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We received dossiers from five pharmaceutical manufacturers: Abbot order clarinex no prescription, Amgen clarinex 5 mg mastercard, Centocor Ortho Biotech discount clarinex 5 mg on-line, Genentech, and UCB Inc. By applying the eligibility and exclusion criteria to titles and abstracts of all identified citations, we obtained full-text copies of 436 citations. After re-applying the criteria for inclusion, we ultimately included 78 new publications, representing 68 unique studies. See Appendix G for a list of excluded studies and reasons for exclusion at this stage. Targeted immune modulators 26 of 195 Final Update 3 Report Drug Effectiveness Review Project a Figure 1. Results of literature search b 4736 (1589) records identified 474 (163) additional records from database searches after identified through other sources removal of duplicates 3647 (1316) records excluded 5210 (1752) records screened at abstract level 1563 (436) full-text articles 1366 (338) full-text articles excluded assessed for eligibility • 12 (12) non English language • 165 (79) outcome not included • 76 (20) intervention not included c 163 (68) studies (197 articles) included • 82 (18) population not included in qualitative synthesis • 274 (83) publication type not included • 70 (28) trials • 358 (86) study design not included • 51 (13) observational studies • 227 (14) study not obtainable • 31 (19) systematic reviews • 36 (2) superseded by newer evidence • 11 (8) others (includes pooled analysis, • 26 (12) high risk of bias post hoc analysis of trials etc). Targeted immune modulators 27 of 195 Final Update 3 Report Drug Effectiveness Review Project Key Question 1. Efficacy and Effectiveness How do included drugs compare in their efficacy and long-term effectiveness for alleviating symptoms and stabilizing the disease in patients with rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, or plaque psoriasis? Rheumatoid Arthritis The following drugs are currently approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis: abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, and tocilizumab. We included 16 trials, 21 systematic reviews and meta-analyses, and seven observational 39 studies. Only one randomized controlled trial was a double-blinded head-to-head trial. One 40 study was characterized as an effectiveness trial. Most of the included efficacy studies were conducted in narrowly defined populations and/or were limited to less than 1 year of follow-up. Summary of findings The only double-blinded head-to-head trial that we found on the comparative efficacy of targeted immune modulators was a fair randomized controlled trial that compared abatacept with 39 infliximab in patients with inadequate response to methotrexate. At 6 months, no differences in efficacy were apparent between patients treated with abatacept or infliximab. After 1 year, however, abatacept was statistically significantly more efficacious on most outcome measures than infliximab (American College of Rheumatology 20 response 72. It has to be noted though, that infliximab was administered at a fixed dose throughout the entire study. Infliximab efficacy trials have shown that up to 30% of patients require dose increases. Other direct comparisons of targeted immune modulators for the treatment of rheumatoid arthritis were limited to one small randomized controlled trial and multiple nonrandomized or observational studies rendering evidence of low strength. These studies indicated no differences in efficacy between adalimumab and etanercept but greater response rates for adalimumab and etanercept compared with infliximab. The only study with a randomized allocation of patients, however, was a fair, small (n=32) open- 41 label trial. Results indicated greater response rates in patients treated with etanercept than with infliximab (74. Six head-to-head observational studies and one nonrandomized trial also reported similar findings of greater efficacy of 40,42-46 etanercept than infliximab. In the Danish (n=1452), 35% of patients treated with adalimumab achieved a LUNDEX-corrected American College of Rheumatology 50 response at 12 months, compared with 25% of patients on infliximab (P< 0. Indirect comparisons of placebo-controlled randomized controlled trials suggest that etanercept is statistically significantly more efficacious than abatacept, anakinra, infliximab, and Targeted immune modulators 28 of 195 Final Update 3 Report Drug Effectiveness Review Project tocilizumab (range of relative risks from 2. No statistically significant differences in efficacy could be detected among adalimumab, anakinra, infliximab, and tocilizumab. The strength of evidence was