Showing papers by "University of Copenhagen published in 2022"
TL;DR: Insect cytochrome P450 monooxygenases (P450s) perform a variety of important physiological functions, but it is their role in the detoxification of xenobiotics, such as natural and synthetic insecticides, that is the topic of this review as mentioned in this paper.
Abstract: Insect cytochrome P450 monooxygenases (P450s) perform a variety of important physiological functions, but it is their role in the detoxification of xenobiotics, such as natural and synthetic insecticides, that is the topic of this review. Recent advances in insect genomics and postgenomic functional approaches have provided an unprecedented opportunity to understand the evolution of insect P450s and their role in insect toxicology. These approaches have also been harnessed to provide new insights into the genomic alterations that lead to insecticide resistance, the mechanisms by which P450s are regulated, and the functional determinants of P450-mediated insecticide resistance. In parallel, an emerging body of work on the role of P450s in defining the sensitivity of beneficial insects to insecticides has been developed. The knowledge gained from these studies has applications for the management of P450-mediated resistance in insect pests and can be leveraged to safeguard the health of important beneficial insects. Expected final online publication date for the Annual Review of Entomology, Volume 67 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
69 citations
TL;DR: In this paper , a systematic evaluation of zinc-and nicotinamide adenine dinucleotide-dependent histone deacetylases (HDACs) for their ability to cleave Lysine L-lactylysine marks is presented.
Abstract: Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε- N -L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements.
68 citations
TL;DR: In this article, the authors describe three complementary Frontier Research Areas: (1) Complex Networks and their Inference, (2) Graph causal models and counterfactuals, and (3) Verification and Explainability methods.
56 citations
TL;DR: In this paper , the authors used airborne eDNA to detect 49 vertebrate species spanning 26 orders and 37 families: 30 mammal, 13 bird, 4 fish, 1 amphibian, and 1 reptile species.
53 citations
TL;DR: In this paper, a low-pressure LNF membrane with ultrahigh permeability was fabricated via one-step interfacial polymerization (IP), in which inexpensive natural carbohydrate-derived sugars with large size and low reactivity were utilized as aqueous monomers to design selective layer.
47 citations
TL;DR: In this article , the authors show that active galactic nuclei disk environments can lead to an excess of eccentric mergers, if the interactions between single and binary black holes are frequent and occur with mutual inclinations of less than a few degrees.
Abstract: There is some weak evidence that the black hole merger named GW190521 had a non-zero eccentricity1,2. In addition, the masses of the component black holes exceeded the limit predicted by stellar evolution3. The large masses can be explained by successive mergers4,5, which may be efficient in gas disks surrounding active galactic nuclei, but it is difficult to maintain an eccentric orbit all the way to the merger, as basic physics would argue for circularization6. Here we show that active galactic nuclei disk environments can lead to an excess of eccentric mergers, if the interactions between single and binary black holes are frequent5 and occur with mutual inclinations of less than a few degrees. We further illustrate that this eccentric population has a different distribution of the inclination between the spin vectors of the black holes and their orbital angular momentum at merger7, referred to as the spin-orbit tilt, compared with the remaining circular mergers.
47 citations
TL;DR: In this article , the infectious microenvironment can cause sensitive bacteria to lose their susceptibility to antibiotics that are effective in standard laboratory susceptibility testing, and the authors advocate that improved antibiotic treatment of chronic infection is achievable when antibiotics are recommended on the basis of susceptibility testing in relevant in vitro conditions that resemble actual infectious microenvironments.
Abstract: Standard doses of antibiotics do not efficiently treat chronic infections of the soft tissue and bone. In this Personal View, we advocate for improving treatment of these infections by taking the infectious microenvironment into account. The infectious microenvironment can cause sensitive bacteria to lose their susceptibility to antibiotics that are effective in standard laboratory susceptibility testing. We propose that bacteria behave substantially different in standard laboratory conditions than they do in actual infections. The infectious microenvironment could impose changes in growth and metabolic activity that result in increased protection against antibiotics. Therefore, we advocate that improved antibiotic treatment of chronic infection is achievable when antibiotics are recommended on the basis of susceptibility testing in relevant in vitro conditions that resemble actual infectious microenvironments. We recommend establishing knowledge of the relevant conditions of the chemical and physical composition of the infectious microenvironment. Recent advances in RNA sequencing, metabolomics, and microscopy have made it possible for the characterisation of the microenvironment of infections and to validate the clinical relevance of in vitro conditions to actual infections.
46 citations
TL;DR: In this article , a low-pressure LNF membrane with ultrahigh permeability was fabricated via one-step interfacial polymerization (IP), in which inexpensive natural carbohydrate-derived sugars with large size and low reactivity were utilized as aqueous monomers to design selective layer.
