Summary Background Patients with radioactive iodine (131 I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment ...options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0–2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov , number NCT00984282 , and with the EU Clinical Trials Register, number EudraCT 2009–012007–25. Findings Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio HR 0·59, 95% CI 0·45–0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand–foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). Interpretation Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).
Recombinant soluble HIV-1 envelope glycoprotein (Env) SOSIP trimers are a design platform for inducing broadly neutralizing antibodies (bNAbs) by vaccination. To date, these and alternative designs ...of native-like trimers, given singly or in pairs, have not induced bNAbs in test animals such as rabbits or macaques. Here, we have evaluated whether trivalent and tetravalent combinations of SOSIP trimers from clades A, B, and C, delivered simultaneously or sequentially, induce better neutralizing antibody responses in rabbits than when given alone. None of the tested formulations led to the induction of bNAbs. We found that BG505 clade A trimers dominated the autologous NAb responses induced by combinations, which probably relates to the presence of immunodominant glycan holes on the BG505 trimer. Furthermore, autologous NAb responses to all individual trimers were reduced when they were delivered in combinations compared with when delivered alone, suggesting that immunogen interference had occurred. Finally, in a sequential regimen, a heterologous clade C trimer cross-boosted NAb responses that were primed by earlier immunizations with clade A and B trimers. Taken together, these findings should allow us to improve the design of immunization regimens based on native-like HIV-1 Env trimers.
A successful HIV-1 vaccine most probably requires a trimeric envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and therefore the only target for neutralizing antibodies. Native-like Env trimers can induce strain-specific neutralizing antibodies but not yet broadly neutralizing antibodies. To try to broaden the antibody response, we immunized rabbits with soluble native-like Env trimers from three different clades using monovalent, multivalent, and sequential regimens. We found that the neutralizing antibody response against each immunogen was reduced when the immunogens were delivered in combination or sequentially compared to the monovalent regimen. In contrast, when the Env trimers from different clades were delivered sequentially, the neutralizing antibody response could be cross-boosted. Although the combination of native-like Env trimers from different clades did not induce broadly neutralizing antibodies, the results provide clues on how to use native-like trimers in vaccination experiments.
1. Central to the success of restoration is how applied activities influence community assembly mechanisms. Phylogenetic and trait-based approaches to community ecology are increasingly being used to ...test for non-random community assembly and are now being applied to assessments of habitat restoration. A critical question for the restoration of tropical forests is how plantings influence the recruitment of new species, and specifically the phylogenetic and functional diversity of restored habitats. 2. We examined 8 years (2006-2014) of tropical-forest recruitment in two restoration planting compositions (12 animal-dispersed and 12 wind-dispersed tree species), with a control (no planting) in 24 plots in Los Tuxtlas, Mexico. Specifically, we assessed the influence of plantings on newly arriving individuals' phylogenetic, functional, taxonomic diversity, abundance and the change of these measures during early succession. 3. The recruiting individuals' phylogenetic, functional, taxonomic diversity and abundance increased through succession. Both animal-dispersed planting and winddispersed planting appeared to accelerate forest succession more than controls (natural succession), and diversity in the animal-dispersed plantings was marginally higher after 8 years. We did not find any difference in recruiting individuals' phylogenetic and functional dispersion (measured as standardized effect sizes) in any given year, or when measured as turnover between successive pairs of years, measuring planting composition and control plots. 4. Recruiting individuals were phylogenetically clustered during early forest restoration regardless of treatment At the same time, the recruits transitioned from appearing randomly constructed to clustering according to functional traits, which suggests an increase in recruits' functional similarity during early succession. ated the increase of recruiting individuals' phylogenetic, functional, taxonomic diversity and abundance during early succession. 5. Synthesis and applications. Both the animal and wind-dispersed plantings accelerated the increase of recruiting individuals' phylogenetic, functional, taxonomic diversity and abundance during early succession. However, planting treatment did not appear to alter community assembly mechanisms of recruiting individuals. Our findings support restoration planting by showing that planting trees with animal dispersal syndrome could accelerate forest restoration more than unassisted forest regeneration. Furthermore, communities appeared to be phylogenetically and functionally clustered during early succession regardless of initial planted composition. Thus, while overall diversity increased with planting, if a restoration goal is to maximize phylogenetic or functional dispersion, the planting composition tested did not provide means to achieve this goal, at least during early succession.
ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine ...causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.
The high viral diversity of HIV-1 is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far ...immunization strategies have failed to efficiently elicit bNAbs. To overcome these obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (MAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive MAbs were isolated using antigen-specific single B-cell sorting. Four of these MAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing MAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles, and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B-neutralizing MAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer-dissociating bNAbs.
Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic, and 1.7 million people still get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing MAbs, combined with detailed characterization of the neutralization epitope, can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination.