low, except for the comparison of etanercept with infliximab for which the strength of evidence was moderate. Data were too heterogeneous to conduct indirect comparisons of certolizumab pegol, golimumab, and rituximab with other targeted immune modulators. Good to fair evidence was found from meta-analyses and large randomized controlled trials that abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, and tocilizumab are statistically significantly more efficacious than placebo for the treatment of rheumatoid arthritis. Treatment effects were large and consistent across studies. Study populations and outcome measures All patients suffered from active rheumatoid arthritis and most randomized controlled trials 4,47 employed the American College of Rheumatology criteria to classify the diagnosis of rheumatoid arthritis. Some trials, however, used stricter eligibility criteria. Disease duration and concomitant treatments also varied across studies. Most patients used nonsteroidal anti- inflammatory drugs or oral corticosteroids in addition to the study medication. The majority of trials enrolled patients who had failed at least one disease-modifying antirheumatic drug treatment or were on a stable dose of methotrexate with unsatisfactory response. Some studies enrolled populations that had also failed an antitumor necrosis factor drug. Patients with an autoimmune disease other than rheumatoid arthritis, a history of active listeriosis or mycobacterial infection, or recent antibiotic treatment were generally excluded from studies. All trials assessed response rates as defined by the American College of Rheumatology or by the European League Against Rheumatism. These scales (American College of Rheumatology 20/50/70, Disease Activity Score 28) combine measures of global disease activity with counts of tender and swollen joints and acute phase laboratory parameters (see Appendix D). In addition, most studies evaluated health outcomes such as quality of life, functional capacity (e. Various observational studies enrolled primary care patients who started on targeted immune modulator treatment. Because these studies included unselected populations, findings were probably more applicable to the average rheumatoid arthritis patient than results from efficacy trials. Limitations with respect to risk of bias have to be kept in mind though. Sponsorship All trials were funded by the pharmaceutical industry. Meta-analyses and cohort studies usually had public or a mix of public and industry funding. Detailed assessment: Direct evidence on comparative effectiveness Overall, we included eight head-to-head studies comparing one targeted immune modulator to 39-45,48 another. These direct comparisons, however, were limited to abatacept compared with infliximab, adalimumab and etanercept compared with infliximab, and adalimumab compared Targeted immune modulators 29 of 195 Final Update 3 Report Drug Effectiveness Review Project with etanercept. We could not find any head-to-head evidence for any of the other drugs. Abatacept compared with infliximab The only double-blinded head-to-head trial, the ATTEST (Abatacept or infliximab compared with placebo, a Trial for Tolerability, Efficacy, and Safety in Treating rheumatoid arthritis) 39 study, was a fair randomized controlled trial that compared abatacept with infliximab. This study enrolled 431 patients and randomized them to abatacept (10 mg/kg every 4 weeks + methotrexate), infliximab (3 mg/kg every 8 weeks + methotrexate), or placebo. The primary outcome was assessed at 6 months followed by a double-blinded extension phase up to 1 year. No statistically significant differences in efficacy were obvious between treatments at 6 months (DAS 28: abatacept ‒2.

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In MONARK purchase discount clarinex line, bone density improved after a switch to darunavir/r monotherapy (Guarladi 2014) buy clarinex 5mg without a prescription. However purchase clarinex overnight delivery, some patients on lopinavir/r show low levels of viremia, especially in combination with low CD4 T cells. They tend to show poor compliance (Campo 2007, Pulido 2008, Gutmann 2010). The same was observed with therapy-naïve patients (see above). For darunavir, the results of two large randomized studies MONET and MONOI with identical design are published (Clumeck 2011, Valentin 2012). In MONET, non-infe- riority of the monotherapy could not completely be shown after 96 weeks, at least regarding the primary endpoints (Clumeck 2011). In total, 82% of patients were below 50 copies/ml in the standard arm at week 96, compared to 78% on darunavir monotherapy. When virologi- cally successful therapies were not evaluated as