46 citations
TL;DR: A review of the latest clinical advances in mRNA-based vaccines for cancer treatment can be found in this paper , where the authors highlight the benefits of using mRNA for cancer immunotherapy and highlight the challenges of using it for standard treatment.
Abstract: Years of research exploring mRNA vaccines for cancer treatment in preclinical and clinical trials have set the stage for the rapid development of mRNA vaccines during the COVID-19 pandemic. Therapeutic cancer vaccines based on mRNA are well tolerated, and the inherent advantage in ease of production, which rivals the best available conventional vaccine manufacture methods, renders mRNA vaccines a promising option for cancer immunotherapy. Technological advances have optimised mRNA-based vaccine stability, structure, and delivery methods, and multiple clinical trials investigating mRNA vaccine therapy are now enrolling patients with various cancer diagnoses. Although therapeutic mRNA-based cancer vaccines have not yet been approved for standard treatment, encouraging results from early clinical trials with mRNA vaccines as monotherapy and in combination with checkpoint inhibitors have been obtained. This Review summarises the latest clinical advances in mRNA-based vaccines for cancer treatment and reflects on future perspectives and challenges for this new and promising treatment approach. Years of research exploring mRNA vaccines for cancer treatment in preclinical and clinical trials have set the stage for the rapid development of mRNA vaccines during the COVID-19 pandemic. Therapeutic cancer vaccines based on mRNA are well tolerated, and the inherent advantage in ease of production, which rivals the best available conventional vaccine manufacture methods, renders mRNA vaccines a promising option for cancer immunotherapy. Technological advances have optimised mRNA-based vaccine stability, structure, and delivery methods, and multiple clinical trials investigating mRNA vaccine therapy are now enrolling patients with various cancer diagnoses. Although therapeutic mRNA-based cancer vaccines have not yet been approved for standard treatment, encouraging results from early clinical trials with mRNA vaccines as monotherapy and in combination with checkpoint inhibitors have been obtained. This Review summarises the latest clinical advances in mRNA-based vaccines for cancer treatment and reflects on future perspectives and challenges for this new and promising treatment approach. IntroductionThe COVID-19 pandemic has directed worldwide focus towards mRNA-based vaccines. Indeed, the foundation for the rapid COVID-19 vaccine development and production was based on years of research exploring mRNA vaccines as a therapeutic strategy against cancer in preclinical and clinical trials.1Dolgin E The tangled history of mRNA vaccines.Nature. 2021; 597: 318-324Crossref PubMed Scopus (84) Google Scholar mRNA brings several benefits to a vaccine setting (panel). Firstly, mRNA-based vaccines are well tolerated, easily degraded, and do not integrate into the host genome.2Karikó K Muramatsu H Welsh FA et al.Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.Mol Ther. 2008; 16: 1833-1840Summary Full Text Full Text PDF PubMed Scopus (681) Google Scholar, 3Guan S Rosenecker J Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems.Gene Ther. 2017; 24: 133-143Crossref PubMed Scopus (198) Google Scholar, 4Thess A Grund S Mui BL et al.Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals.Mol Ther. 2015; 23: 1456-1464Summary Full Text Full Text PDF PubMed Scopus (252) Google Scholar Secondly, mRNA molecules are non-infectious, and mRNA vaccines have the potential to induce both humoral and cell-mediated immunity (figure).5Kowalzik F Schreiner D Jensen C Teschner D Gehring S Zepp F mRNA-based vaccines.Vaccines. 2021; 9: 390Crossref PubMed Scopus (27) Google Scholar, 6Faghfuri E Pourfarzi F Faghfouri AH Abdoli Shadbad M Hajiasgharzadeh K Baradaran B Recent developments of RNA-based vaccines in cancer immunotherapy.Expert Opin Biol Ther. 2021; 21: 201-218Crossref PubMed Scopus (25) Google Scholar Lastly, the production of mRNA vaccines is fast and inexpensive.7Pardi N Hogan MJ Porter FW Weissman D mRNA vaccines— a new era in vaccinology.Nat Rev Drug Discov. 