HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide ("Man
-V3") for structural studies of an HIV Env ...third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage ("DH270"), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man
-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs-the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.
Salvage surgical resection for non-small cell lung cancer (NSCLC) patients initially treated with definitive chemotherapy and radiotherapy can be performed safely, but the long-term benefits are not ...well characterized.
Perioperative complications and long-term survival of all patients with NSCLC who received curative-intent definitive radiotherapy, with or without chemotherapy, followed by lobectomy from 1995 to 2012 were evaluated.
During the study period, 31 patients met the inclusion criteria. Clinical stage distribution was stage I in 2 (6%), stage II in 5 (16%), stage IIIA in 15 (48%), stage IIIB in 5 (16%), stage IV in 3 (10%), and unknown in 1 (3%). The reasons surgical resection was initially not considered were: patients deemed medically inoperable (5 16%); extent of disease was considered unresectable (21 68%); small cell lung cancer misdiagnosis (1 3%), and unknown (4 13%). Definitive therapy was irradiation alone in 2 (6%), concurrent chemoradiotherapy in 28 (90%), and sequential chemoradiotherapy in 1 (3%). The median radiation dose was 60 Gy. Patients were subsequently referred for resection because of obvious local relapse, medical tolerance of surgical intervention, or posttherapy imaging suggesting residual disease. The median time from radiation to lobectomy was 17.7 weeks. There were no perioperative deaths, and morbidity occurred in 15 patients (48%). None of the 3 patients with residual pathologic nodal disease survived longer than 37 months, but the 5-year survival of pN0 patients was 36%. Patients who underwent lobectomy for obvious relapse (n = 3) also did poorly, with a median overall survival of 9 months.
Lobectomy after definitive radiotherapy can be done safely and is associated with reasonable long-term survival, particularly when patients do not have residual nodal disease.
The objective of this study was to evaluate the impact of the video-assisted thoracoscopic (VATS) approach on the outcomes of patients who underwent pneumonectomy.
The effect of the surgical approach ...on perioperative complications and survival in patients who underwent pneumonectomy for nonmetastatic non–small cell lung cancer across 3 institutions (2000-2016) was assessed using multivariable logistic regression, Cox proportional hazards analysis, and propensity-score matching. Completion pneumonectomies were excluded from this study, and an “intent-to-treat” analysis was performed.
During the study period, 359 patients met inclusion criteria and underwent pneumonectomy for nonmetastatic non–small cell lung cancer; 124 (35%) underwent pneumonectomy via VATS and 235 (65%) via thoracotomy. Perioperative mortality (VATS, 7% n = 9 vs open, 8% n = 19; P = .75) and morbidity (VATS, 28% n = 35 vs open, 28% n = 65; P = .91) were similar between the groups, even after multivariable adjustment. VATS showed similar 5-year survival when compared with thoracotomy in unadjusted analysis (47% 95% confidence interval (CI), 36-56 vs 33% 95% CI, 27-40; P = .19), even after multivariable adjustment (hazard ratio, 0.76 95% CI, 0.50-1.18; P = .23). In a propensity score–matched analysis that balanced patient characteristics, there were no significant differences found in overall survival between the 2 groups (P = .69).
Although the role of VATS pneumonectomy will likely become clearer as more surgeons report results, this multicenter study suggests that the VATS approach for pneumonectomy can be performed safely, with at least equivalent oncologic outcomes when compared with thoracotomy.
HIV-1 broadly neutralizing antibodies (bnAbs) require high levels of activation-induced cytidine deaminase (AID)-catalyzed somatic mutations for optimal neutralization potency. Probable mutations ...occur at sites of frequent AID activity, while improbable mutations occur where AID activity is infrequent. One bottleneck for induction of bnAbs is the evolution of viral envelopes (Envs) that can select bnAb B cell receptors (BCR) with improbable mutations. Here we define the probability of bnAb mutations and demonstrate the functional significance of key improbable mutations in three bnAb B cell lineages. We show that bnAbs are enriched for improbable mutations, which implies that their elicitation will be critical for successful vaccine induction of potent bnAb B cell lineages. We discuss a mutation-guided vaccine strategy for identification of Envs that can select B cells with BCRs that have key improbable mutations required for bnAb development.
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•HIV-1 broadly neutralizing antibodies are enriched with low-probability mutations•Improbable mutations can be functionally critical for bnAb neutralization breadth•Critical improbable mutations are high-value targets for selection with vaccines
Not all mutations during B cell affinity maturation are equally probable. Wiehe et al. show that HIV-1 broadly neutralizing antibodies (bnAbs) are enriched with low-probability mutations and that these improbable mutations are often critical for HIV-1 bnAb neutralization breadth, thus making improbable mutations key targets for selection with vaccines.
The role of cancer-directed surgery in the treatment of stage I-IIIA malignant pleural mesothelioma (MPM) by histologic subtypes remains controversial. The objective of this study was to evaluate the ...survival of the different histologic subtypes for stage I-IIIA MPM stratified by cancer-directed surgery and nonoperative management.