failure, a difference was not observed. The results can be explained by a possibly low adherence in the mono-arm (with significantly more HCV-coinfected patients). In MONOI, transient viremia was more frequent on monotherapy and a permanent control under 50 copies/ml without blips was observed in 59% versus 70% of patients at week 96 (Valantin 2012). Virologic failure was associated with levels of proviral DNA at baseline (Marcelin 2011), but also with low adherence (Lambert-Niclot 2011). Of note, darunavir RAMs were not observed either in MONET or in MONOI (Lambert- Niclot 2012, Pulido 2012). Possibly, darunavir levels are lower without NRTIs (Garvey 2010). In MONOI, lipoatrophy improved in some patients (Valantin 2012). For indinavir/r, saquinavir/r and fosamprenavir/r there are one-arm pilot studies with weak results (Kahlert 2004, Patricia 2010, Saumoy 2011). The Ataritmo study observed an elevated viral load in cerebrospinal fluid within some patients on atazanavir with otherwise well suppressed viral loads. In the OREY study, 9/63 patients developed virological failure (Pulido 2009). In a systematic review of 10 randomized trials of 1,964 patients with HIV RNA suppression at baseline, PI monotherapy showed a higher risk of HIV RNA eleva- tions, and small numbers with HIV RNA detectable in CSF and concomitantly in the plasma. However, there was no increased risk of treatment-emergent drug resistance (Arribas 2014). The risk of treatment emergent NRTI or PI resistance was 11/973 (1. HIV-1 RNA suppression rates after intensification were similar between PI monotherapy and triple therapy. More recently, new approaches such as dual therapies (ususally with 3TC as a single NRTI) have been evaluated. In studies like SALT and OLE, atazanavir/r or lopinavir/r have been combined with 3TC (see above), the results are encouraging. In contrast, dual therapy with an NNRTI is not recommended. In the COOL study, many patients developed virological failure on TDF plus efavirenz (Girard 2006). Conclusion: Monotherapies with boosted PIs such as lopinavir/r and darunavir/r are slightly less effective than classic therapies (review: Mathis 2011). In most cases, low- level viremia without resistance appears that does disappear upon intensification (Arribas 2014). Risk factors for monotherapy failure are poor adherence, a prior viro- logical failure and a low CD4 T cell nadir. Monotherapies as a strategy can not be justified at this time. In individual cases, however, they may be able to reduce adverse events. Dual therapy of a boosted PI and 3TC are promising, coformulations are in development. These combinations may have the potential to reduce some of the long-term toxic effects associated with NRTIs, preserve future treatment options, and reduce the cost of antiretroviral therapy. Switching to simplify – triple-nukes revisited Triple nuke therapy, fairly obsolete for first-line therapy, may be justifiable in maintenance therapy. Several randomized studies have not detected any virologic disadvantage (Katlama 2003, Markowitz 2005, Sprenger 2010). In the ESS40013 study, a total of 448 patients were treated with AZT+3TC+ABC plus efavirenz. After 36 or 44 weeks, 282 patients with undetectable viral load were ran- domized to continue with the same therapy or to stop efavirenz. After 96 weeks, 79% versus 77% of patients were still below 50 copies/ml, proving that triple nuke was not inferior (Markowitz 2005). Similar results were also seen in the TRIZAL and FREE study, in which 209 patients were randomized (Katlama 2003, Sprenger 2010). In the Swiss Cohort, the failure rate was low in 495 patients with suppressed viral load and switch to Trizivir. Patients with earlier exposure to mono- or dual-NRTI therapy, low CD4 T cell count at time of switch, or AIDS were at increased risk of treatment failure, limiting the use of Trizivir in these patient groups (Wolbers 2007). Some long-term data for the quadruple-nuke strategy with Trizivir plus tenofovir (d’Ettore 2007, Llibre 2008) also exist. Taken together, maintenance therapy using Trizivir seems feasible. Three or four NRTIs are possibly more toxic than other strategies. Strategies such as monotherapy with boosted PIs are not yet justifiable outside clinical trials. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treat- ment-naive, HIV-1-infected subjects over 48 weeks. Comparative biological and clinical outcomes after a switch from a viro- logically unsuccessful first protease inhibitor-containing antiretroviral combination to a 3-drug regimen con- taining efavirenz, nevirapine, or abacavir. Abgrall S; The Antiretroviral Therapy Cohort Collaboration (ART-CC). Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and N.

