for varus knee OA, medially directed patellar taping, manual therapy, walking aids, thermal agents, tai chi, self management programs, and psychosocial interventions. Pharmacologic modalities conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections; intraarticular hyaluronate injections, duloxetine, and opioids were conditionally recommended in patients who had an inadequate response to initial therapy. Opioid analgesics were strongly recommended in patients who were either not willing to undergo or had contraindications for total joint arthroplasty after having failed medical therapy. Recommendations for hip OA were similar to those for the management of knee OA. CONCLUSION: These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines, informed by available evidence, balancing the benefits and harms of both nonpharmacologic and pharmacologic modalities, and incorporating their preferences and values. It is hoped that these recommendations will be utilized by health care providers involved in the management of patients with OA.

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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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. 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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). The protein of these now to be that the is of Bax to be these large Bax constitute the cytochrome channel in mitochondria. for and and for of the for and for

Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor-β (TGF-β) receptor II, which functions as a "trap" for all three TGF-β isoforms. We demonstrate that M7824 efficiently, specifically, and simultaneously binds PD-L1 and TGF-β. In syngeneic mouse models, M7824 suppressed tumor growth and metastasis more effectively than treatment with either an anti-PD-L1 antibody or TGF-β trap alone; furthermore, M7824 extended survival and conferred long-term protective antitumor immunity. Mechanistically, the dual anti-immunosuppressive function of M7824 resulted in activation of both the innate and adaptive immune systems, which contributed to M7824's antitumor activity. Finally, M7824 was an effective combination partner for radiotherapy or chemotherapy in mouse models. Collectively, our preclinical data demonstrate that simultaneous blockade of the PD-L1 and TGF-β pathways by M7824 elicits potent and superior antitumor activity relative to monotherapies.

Abstract Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.” Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.

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.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. PATIENTS AND METHODS: Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. CONCLUSIONS: With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02155647.

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development-analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

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.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcγ receptor (FcγR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FcγRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FcγRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3(+) regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FcγR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FcγR-expressing immune cells, and facilitate subsequent antitumor immunity.

Circulating levels of luteinizing hormone (LH) are essential for the production of steroid hormones that regulate the timing of ovulation and target tissue responses, as well as maintenance of the corpus luteum and therefore early pregnancy. Clinical and basic science observations show that elevated levels of serum LH during the follicular phase of the menstrual cycle are not only unnecessary for follicular maturation but are deleterious to normal reproductive processes. These elevations may occur as a result of administration of exogenous LH or through an endogenous pathological process (i.e. polycystic ovarian disease, PCOD). Resting levels of LH, synergizing with locally produced IGFs, inhibin and perhaps other growth factors, are adequate for normal follicular growth and steroidogenesis. Elevations in serum LH above these resting levels may result in increased androgen production that diminishes follicular function and reduces early embryo viability. Elevated LH levels during the preovulatory period may also negatively influence post-ovulatory events such as conception and implantation. With these facts in mind, the best results for ovulation induction would be expected with purified follicle-stimulating hormone (FSH) administration to women following gonadotrophin releasing hormone (GnRH) down-regulation. It is hoped that this review provides the reader with an analysis of the complex series of events that regulate normal follicular maturation. The reevaluation of the two cell-two gonadotrophin theory suggests that during the preovulatory period, resting levels of LH are adequate for normal follicular maturation. Indeed, overstimulation of the ovary with excessive amounts of LH may diminish the ability of that target organ to produce fertile ova. A review of both clinical and basic science information supports the contention that successful ovulation induction should employ techniques that elevate serum levels of FSH but not LH. One may, therefore, envisage the role of LH during the follicular phase of the menstrual cycle to be a crescendo: of little importance during the early follicular phase and most important at the time of ovulation. FSH, on the other hand, has a reversed pattern of importance: essential for early events and having a relatively minor role at the time of ovulation.