2018; 17: 261-279Crossref PubMed Scopus (1519) Google ScholarPanelAdvantages of mRNA vaccines for the treatment of cancer•Well tolerated: adverse events are generally manageable and transient•No genome integration: eliminates the risk of insertional mutagenesis•Non-infectious: no pathogenic viral agents are used•Easily degraded: reduces risk of toxicity•Humoral and cellular immunity: necessary for activating and sustaining anti-tumour responses•Fast and inexpensive production: laboratory-based and cell-free productionIn 1996, the first mRNA-based cancer vaccine study tested dendritic cells pulsed with RNA in vitro.8Boczkowski D Nair SK Snyder D Gilboa E Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo.J Exp Med. 1996; 184: 465-472Crossref PubMed Scopus (807) Google Scholar Nowadays, technological advances have led to optimised mRNA structure, stability, and delivery methods, and multiple clinical trials are now enrolling patients with cancer for mRNA-based vaccine treatments (Table 1, Table 2).2Karikó K Muramatsu H Welsh FA et al.Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability.Mol Ther. 2008; 16: 1833-1840Summary Full Text Full Text PDF PubMed Scopus (681) Google Scholar, 3Guan S Rosenecker J Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems.Gene Ther. 2017; 24: 133-143Crossref PubMed Scopus (198) Google Scholar mRNA vaccine administration routes include intradermal, subcutaneous, intranasal, intranodal, intramuscular, intratumoural, and intravenous delivery.9Hou X Zaks T Langer R Dong Y Lipid nanoparticles for mRNA delivery.Nat Rev Mater. 2021; 6: 1078-1094Crossref PubMed Scopus (328) Google Scholar The ex-vivo engineering of autologous dendritic cells with mRNA has been the method of choice for tumour antigen delivery, but most mRNA vaccine approaches focus on direct mRNA administration using lipid nanoparticulate formulation carriers (table 1).Table 1ClinicalTrials.gov-registered mRNA-based cancer vaccine trials by type of formulationTrial phaseTarget antigenCancer typeCombinationVaccine route of administrationSponsorLipid nanoparticle formulationNCT039487631mRNA-5671 (KRAS gene driver mutations)Non-small-cell lung, pancreatic, and colorectal neoplasmsWith pembrolizumabIntramuscularMerck Sharp & DohmeNCT033137781mRNA-4157 (personalised cancer vaccine encoding several neoantigens)Solid tumours (resected)With pembrolizumabIntramuscularModernaNCT038978812mRNA-4157 (personalised cancer vaccine encoding 20 different mutated neoepitopes)MelanomaWith pembrolizumabIntramuscularModernaNCT045731401Formulation with pp65 LAMP and tumour mRNAGlioblastomaNoneIntravenousUniversity of Florida (Gainesville, FL, USA)Lipoplex formulationNCT024107331BNT111 (NY-ESO-1 [CTAG1A], tyrosinase, MAGE-A3, and TPTE)MelanomaNoneIntravenousBioNTechNCT045268992BNT111 (NY-ESO-1, tyrosinase, MAGE-A3, and TPTE)MelanomaWith cemiplimabIntravenousBioNTechNCT043828981/2BNT112 (PAP, PSA, and three undisclosed antigens)ProstateWith cemiplimabIntravenousBioNTechNCT045342052BNT113 (HPV16 E6 and E7 oncoproteins)Head and neck squamous cell carcinomaWith pembrolizumabIntravenousBioNTechNCT034184801/2BNT113 (HPV16 E6 and E7 oncoproteins)HPV16-positive solid tumoursWith anti-CD40 antibodiesIntravenousUniversity of Southampton (Southampton, UK)NCT051421891BNT116 (non-small-cell lung cancer tumour-associated antigens)Non-small-cell lung cancerWith cemiplimab plus docetaxelIntravenousBioNTechNCT044863782BNT122 (personalised cancer vaccine encoding individual tumour mutations)ColorectalNoneIntravenousBioNTechNCT023164571BNT-114 plus BNT-122 (personalised set of pre-manufactured non-mutated shared tumour-associated antigens plus a personalised cancer vaccine encoding individual tumour mutations)Triple-negative breast cancerNoneIntravenousBioNTechNCT041630941BNT115 (ovarian cancer tumour-associated antigens)OvarianWith carboplatin plus paclitaxelIntravenousUniversity Medical Center Groningen (Groningen, Netherlands)NCT041617551BNT122 (personalised cancer vaccine encoding individual tumour mutations)PancreaticWith oxaliplatin, irinotecan, fluorouracil, leucovorin, and atezolizumabIntravenousMemorial Sloan Kettering Cancer Center (New York, NY, USA)NCT038150582BNT122 (personalised cancer vaccine encoding individual tumour mutations)Advanced melanomaWith pembrolizumabIntravenousGenentechNCT032899621BNT122 (personalised cancer vaccine encoding individual tumour mutations)Solid tumoursWith atezolizumabIntravenousGenentechNCT045032781/2CARVac (CLDN6)Solid tumoursWith chimeric antigen receptor therapyIntravenousBioNTech and Gene TherapiesTrials with recruitment status “not yet recruiting,” “recruiting,” and “active, not recruiting” were found on ClinicalTrials.gov with the search terms “cancer” and “RNA, vaccine” on Feb 7, 2022, and through