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Longer follow-up of this four patients were enrolled in the phase 1 trial; their median age was trial is now available and has demonstrated impressive results buy clarinex 5 mg with amex. Seventeen patients With a median follow-up of 33 months order 5mg clarinex, the relapse-free survival had evaluable cytogenetics: 5 favorable buy clarinex online from canada, 8 intermediate, and 2 poor rate is 61%. The nonhematologic toxicities were mild; hematologic remission. However, even more exciting, 6 of 11 however, 4 patients developed grade 3-4 myelosuppression and 4 patients not proceeding to transplantation remain in remission. Serial MRD measure- A subsequent trial has evaluated blinatumomab in morphologically ments were performed by quantitative clone-specific PCR in 11 27 relapsed/refractory ALL. In this trial, blinatumomab was adminis- cases and demonstrated a median 1 log decrease in MRD in the 20 22 tered as a continuous infusion for 28 days, which was followed by a and 30 mg dosing cohorts. The dosing for the first week was 5 g/m /d because weeks after the last dose was administered. With a median 27 of concern for infusion reactions with active disease. The majority follow-up of 51 months at last presentation, the median disease-free of AEs were grade 1-2 (pyrexia: 67%; headaches 33%), with 7 grade survival was 53 months and the median overall survival was 55 22 3 or higher AEs occurring in 5 patients (infection, seizures, months, which is impressive. A phase 2 trial studying 70 27 decreased platelets). Responders were allowed to receive 3 additional patients has completed accrual and the results are awaited additional cycles of therapy. As of the last report, 36 patients had to determine the efficacy and toxicity of this approach. Seventeen patients had of strategies such as CMV prophylaxis to decrease toxicities will be achieved CR or CR with partial hematologic recovery and MRD important if this approach demonstrates promising results. BiTE antibodies are a novel class of bispecific single-chain antibod- This latter mechanism of resistance is a concern with the develop- ies that retarget cytotoxic T lymphocytes at preselected surface ment of antibody-targeted therapies and approaching this mecha- antigens on tumor cells. Blinatumomab Of the various novel therapeutics, blinatumomab is one of the most CD19 is the most commonly expressed antigen in pre-B-ALL and promising. Ultimately, moving blinatumomab to the upfront setting has the highest density of expression. The US Intergroup Hematology 2013 133 (E1910) is planning a trial of chemotherapy with and without blinatu- activity in cell line and patient samples. In a pediatric study, 3 of 17 momab in adults with newly diagnosed ALL to help address this ALL patients achieved a CR. The initiation and outcome of this trial are eagerly awaited. This appears to be due to a unique amino acid motif in the ricin toxin Immunotoxins/immunoconjugates A chain that damages vascular endothelial cells. Ongoing ap- proaches include mutating the recombinant ricin toxin A to disable Immunotoxins/immunoconjugates are composed of a monoclonal this site. Another approach is to shorten the half-life of the immuno- antibody or a cell-antigen-binding fragment and a toxin moiety that toxin in vivo, and studies with this latter approach are ongoing. Serum levels of the agent correlated with dose level and fragment of an antibody linked to a 38 kDa truncated derivative of the percentage of circulating blasts. The often rapid rebound in Pseudomonas exotoxin A (PE38) as the toxin moiety for their 29 peripheral blasts after the last dose of combotox suggests that immunotoxins. These agents bind to CD22, after which they are continued dosing with a reduced dose might lead to more durable internalized via receptor-mediated endocytosis and processed by remissions. BL22 and CAT-8015 CD22 represents an attractive therapeutic target for this approach because the CD22 antigen-immunotoxin is rapidly internalized. In a phase 1 trial including ALL patients, no allergic/infusion reactions, vascular leak, or hemolytic uremic is extremely potent, with an EC50 in the subnanomolar