Human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor (LHCGR) but it is not known whether they elicit the same cellular and molecular response. This study compares for the first time the activation of cell-signalling pathways and gene expression in response to hLH and hCG. Using recombinant hLH and recombinant hCG we evaluated the kinetics of cAMP production in COS-7 and hGL5 cells permanently expressing LHCGR (COS-7/LHCGR, hGL5/LHCGR), as well as cAMP, ERK1/2, AKT activation and progesterone production in primary human granulosa cells (hGLC). The expression of selected target genes was measured in the presence or absence of ERK- or AKT-pathways inhibitors. In COS-7/LHCGR cells, hCG is 5-fold more potent than hLH (cAMP ED(50): 107.1±14.3 pM and 530.0±51.2 pM, respectively). hLH maximal effect was significantly faster (10 minutes by hLH; 1 hour by hCG). In hGLC continuous exposure to equipotent doses of gonadotropins up to 36 hours revealed that intracellular cAMP production is oscillating and significantly higher by hCG versus hLH. Conversely, phospho-ERK1/2 and -AKT activation was more potent and sustained by hLH versus hCG. ERK1/2 and AKT inhibition removed the inhibitory effect on NRG1 (neuregulin) expression by hLH but not by hCG; ERK1/2 inhibition significantly increased hLH- but not hCG-stimulated CYP19A1 (aromatase) expression. We conclude that: i) hCG is more potent on cAMP production, while hLH is more potent on ERK and AKT activation; ii) hGLC respond to equipotent, constant hLH or hCG stimulation with a fluctuating cAMP production and progressive progesterone secretion; and iii) the expression of hLH and hCG target genes partly involves the activation of different pathways depending on the ligand. Therefore, the LHCGR is able to differentiate the activity of hLH and hCG.

BACKGROUND: The goal of the study was to determine the prognostic value of nonsustained ventricular tachycardia (NSVT) in total mortality in severe congestive heart failure (CHF) and in death modes. NSVT is associated with an increased mortality in CHF. However, the predictive value of NSVT as a marker for sudden death or death due to progressive heart failure has not been determined. METHODS AND RESULTS: Five hundred sixteen patients from the GESICA trial (33.4% with NSVT) were initially studied with the results of 24-hour Holter and 2 years of follow-up. Within 2 years, 87 of 173 patients (50.3%) with NSVT and 106 of 343 patients (30.9%) without NSVT died. Relative risk (RR) was 1.69 (95% confidence interval [CI], 1.27 to 2.24; P < .0002), and Cox proportional hazard analysis was 1.62 (95% CI, 1.22 to 2.16; P < .001). Sudden death increased from 8.7% (30 of 343) to 23.7% (41 of 173) in patients with NSVT (RR, 2.77; 95% CI, 1.78 to 4.44; P < .001). Progressive heart failure death was also increased from 17.5% (60 of 343) to 20.8% (36 of 173) (P = .22). Quantitative analysis of 24-hour Holter (first 295 patients) demonstrated that couplets had a similar RR to that of NSVT for both total mortality (RR, 1.81; 95% CI, 1.22 to 2.66; P < .002) and sudden death (RR, 3.37; 95% CI, 1.57 to 7.25; P < .0005). Couplets and/or NSVT (ventricular repetitive beats) were even more predictive for sudden death (RR, 10.1; 95% CI, 1.91 to 52.7; P < .01). CONCLUSIONS: In patients with CHF, NSVT is an independent marker for increased overall mortality rate and sudden death. The absence of NSVT and ventricular repetitive beats in a 24-hour Holter indicates a low probability of sudden death.

BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform--MSBase--has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.

The newest techniques and theories covering the design and management of thermal energy storage systems in the areas of heat recovery and in circumstances where energy availability does not coincide chronologically with demand are presented. Techniques that predict the performance of sensible heat storage units in a broad range of operating conditions and methods for designing energy storage units for a variety of applications are covered comprehensively. The single blow problem of gas passing through heat-storing packing continuously in one direction is discussed. Solutions to this problem facilitate the control of the drying or cooling of beds of grain, other food stuffs, and industrial granular or powder products. These same solutions are applicable to the crucial issues of heat storage capabilities of particular construction in buildings and thermal stores built into solar collectors. Detailed information is included about counterflow regenerators including finite conductivity and nonlinear models. New concepts in computational methodology, parallel flow regenerators, heat storage exchangers, and packed beds are also covered. The optimization of prediction of heat storage systems and useful engineering correlations for thermal and hydraulic aspects of storage unit design are presented and explained in detail.