a PubMed search (see Search strategy and selection criteria panel). HPV=human papillomavirus. Open table in a new tab Table 2mRNA-based dendritic cell cancer vaccinesTrial phaseTarget antigenCancer typeCombinationVaccine route of administrationSponsorNCT05000801Not describedWT1, hTERT, and survivin-loaded dendritic cellsAcute myeloid leukaemiaWith follow-up careNot describedAffiliated Hospital to Academy of Military Medical Sciences (Beijing, China)NCT016863342WT1Acute myeloid leukaemiaWith follow-up careIntradermalAntwerp University Hospital (Antwerp, Belgium)NCT026498291/2WT1Pleural mesotheliomaWith standard therapyIntradermalAntwerp University HospitalNCT049116211/2WT1High-grade glioma and diffuse intrinsic pontine gliomaWith chemoradiation (with or without standard therapy)IntradermalAntwerp University HospitalNCT026495821/2WT1Glioblastoma multiformeWith temozolomideIntradermalAntwerp University HospitalNCT041571271Pancreatic adenocarcinoma mRNA and lysatePancreatic adenocarcinomaWith standard therapyIntradermalBaylor College of Medicine (Houston, TX, USA)NCT006396391Cytomegalovirus pp65-LAMPGlioblastoma multiformeWith autologous lymphocyte transfer and TdIntradermalDuke University (Durham, NC, USA)NCT036881782 (randomised)Cytomegalovirus pp65-flLAMPGlioblastoma multiformeWith temozolomide, varlilumab, and TdIntradermalDuke UniversityNCT043358901Autologous tumour RNA with gp100, tyrosinase, PRAME, MAGE-A3, IDO, and different driver mutationsUveal melanomaWith standard therapyIntravenousHasumi International Research FoundationNCT024652682 (randomised)HCMV pp65-shLAMP or pp65-flLAMPGlioblastoma multiformeWith temozolomide, GM-CSF, and TdNot describedImmunomic TherapeuticsNCT019957081CT7, MAGE-A3, and WT1 (Langerhans-type dendritic cells)Multiple myelomaWith standard treatmentIntradermalMemorial Sloan Kettering Cancer Center (New York, NY, USA)NCT014561041Trp2 (Langerhans-type dendritic cells)MelanomaNoneNot describedMemorial Sloan Kettering Cancer CenterNCT011976251/2hTERT, survivin, and mRNA from primary prostate cancer tissueProstate cancerNoneNot describedOslo University Hospital (Oslo, Norway)NCT035485712/3hTERT, survivin, and mRNA from autologous tumour stem cellsGlioblastoma multiformeWith temozolomideIntradermalOslo University HospitalNCT019837483 (randomised)Autologous tumour RNAUveal melanomaNoneIntravenousUniversity Hospital Erlangen (Erlangen, Germany)NCT030830541/2WT1Myelodysplastic syndromes, acute myeloid leukaemiaNoneNot describedUniversity of Campinas (Campinas, Brazil)NCT049634131Cytomegalovirus pp65-flLAMPGlioblastoma multiformeWith temozolomide, GM-CSF, and TdNot describedUniversity of Florida (Gainesville, FL, USA)NCT033965751TTRNABrainstem gliomasWith cyclophosphamide, fludarabine, temozolomide, TTRNA-xALT, autologous haematopoietic stem cells, GM-CSF, and TdIntradermalUniversity of FloridaNCT013261041/2TTRNAMedulloblastoma, neuroectodermal tumourWith TTRNA-xALTIntradermalUniversity of FloridaTrials with recruitment status: “not yet recruiting,” “recruiting,” and “active, not recruiting” were found on ClinicalTrial.gov with the search terms: “cancer” and “RNA, vaccine” on Feb 7, 2022, and through a PubMed search (see Search strategy and selection criteria panel). Td=tetanus-diphtheria toxoid vaccine. TTRNA=tumour mRNA-pulsed autologous dendritic cells. TTRNA-xALT=tumour-specific autologous lymphocyte transfer. Open table in a new tab The clinical efficacy and immunogenicity of mRNA vaccines have been evaluated across cancer diagnoses and administration methods (table 3). A few trials have reported durable objective responses in patients with cancer after mRNA-based vaccine treatment, without unmanageable toxic effects.10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google Scholar, 14Papachristofilou A Hipp MM Klinkhardt U et al.Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.J Immunother Cancer. 2019; 7: 38Crossref PubMed Scopus (73) Google Scholar, 15Sahin U Oehm P Derhovanessian E et al.An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.Nature. 2020; 585: 107-112Crossref PubMed Scopus (230) Google Scholar, 16Mackensen A Koenecke C Haanen J et al.BNT211: a phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors.J Immunother Cancer. 2021; 9A1008Crossref Google Scholar, 19Burris HA Patel MR Cho DC et al.A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.J Clin Oncol. 2019; 372523Crossref Google Scholar mRNA vaccines are promising therapeutic candidates for future cancer treatments, especially in combination with additional immunotherapies.14Papachristofilou A Hipp MM Klinkhardt U et al.Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.J Immunother Cancer. 2019; 7: 38Crossref PubMed Scopus (73) Google Scholar, 19Burris HA Patel MR Cho DC et al.A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.J Clin Oncol. 2019; 372523Crossref Google Scholar, 20De Keersmaecker B Claerhout S Carrasco J et al.TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma.J Immunother Cancer. 2020; 8e000329Crossref PubMed Scopus (46) Google Scholar However, no phase 3 studies are ongoing, and, at the time of writing, the US Food and Drug Administration (FDA) has not yet approved a therapeutic mRNA-based cancer vaccine.21Miao L Zhang Y Huang L mRNA vaccine for cancer immunotherapy.Mol Cancer. 2021; 20: 41Crossref PubMed Scopus (138) Google ScholarTable 3A summary of the published results (2017–22) from mRNA cancer vaccine trials by type of formulationTrial phaseTarget antigenCancer typePatients, nCombinationImmune responseClinical responseNon-formulated (naked)NCT020359561An individualised tumour mutation signature with ten selected neoepitopes for each patientMelanoma (stages III and IV)13NoneT-cell responses against numerous vaccine neoepitopesOne (8%) patient had complete response and another patient (8%) had partial response10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google ScholarNCT033949371CD40L, CD70, caTLR4; tumour-associated antigens: tyrosinase, gp100, MAGE-A3, MAGE-C2, and PRAMEResected melanoma (stages IIc, III, and IV)20NoneVaccine-induced immune responses in four (40%) of ten patients (low dose) and three (33%) of nine patients (high dose)Not reported11Arance Fernandez AM Baurain J-F Vulsteke C et al.A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: analysis of safety and immunogenicity.J Clin Oncol. 2019; 372641Crossref Google ScholarProtamine formulationNCT018177381/2PSA, PSMA, PSCA, STEAP1, PAP, and MUC1Metastatic castration-resistant prostate cancer197NoneNot reportedNo significant differences in progression-free survival12Stenzl A Feyerabend S Syndikus I et al.Results of the randomized, placebo-controlled phase I/IIB trial of CV9104, an mRNA based cancer immunotherapy, in patients with metastatic castration-resistant prostate cancer (mCRPC).Ann Oncol. 2017; 28: v408-v409Summary Full Text Full Text PDF PubMed Google ScholarNCT009233121/2MAGE-C1, MAGE-C2, NY-ESO-1, survivin, and 5T4Non-small-cell lung cancer (stages IIIb and IV)46NoneT-cell responses against at least one tumour-associated antigen in 19 (63%) patientsNo objective responses; progression-free survival and overall survival not improved13Sebastian M Schröder A Scheel B et al.A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer.Cancer Immunol Immunother. 2019; 68: 799-812Crossref PubMed Scopus (66) Google ScholarNCT019155241MAGE-C1, MAGE-C2, NY-ESO-1, survivin, 5T4, and MUC-1Non-small-cell lung cancer (stage IV)26With local irradiation (with or without pemetrexed and with or without EGFR tyrosine-kinase inhibitor)Detectable antigen-specific immunity in 21 (84%) patientsOne (4%) patient had partial response in combination with chemotherapy treatment, and 12 (46%) patients had stable disease14Papachristofilou A Hipp MM Klinkhardt U et al.Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.J Immunother Cancer. 2019; 7: 38Crossref PubMed Scopus (73) Google ScholarLipoplex formulationNCT024107331NY-ESO-1, tyrosinase, MAGE-A3, and TPTEMelanoma25 (monotherapy); 17 (combination)With or without standard PD-1 therapyImmune responses against a minimum of one tumour-associated antigen in 39 (75%) patientsmRNA vaccine with anti-PD-1 therapy: six (35%) patients had partial response and two (12%) had stable disease; mRNA vaccine monotherapy: three (12%) patients had partial response, and seven (28%) had stable disease15Sahin U Oehm P Derhovanessian E et al.An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.Nature. 2020; 585: 107-112Crossref PubMed Scopus (230) Google ScholarNCT045032781/2CLDN6 (CARVac)Solid tumours (CLDN6 CAR T cells with CARVac)7With CLDN6 CAR T cellsEngraftment of CAR T cells in all patientsFour (57%) patients had partial response and one (14%) patient had stable disease at the 6-week evaluation16Mackensen A Koenecke C Haanen J et al.BNT211: a phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors.J Immunother Cancer. 2021; 9A1008Crossref Google Scholar, 17Haanen J Gunther J Orleans NEW et al.BNT211: a phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors.https://www.abstractsonline.com/pp8/#!