range. Three of 23 patients did develop neutraliz- SAR3419 binds to CD19 and is subsequently internalized via ing antibodies. Only modest activity was noted in ALL and there were no CRs. Sixteen of 23 patients did have a other grade 3 or 4 toxicities exceeded 10% and there were no reduction in blast count. SAR3419 seems to have a large therapeutic window with minimal toxicity. Serial modifications have reduced nonspecific toxicities, increased stability, enhanced tissue penetration, and SAR3419 is ongoing in adults with relapsed/refractory ALL. However, immu- best studied and most promising new agents in relapsed/refractory notoxin resistance has been observed in ALL cell lines due to a low 30 ALL. The drug conjugate consists of a monoclonal antibody against level of DPH4 mRNA and protein. This renders EF2 refractory to 4 CD22 bound to calicheamicin. Calicheamicin is a potent cytotoxic the effects of CAT-8015; protein synthesis is not inhibited and cell agent that binds the minor DNA groove and causes breaks in death does not occur. Further analysis of the DPH4 gene promoter double-stranded DNA in a sequence-specific manner, leading to demonstrated heavy methylation in the resistant cells. The ADC is rapidly internalized and delivers tance could be reversed by the treatment of cells with the hypomethy- calicheamicin intracellularly. Initial phase 1/2 studies in lymphoma lating agent 5-azacitidine and suggests that such an approach may demonstrated encouraging response rates and established a recom- be applied clinically. Study of such mechanisms of resistance and 2 mended phase 2 dose of 1. Mild to moderate elevations in transaminases in the development of other antibody-based therapies. A phase 1/2 trial was conducted in adults with relapsed/refractory CD22 ALL (n 49). The median age Combotox is a 1:1 mixture of immunotoxins prepared by coupling a was 36 years (range 16-80). All patients had 50% CD22 deglycosylated ricin A chain to monoclonal antibody directed lymphoblasts and the majority were heavily pretreated: 27% salvage against CD22 and CD19. Preclinical studies demonstrated undergone prior AHCT. In addition, almost half had poor-risk 134 American Society of Hematology Table 4. Summary of the various antibody-based approaches Target Drug Class Results Clinical trials CD20 Rituximab Naked antibody Phase 2 results in adults 60 years of Phase 3 GRAAL 2005 ongoing in newly age with newly diagnosed ALL diagnosed CD20 Ph ALL demonstrate superior CMR, RFS, and OS6,7 CD22 Epratuzumab Naked antibody Encouraging Phase 2 results in IntERALL phase 3 trial in relapsed combination with chemotherapy for pediatric ALL relapsed ALL in children and adults20,21 CD52 Alemtuzumab Naked antibody Encouraging DFS in Phase 1 trial in Results of a larger phase 2 trial pending combination with chemotherapy (CALGB 10102) (newly diagnosed ALL)23 CD19 Blinatumomab BiTE antibody Encouraging results in MRD ALL and Phase 3 randomized trial in adults with relapsed/refractory adult ALL25,27 newly diagnosed ALL (E1910) CD22 CAT-8015 Immunotoxin Encouraging phase 1 results in relapsed Ongoing trial (NCT00659425) in pediatric ALL28 children and young adults with CD22 relapsed/refractory ALL and NHL CD19 and CD22 Combotox Immunotoxin Phase 1 trial in pediatric ALL; 3/17 CR31 Phase 1 adult trial in combination with cytarabine (NCT01408160) CD19 SAR3419 Immunoconjugate Phase 2 trial in relapsed/refractory ALL CD22 Inotuzumab Immunoconjugate Phase 1/2 trials in ALL4; CR/CRi rate Phase 3 trial ongoing (B1931022) in 57%; high CMR salvage 1/2 CD19 CAR CAR Phase 1 ongoing RFSindicatesrelapse-freesurvival;OS,overallsurvival;andDFS,disease-freesurvival. Chimeric antigen receptors Grade 3-4 AEs included drug-related fever (n 9), hypotension Most of the work with chimeric antigen receptors (CARs) has been related to drug (n 1), hyperbilirubinemia (n 2), transaminase performed in chronic lymphocytic leukemia; however, recent elevations (n 1), and high lipase levels (n 1). Grade 3-4 experience in ALL is generating great excitement. CARs are myelosuppression was observed (both neutropenia and thrombocy- composed of a single-chain variable-fragment antibody specific to topenia).