How is the histologic subtype, clinical stage, and use of cancer-directed surgery for MPM associated with overall survival?
Overall survival of patients with stage I-IIIA epithelioid, sarcomatoid, and biphasic MPM in the National Cancer Database from 2004 through 2017 who underwent cancer-directed surgery (ie, surgery with or without chemotherapy or radiation) or chemotherapy with or without radiation (nonoperative management) was evaluated using Kaplan-Meier analysis, multivariable Cox proportional hazards analysis, and propensity score-matched analysis.
Of 2,285 patients with stage I-IIIA MPM who met inclusion criteria, histologic subtype was epithelioid in 71% of patients, sarcomatoid in 12% of patients, and biphasic in 17% of patients. Median survival was 20 months in the epithelioid group, 8 months in the sarcomatoid group, and 13 months in the biphasic group (P < .01). Among patients who underwent surgery, median survival was 25 months in the epithelioid group, 8 months in the sarcomatoid group, and 15 months in the biphasic group (P < .01). In multivariable Cox proportional hazards analyses, surgery was associated with improved survival in the epithelioid group (P < .01) but not in the sarcomatoid (P = .63) or biphasic (P = .21) groups. These findings were consistent in propensity score-matched analyses for each MPM histologic type.
In this national analysis, cancer-directed surgery was found to be associated with improved survival for stage I-IIIA epithelioid MPM, but not for biphasic or sarcomatoid MPM.
A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) ...third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man
-V3). V3-glycan bnAbs bound to Man
-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man
-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man
-V3 induced V3-glycan-targeted antibodies. Thus, the Man
-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.
Induction of broadly neutralizing antibodies (bnAbs) that target HIV-1 envelope (Env) is a goal of HIV-1 vaccine development. A bnAb target is the Env third variable loop (V3)-glycan site. To ...determine whether immunization could induce antibodies to the V3-glycan bnAb binding site, we repetitively immunized macaques over a 4-year period with an Env expressing V3-high mannose glycans. Env immunizations elicited plasma antibodies that neutralized HIV-1 expressing only high-mannose glycans—a characteristic shared by early bnAb B cell lineage members. A rhesus recombinant monoclonal antibody from a vaccinated macaque bound to the V3-glycan site at the same amino acids as broadly neutralizing antibodies. A structure of the antibody bound to glycan revealed that the three variable heavy-chain complementarity-determining regions formed a cavity into which glycan could insert and neutralized multiple HIV-1 isolates with high-mannose glycans. Thus, HIV-1 Env vaccination induced mannose-dependent antibodies with characteristics of V3-glycan bnAb precursors.
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•Env vaccination elicits antibodies that target the V3-glycan-neutralizing epitope•Repetitive vaccination with a single Env over 4 years induced V3-glycan antibodies•V3-glycan bnAb precursors recognize Env Man9GlcNAc2 to neutralize
Most bnAb epitopes on HIV-1 Envelope include host glycans, but previous Env vaccines have not induced glycan-dependent antibodies. Saunders et al. describe here the ontogeny, crystal structure with glycan, and virion Man9GlcNAc2-dependent neutralization for glycan-reactive antibodies induced by envelope vaccination.
This study analyzes the impact of age on perioperative outcomes and long-term survival of patients undergoing surgery after induction chemotherapy for non-small cell lung cancer.
Short- and long-term ...outcomes of patients with non-small cell lung cancer who were at least 70 years and received induction chemotherapy followed by major lung resection (lobectomy or pneumonectomy) from 1996 to 2012 were assessed using multivariable logistic regression, Kaplan-Meier, and Cox proportional hazard analysis. The outcomes of these elderly patients were compared with those of patients younger than 70 years who underwent the same treatment from 1996 to 2012.
Of the 317 patients who met the study criteria, 53 patients were at least 70 years. The median age was 74 years (range, 70 to 82 years) in the elderly group, and induction chemoradiation was used in 24 (45%) patients. Thirty-day mortality was similar between the younger (n = 12) and elderly (n = 3) patients (5% versus 6%; p = 0.52). There were no significant differences in the incidence of postoperative complications between younger and elderly patients (49% versus 57%; p = 0.30). Patients younger than 70 years had a median overall survival (30 months; 95% confidence interval CI, 24 to 43) and a 5-year survival (39%; 95% CI, 33 to 45) that was not significantly different from patients at least 70 years (median overall survival, 30 months; 95% CI, 18 to 68; and 5-year overall survival, 36%; 95% CI, 21 to 51). However, there was a trend toward worse survival in the elderly group after multivariable adjustment (hazard ratio, 1.43; 95% CI, 0.97 to 2.12; p = 0.071).
Major lung resection after induction chemotherapy can be performed with acceptable short- and long-term results in appropriately selected patients at least 70 years, with outcomes that are comparable to those of younger patients.
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