/10517/presentation/20144Date: 2022Date accessed: April 18, 2022Google ScholarLipid nanoparticle formulationNCT034801521/2Neoantigen-specific mRNAGastrointestinal cancer4NoneMutation-specific CD4+ and CD8+ T-cell responses against predicted neoepitopes in three (75%) of four patientsNo objective clinical responses18Cafri G Gartner JJ Zaks T et al.mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.J Clin Invest. 2020; 130: 5976-5988Crossref PubMed Scopus (85) Google ScholarNCT033137781Personalised cancer vaccine encoding several neoantigensSolid tumours (resected)13 (monotherapy); 19 (combination)With pembrolizumabDetectable neoantigen T-cell responsesVaccine monotherapy: 12 patients were cancer-free on study treatment with a median follow-up of 8 months; combination treatment: one patient had complete response before vaccination, two patients had partial response, five patients had stable disease, five had disease progression, and two had unconfirmed disease progression19Burris HA Patel MR Cho DC et al.A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.J Clin Oncol. 2019; 372523Crossref Google ScholarCAR=chimeric antigen receptor. Open table in a new tab This Review summarises the latest clinical advances in therapeutic mRNA-based cancer vaccines, with a focus on direct mRNA administration methods.mRNA-based cancer vaccine trialsThe aim of mRNA-based vaccination is to induce or boost an effective anti-tumour immune response.22Beck JD Reidenbach D Salomon N et al.mRNA therapeutics in cancer immunotherapy.Mol Cancer. 2021; 20: 69Crossref PubMed Scopus (54) Google Scholar Synthetic mRNA encoding tumour-associated or tumour-specific antigens is delivered through autologous dendritic cells engineered with mRNA ex vivo or through formulated or non-formulated mRNA injections.23Hollingsworth RE Jansen K Turning the corner on therapeutic cancer vaccines.NPJ Vaccines. 2019; 4: 7Crossref PubMed Scopus (306) Google Scholar After vaccination and cellular uptake by antigen-presenting cells, mRNA is transported to the cytoplasm and undergoes antigen processing and enters the MHC presentation cascade. Thus, antigen-presenting cells present tumour-associated antigens on MHC class I and MHC class II to activate CD8+ and CD4+ T cells. In addition, CD4+ T cells can co-activate antigen-specific B cells and induce a humoral immune response. B cells that function as antigen-presenting cells can conversely activate CD4+ T cells after internalisation of extracellular proteins and presentation on B cells’ MHC class II (figure).9Hou X Zaks T Langer R Dong Y Lipid nanoparticles for mRNA delivery.Nat Rev Mater. 2021; 6: 1078-1094Crossref PubMed Scopus (328) Google Scholar, 24Hong S Zhang Z Liu H et al.B cells are the dominant antigen-presenting cells that activate naive CD4+ T cells upon immunization with a virus-derived nanoparticle antigen.Immunity. 2018; 49: 695-708.e4Summary Full Text Full Text PDF PubMed Scopus (126) Google ScholarSeveral clinical trials (eg, NCT04534205, NCT03313778, and NCT04503278) are enrolling patients for various mRNA-based cancer vaccine therapy studies with the aim of inducing an mRNA-based anti-tumour response (Table 1, Table 2).Non-formulated (naked) mRNA-based cancer vaccinesNaked or non-formulated mRNA vaccines contain mRNA molecules in a buffer solution.10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google Scholar The non-formulated vaccines are administered either intradermally or intranodally.10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google Scholar, 25Rittig SM Haentschel M Weimer KJ et al.Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients.Mol Ther. 2011; 19: 990-999Summary Full Text Full Text PDF PubMed Scopus (163) Google Scholar The administration of non-formulated mRNA intranodally enables the delivery of antigens to antigen-presenting cells at the actual location of T-cell activation, thereby avoiding the requirement for antigen-presenting cell migration.26Diken M Kreiter S Selmi A et al.Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation.Gene Ther. 2011; 18: 702-708Crossref PubMed Scopus (128) Google Scholar Several studies have shown that dendritic cells can take up intranodally injected non-formulated mRNA and induce potent anti-tumour T-cell responses.7Pardi N Hogan MJ Porter FW Weissman D mRNA vaccines— a new era in vaccinology.Nat Rev Drug Discov. 