Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC00100

Information-driven modeling of biomolecular complexes

Proteins play crucial roles in every cellular process by interacting with each other, nucleic acids, metabolites, and other molecules. The resulting assemblies can be very large and intricate and pose challenges to experimental methods. In the current era of integrative modeling, it is often only by a combination of various experimental techniques and computations that three-dimensional models of those molecular machines can be obtained. Among the various computational approaches available, molecular docking is often the method of choice when it comes to predicting three-dimensional structures of complexes. Docking can generate particularly accurate models when taking into account the available information on the complex of interest. We review here the use of experimental and bioinformatics data in protein-protein docking, describing recent software developments and highlighting applications for the modeling of antibody–antigen complexes and membrane protein complexes, and the use of evolutionary and shape information

A Membrane Protein Complex Docking Benchmark

We report the first membrane protein-protein docking benchmark consisting of 37 targets of diverse functions and folds. The structures were chosen based on a set of parameters such as the availability of unbound structures, the modelling difficulty and their uniqueness. They have been cleaned and consistently numbered to facilitate their use in docking. Using this benchmark, we establish the baseline performance of HADDOCK, without any specific optimization for membrane proteins, for two scenarios: True interface-driven docking and ab-initio docking. Despite the fact that HADDOCK has been developed for soluble complexes, it shows promising docking performance for membrane systems, but there is clearly room for further optimisation. The resulting set of docking decoys, together with analysis scripts are made freely available. These can serve as a basis for the optimisation of membrane complex-specific scoring functions

A Membrane Protein Complex Docking Benchmark

We report the first membrane protein-protein docking benchmark consisting of 37 targets of diverse functions and folds. The structures were chosen based on a set of parameters such as the availability of unbound structures, the modelling difficulty and their uniqueness. They have been cleaned and consistently numbered to facilitate their use in docking. Using this benchmark, we establish the baseline performance of HADDOCK, without any specific optimization for membrane proteins, for two scenarios: True interface-driven docking and ab-initio docking. Despite the fact that HADDOCK has been developed for soluble complexes, it shows promising docking performance for membrane systems, but there is clearly room for further optimisation. The resulting set of docking decoys, together with analysis scripts are made freely available. These can serve as a basis for the optimisation of membrane complex-specific scoring functions

Information-driven modeling of biomolecular complexes

Proteins play crucial roles in every cellular process by interacting with each other, nucleic acids, metabolites, and other molecules. The resulting assemblies can be very large and intricate and pose challenges to experimental methods. In the current era of integrative modeling, it is often only by a combination of various experimental techniques and computations that three-dimensional models of those molecular machines can be obtained. Among the various computational approaches available, molecular docking is often the method of choice when it comes to predicting three-dimensional structures of complexes. Docking can generate particularly accurate models when taking into account the available information on the complex of interest. We review here the use of experimental and bioinformatics data in protein-protein docking, describing recent software developments and highlighting applications for the modeling of antibody–antigen complexes and membrane protein complexes, and the use of evolutionary and shape information

Partial avoidance of female inflorescences of a dioecious fig by their mutualistic pollinating wasps

Every dioecious species of fig is pollinated by a specific wasp that only reproduces within the inflorescences of male trees. Pollinators usually die within the closed urn-shaped inflorescence (fig or syconium) they visit. Thus pollinators that enter female syconia allow seed production but die without reproducing. In a previous study, pollinators of one dioecious fig where male and female trees flower synchronously, Ficus hispida, did not exhibit differential attraction or choice between inflorescences of the two sexes. Here we show that Blastophaga psenes, the pollinator of another dioecious species of different lineage, the common fig (F. carica), significantly avoided female syconia, when we experimentally induce a situation of choice. Paradoxically, choosiness can be demonstrated in F. carica where usually wasps do not face a choice because male and female trees do not flower synchronously. We discuss how the mutualism may be stable despite this discrimination and hypothesize why the two species of fig-pollinators exhibit different behaviour on dioecious figs

Therapeutic neck dissection in head and neck melanoma patients: Comparing extent of surgery and clinical outcome in two cohorts

BACKGROUND: The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach. METHODS: Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I-V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3-4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS). RESULTS: Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92). CONCLUSION: This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND

Blind prediction of homo- and hetero- protein complexes : The CASP13-CAPRI experiment

We present the results for CAPRI Round 46, the 3rd joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo-oligomers and 6 hetero-complexes. Eight of the homo-oligomer targets and one hetero-dimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homo-dimers, 3 hetero-dimers and two higher-order assemblies. These were more difficult to model, as their prediction mainly involved 'ab-initio' docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the 9 easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance 'gap' was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template-based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements. This article is protected by copyright. All rights reserved