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However clarinex 5mg low cost, in serotype C purchase clarinex line, the GH loop and the carboxy-terminal end of VP1 form independent 5mg clarinex with amex, continuous epitopes. The high specificity of antibodies means that the sequence and conformational differences between serotypes change the detailed antigenic properties of particular regions. Studies focused on natu- ral selection of particular amino acid residues must account for back- ground differences of sequence and conformation among test strains. One can develop a map of natural escape variants by comparing changes in sequence with differences in binding affinity to a panel of MAbs. Two problems of interpreting selective pressures arise from an escape map based on natural variants. First, field isolates do not control the multitude of evolutionary pressures on variation. Mutants may spread EXPERIMENTAL EVOLUTION: FMDV 193 either in direct response to antibody pressure, in response to other se- lective pressures, or by stochastic fluctuations independent of selective forces. Lack of variability may result either from lack of antibody pres- sure or from constraining selective pressures such as binding to host receptors. The second problem for interpreting selective pressures from natu- ral isolates concerns lack of control over genetic background. Whether aparticularamino acid site affects antibody affinity may depend on conformation-changing variants at other sites. Site-directed mutagenesis controls amino acid replacements in a fixed genetic background. One can alter sites that do not vary naturally to test for effects on antibody binding. Site-directed mutagenesis has provided useful information for FMDV (Mateu et al. But this method can only define changes in antibody binding; it does not show how viral populations actually respond to immune pressure. Several studies have applied monoclonal or polyclonal antibodies to FMDV in laboratory culture (Mateu 1995; Sobrino et al. This al- lows direct control of selective pressure by comparing lines with and without exposure to antibodies. In addition, cultures can be started with genetically monomorphic viruses to control genetic background. These viruses were grown on baby hamster kidney cells (BHK-21). All host cells were derived from a single precur- sor cell. C-S8c1 developed through three successive plaque isolations. C-S8c1p100 began with C- S8c1 and developed through one hundred serial passages on a mono- layer of BHK-21 cells. The host cells were refreshed from independent stock in each passage and therefore did not coevolve with the virus over the passage history. In natural isolates, extensive sequence variability in the GH loop of VP1 correlates with escape from antibody neutralization. However, the Arg-Gly-Asp (RGD) sequence near the center of this GH loop is invariant in field isolates (Sobrino et al. Controlled studies of laboratory evolution provide some insight into the evolution of this region. The monoclonal antibody SD6 binds to an epitope spanning residues 136–147 in the GH loop of VP1. Nucleo- tide sequences of escape mutants were obtained. Each mutant (except one) escaped antibody neutralization by a single amino acid change. The different locations of these muta- tions in the original (C-S8c1) line compared with the serially passaged (C-S8c1p100) line provide the most striking result of this study. The original line conserved the Arg-Gly-Asp (RGD) motif at positions 141– 143. By contrast, the serially passaged line had numerous mutations within the RGD motif. Variants in the RGD motif had not previously been observed in spite of neutralizing antibodies’ affinity for this region. The RGD motif was thought to be invariant because of its essential role in binding to the host cell. Yet the serially passaged line accumulated variants in this region. Those variants replicated with the same kinetics as the parental viruses of C-S8c1p100, with no loss in fitness. The escape mutant from the serially passaged line differed from the parental virus of this line only at a single site in the EXPERIMENTAL EVOLUTION: FMDV 195 G N P I D R R 133 156 TTTYTASARGDLAHLTTTHARHLP D I E G V V N S Figure 12. The start and stop numbers label amino acid po- sitions. The monoclonal antibody SD6 recognizes the continuous epitope defined by the underlined po- sitions. Black triangles show positions at which most replacement amino acids greatly reduce binding by SD6; in other words, a single replacement at any of these sites creates an escape mutant. The white triangles denote positions that can tolerate certain amino acid replacements without greatly affecting antibody binding. Unmarked positions in the epitope can vary without much change in binding. The letters above the sequence summarize the escape mutants of C-S8c1 (original line); letters below the sequence summarize escape mutants of C-S8c1p100 (passaged line). Letters denote amino acids according to the standard single-letter code. Tolerance to replacements in the RGD region must follow from the differences accumulated by C-S8c1p100 during serial passage. Apparently those substitutions changed cell 196 CHAPTER 12 tropism properties of the virus and allowed variation in the previously invariant RGD motif. Experimental evolution provides one approach to analyzing those selective forces, as described in the previous section. In this section, I briefly summarize further studies of amino acid variation in the FMDV capsid and the consequences for attachment and entry to host cells. Natural isolates of FMDV use cellular integrin receptors for some of thesteps in attachment and entry (Berinstein et al. Integrins are transmembrane glycoproteins composed of two different subunits, α and β. Variousintegrins mediate adhesion between cells, attachment of cells to theextracellular matrix, and signal transduction of pathways that affect cell proliferation,morphology, mi- gration, and apoptosis (Springer 1990; Hynes 1992; Montgomery et al.