2018; 17: 261-279Crossref PubMed Scopus (1519) Google Scholar, 10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google ScholarOnly a few clinical trials have treated patients with cancer with non-formulated mRNA vaccines in the past 5 years (table 3). In a phase 1 clinical trial, non-formulated mRNA vaccines were administered intranodally in 13 patients with stage III or IV melanoma with stable disease, partial response, or complete response after previous treatment. This neoepitope-targeting vaccine encoded a unique and individualised tumour mutation signature with ten selected neoepitopes for each patient. All patients developed T-cell responses against numerous vaccine-encoded neoepitopes, and vaccine-related clinical responses were observed in two (40%) of the five patients with stage IV melanoma.10Sahin U Derhovanessian E Miller M et al.Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.Nature. 2017; 547: 222-226Crossref PubMed Scopus (11) Google Scholar In a recently concluded phase 1 clinical trial (NCT03394937), 20 patients with resected melanoma (stages IIc, III, and IV) received an intranodally injected non-formulated mRNA vaccine (ECI-006). The vaccine included mRNAs encoding three dendritic cell-activating molecules (TriMix) and five tumour-associated antigens (table 3).11Arance Fernandez AM Baurain J-F Vulsteke C et al.A phase I study (E011-MEL) of a TriMix-based mRNA immunotherapy (ECI-006) in resected melanoma patients: analysis of safety and immunogenicity.J Clin Oncol. 2019; 372641Crossref Google Scholar In a second study cohort (NCT03394937), patients with metastatic melanoma with stable disease after 3–12 months of standard treatment received the ECI-006 vaccine in combination with standard anti-PD-1 therapy; results are not yet published. No clinical trials registered at ClinicalTrials.gov are currently recruiting patients for non-formulated mRNA cancer vaccine treatment.Formulated mRNA-based cancer vaccinesNon-formulated mRNA is easily degraded by extracellular RNases.27Tsui NBY Ng EKO Lo YMD Stability of endogenous and added RNA in blood specimens, serum, and plasma.Clin Chem. 2002; 48: 1647-1653Crossref PubMed Scopus (460) Google Scholar Consequently, several nanocarrier pharmaceutical systems, generally containing polymers such as peptides or lipids, have been developed to optimise mRNA preservation and facilitate mRNA uptake by antigen-presenting cells.3Guan S Rosenecker J Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems.Gene Ther. 2017; 24: 133-143Crossref PubMed Scopus (198) Google Scholar, 28Midoux P Pichon C Lipid-based mRNA vaccine delivery systems.Expert Rev Vaccines. 2015; 14: 221-234Crossref PubMed Scopus (117) Google Scholar, 29Reichmuth AM Oberli MA Jaklenec A Langer R Blankschtein D mRNA vaccine delivery using lipid nanoparticles.Ther Deliv. 2016; 7: 319-334Crossref PubMed Scopus (263) Google ScholarProtamine-formulated mRNA-based cancer vaccinesProtamines are positively charged polycationic peptides that form complexes with negatively charged mRNA and protect the molecules from degradation.30Zeng C Zhang C Walker PG Dong Y Formulation and delivery technologies for mRNA vaccines.Curr Top Microbiol Immunol. 2020; 2: 1-40Google Scholar Protamine-formulated mRNA vaccines have been evaluated in diverse clinical trials in the form of RNActive vaccines.12Stenzl A Feyerabend S Syndikus I et al.Results of the randomized, placebo-controlled phase I/IIB trial of CV9104, an mRNA based cancer immunotherapy, in patients with metastatic castration-resistant prostate cancer (mCRPC).Ann Oncol. 2017; 28: v408-v409Summary Full Text Full Text PDF PubMed Google Scholar, 13Sebastian M Schröder A Scheel B et al.A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer.Cancer Immunol Immunother. 2019; 68: 799-812Crossref PubMed Scopus (66) Google Scholar, 14Papachristofilou A Hipp MM Klinkhardt U et al.Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.J Immunother Cancer. 2019; 7: 38Crossref PubMed Scopus (73) Google Scholar RNActive vaccines incorporate nucleotide modified mRNA molecules complexed with protamine to enhance protein expression and immunogenicity.31Kallen K-J Heidenreich R Schnee M et al.A novel, disruptive vaccination technology: self-adjuvanted RNActive(®) vaccines.Hum Vaccin Immunother. 2013; 9: 2263-2276Crossref PubMed Scopus (135) Google Scholar At the time of writing, no clinical trials registered at ClinicalTrials.gov are rec
46 citations
01 Jan 2022
TL;DR: In this paper , the authors evaluated skin prick test (SPT) results and in vitro reactivity over time to different MW PEGs and assessed cross-sensitization patterns in PEG allergy.