Recently, there has been a renewed interest in the development of distributed model predictive control (MPC) techniques capable of inheriting the properties of centralized predictive controllers, ...such as constraint satisfaction, optimal control, closed-loop stability, etc. The objective of this paper is to design and implement in a four-tank process several distributed control algorithms that are under investigation in the research groups of the authors within the European project HD-MPC. The tested controllers are centralized and decentralized model predictive controllers schemes for tracking and several distributed MPC schemes based on (i) cooperative game theory, (ii) sensivity-based coordination mechanisms, (iii) bargaining game theory, and (iv) serial decomposition of the centralized problem. In order to analyze the controllers, a control test is proposed and a number of performance indices are defined. The experimental results of the benchmark provide an overview of the performance and the properties of several state-of-the-art distributed predictive controllers.
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 ...SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).
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•The stability of HIV-1 envelope trimers can be increased by structure-based design•Design improvements are applicable to envelope trimers from different HIV-1 isolates•Immunization of stabilized HIV-1 envelope trimers is improved
Native-like HIV-1 envelope trimers are a platform for efforts to induce broadly neutralizing antibodies. Torrents de la Peña et al. design HIV-1 envelope trimers with enhanced stability and reduced flexibility. These modified trimers improve the induction of neutralizing antibodies and provide new opportunities toward elicitation of broadly neutralizing antibodies.
Zika virus (ZIKV) is a flavivirus that has recently been associated with an increased incidence of neonatal microcephaly and other neurological disorders. The virus is primarily transmitted by ...mosquito bite, although other routes of infection have been implicated in some cases. The Aedes aegypti mosquito is considered to be the main vector to humans worldwide; however, there is evidence that other mosquito species, including Culex quinquefasciatus, transmit the virus. To test the potential of Cx. quinquefasciatus to transmit ZIKV, we experimentally compared the vector competence of laboratory-reared Ae. aegypti and Cx. quinquefasciatus. Interestingly, we were able to detect the presence of ZIKV in the midgut, salivary glands and saliva of artificially fed Cx. quinquefasciatus. In addition, we collected ZIKV-infected Cx. quinquefasciatus from urban areas with high microcephaly incidence in Recife, Brazil. Corroborating our experimental data from artificially fed mosquitoes, ZIKV was isolated from field-caught Cx. quinquefasciatus, and its genome was partially sequenced. Collectively, these findings indicate that there may be a wider range of ZIKV vectors than anticipated.
Emerging Microbes & Infections (2017) 6, e69; doi:10.1038/emi.2017.59; published online 9 August 2017
Generating tier 2 HIV-neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses with Env immunogens remain ...unclear. Here, some rhesus monkeys developed autologous tier 2 nAbs upon HIV Env trimer immunization (SOSIP.v5.2) whereas others did not. This was not because HIV Env trimers were immunologically silent because all monkeys made similar ELISA-binding antibody responses; the key difference was nAb versus non-nAb responses. We explored the immunological barriers to HIV nAb responses by combining a suite of techniques, including longitudinal lymph node fine needle aspirates. Unexpectedly, nAb development best correlated with booster immunization GC B cell magnitude and Tfh characteristics of the Env-specific CD4 T cells. Notably, these factors distinguished between successful and unsuccessful antibody responses because GC B cell frequencies and stoichiometry to GC Tfh cells correlated with nAb development, but did not correlate with total Env Ab binding titers.
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•Fine needle aspirates quantitatively monitor germinal center activity in lymph nodes•Neutralizing antibodies correlate with GC B cell magnitude, not ELISA Ab titers•Tfh cell quality is associated with vaccine-elicited HIV-neutralizing antibodies•LN FNA probing of GCs should be an immune correlate in HIV vaccine trials
This study explores the immunological process by which a protein vaccine elicits HIV-neutralizing antibodies. Using direct probing of lymph nodes, Havenar-Daughton et al. show that neutralizing antibody development correlates with germinal center B cell frequencies and Tfh cells and that those responses can be tracked by LN FNAs over time.
The HIV‐1 envelope gp160 glycoprotein (Env) is a trimer of gp120 and gp41 heterodimers that mediates cell entry and is the primary target of the humoral immune response. Broadly neutralizing ...antibodies (bNAbs) to HIV‐1 have revealed multiple epitopes or sites of vulnerability, but mapping of most of these sites is incomplete owing to a paucity of structural information on the full epitope in the context of the Env trimer. Here, a crystal structure of the soluble BG505 SOSIP gp140 trimer at 4.6 Å resolution with the bNAbs 8ANC195 and PGT128 reveals additional interactions in comparison to previous antibody–gp120 structures. For 8ANC195, in addition to previously documented interactions with gp120, a substantial interface with gp41 is now elucidated that includes extensive interactions with the N637 glycan. Surprisingly, removal of the N637 glycan did not impact 8ANC195 affinity, suggesting that the antibody has evolved to accommodate this glycan without loss of binding energy. PGT128 indirectly affects the N262 glycan by a domino effect, in which PGT128 binds to the N301 glycan, which in turn interacts with and repositions the N262 glycan, thereby illustrating the important role of neighboring glycans on epitope conformation and stability. Comparisons with other Env trimer and gp120 structures support an induced conformation for glycan N262, suggesting that the glycan shield is allosterically modified upon PGT128 binding. These complete epitopes of two broadly neutralizing antibodies on the Env trimer can now be exploited for HIV‐1 vaccine design.
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