OBJECTIVE: To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. RESULTS: Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n=4) versus 2.5% (n=1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. CONCLUSION: The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

Quality by Design (QbD) is a new approach to the development of recombinant therapeutic protein products that promotes a better understanding of the product and its manufacturing process. The first step in the QbD approach consists in identifying the critical quality attributes (CQA), i.e., those quality attributes of the product that have an impact on its clinical efficacy or safety. CQAs are identified through a science-based risk assessment taking into consideration a combination of clinical and nonclinical data obtained with the molecule or other similar molecules or platform products, as well as the published literature. The purpose of this article is to perform a comprehensive review of the published literature, supporting an assessment of the impact on safety and efficacy of the quality attributes commonly encountered in recombinant therapeutic proteins, more specifically those produced in mammalian cell expression systems. Quality attributes generally observed in biopharmaceutical proteins including product-related impurities and substances, process-related impurities, product attributes, and contaminants are evaluated one by one for their impact on biological activity, pharmacokinetics and pharmacodynamics, immunogenicity, and overall safety/toxicity.

OBJECTIVE: Tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of severe rheumatoid arthritis (RA), yet drug discontinuation is common. The aim of this study was to compare treatment retention rates and specific causes of anti-TNF discontinuation in a population-based RA cohort. METHODS: All patients treated with etanercept, infliximab, or adalimumab within the Swiss Clinical Quality Management RA cohort between 1997 and 2006 were included in the study. Causes of treatment discontinuation were broadly categorized as adverse events (AEs) or nontoxic causes, and further subdivided into specific categories. Specific causes of treatment interruption were analyzed using a Cox proportional hazards model and adjusted for potential confounders. RESULTS: A total of 2,364 anti-TNF treatment courses met the inclusion criteria. Treatment discontinuation was reported 803 times: 309 with etanercept, 249 with infliximab, and 245 with adalimumab. Drug inefficacy represented the largest single cause of treatment discontinuation (55.8% of cases). The median time of receiving anti-TNF therapy was 37 months, but discontinuation rates differed between the 3 anti-TNF agents (P < 0.001), with shorter retention rates for infliximab (hazard ratio [HR] 1.24, 99% confidence interval [99% CI] 1.01-1.51). The specific causes of treatment discontinuation revealed an increased risk of AEs with infliximab (HR 1.4, 99% CI 1.003-1.96), mostly due to an increased risk of infusion or allergic reactions (HR 2.11, 99% CI 1.23-3.62). Other discontinuation causes were equally distributed between the anti-TNF agents. CONCLUSION: In this population, infliximab was associated with higher overall discontinuation rates compared with etanercept and adalimumab, which is mainly due to an increased risk of infusion or allergic reactions.

Abstract Carry trades—popular strategies in the foreign exchange market—are long positions in high interest rate currencies financed through funds borrowed from low interest rate currencies. It has been shown for a number of bilateral exchange rates vis‐à‐vis the US dollar that shocks to interest rate differentials foster carry trade activity and lead to significant changes in the foreign exchange level. This paper considers which (or which combination of) structural shocks can be consistent with the implications of such an interest rate differential shock that has been identified in previous studies. It is especially demand and confidence shocks, rather than supply or monetary policy shocks, which are found to generate effects similar to those produced by an unexpected widening of the interest rate differential and overall lead to longer‐term gains from carry trade activity. Also provided is a measure of the potential gain/losses experienced by the actual positioning of market participants in the foreign exchange futures and conditional on the knowledge of the macroeconomic shock that occurred at the time of positioning.