Abstract: Polyethylene glycols (PEGs) are polymers of varying molecular weight (MW) used widely as excipients in drugs and other products, including the mRNA vaccines against coronavirus disease 2019. Allergy to PEGs is rare. Skin testing and graded challenge carries a high risk of inducing systemic reactions.We evaluated skin prick test (SPT) results and in vitro reactivity over time to different MW PEGs and assessed cross-sensitization patterns in PEG allergy.Ten patients with previously diagnosed PEG allergy underwent SPT twice with PEGs 26 months apart. Lower MW (PEG 300, 3000, 6000) were tested, followed by PEG 20,000, in stepwise, increasing concentrations. Cross-sensitization to polysorbate 80 and poloxamer 407 was assessed. SPT was performed in 16 healthy controls. In vitro basophil histamine release (HR) test and passive sensitization HR test were performed in patients and controls.Patients previously testing positive on SPT to PEG 3000 and/or 6000 also tested positive to PEG 20,000. Patients with a longer interval since diagnosis tested negative to lower MW PEGs and positive mainly to higher concentrations of PEG 20,000. Three patients developed systemic urticaria during SPT. Eight patients showed cross-sensitization to poloxamer 407 and 3 to polysorbate 80. All controls tested negative. In vitro tests showed limited usefulness.Skin test reactivity to PEG can decrease over time, but titrated SPT with increasing concentrations of PEG 20,000 can be diagnostic when lower MW PEGs test negative. To avoid systemic reactions, stepwise SPT is mandatory.
41 citations
TL;DR: Schaafsma et al. as discussed by the authors used protein stability and sequence conservation to predict variant effects and found that about half of the loss-of-function variants lose function with loss of stability.
TL;DR: In this paper , the authors review the recent empirical evidence on how prosocial concerns relate to vaccination intentions and promote prosocial vaccination through explaining community protection or inducing concern for vulnerable others, and point out several areas in which future research can test the boundary conditions of this approach and increase its effectiveness.
Abstract: Most vaccines not only directly protect vaccinated individuals but also provide a social benefit through community protection. Therefore, vaccination can be considered a prosocial act to protect others. We review the recent empirical evidence on (i) how prosocial concerns relate to vaccination intentions and (ii) promoting prosocial vaccination through explaining community protection or inducing concern for vulnerable others. The available evidence suggests that promoting the prosocial aspect of vaccinations could be a vaccination communication strategy to improve vaccine uptake. We point to several areas in which future research can test the boundary conditions of this approach and increase its effectiveness.
TL;DR: In this paper, the authors investigated the filtration and separation performance of ultrafiltration during the treatment of algae-laden water in the presence of anionic surfactants (the most widely used surfactant type).
TL;DR: In this article , the authors investigated the filtration and separation performance of ultrafiltration during the treatment of algae-laden water in the presence of anionic surfactants (the most widely used surfactant type).
TL;DR: In this article , a prospective, population-based cohort study included patients aged 0-17 years hospitalised with multisystem inflammatory syndrome in Denmark, according to the US Centers for Disease Control and Prevention case definition, from Aug 1, 2021, to Feb 1, 2022, a period dominated by the delta variant of SARS-CoV-2 (B.1.617.2 and sublineages) according to vaccination status.
TL;DR: In this article, three Natural Deep Eutectic Solvents (NADES) systems based on choline chloride (ChCl) as a hydrogen bond acceptor (HBA) and malic acid, urea, and fructose (MalA, Ur, and Fru) as hydrogen bond donors (HBD) were used.
TL;DR: In this paper, the authors used pinewood biochar to study phenol biodegradation from synthetic effluents and found that the biochar greatly facilitated the phenol bioodegradation rate, especially in the presence of biochar.
TL;DR: In this article , the authors show that the coarse-grained force field Martini 3 underestimates the global dimensions of intrinsically disordered proteins (IDPs) and multidomain proteins when compared with small-angle X-ray scattering (SAXS) data and that increasing the strength of protein-water interactions favors more expanded conformations.
Abstract: Coarse-grained molecular dynamics simulations are a useful tool to determine conformational ensembles of proteins. Here, we show that the coarse-grained force field Martini 3 underestimates the global dimensions of intrinsically disordered proteins (IDPs) and multidomain proteins when compared with small-angle X-ray scattering (SAXS) data and that increasing the strength of protein-water interactions favors more expanded conformations. We find that increasing the strength of interactions between protein and water by ca. 10% results in improved agreement with the SAXS data for IDPs and multidomain proteins. We also show that this correction results in a more accurate description of self-association of IDPs and folded proteins and better agreement with paramagnetic relaxation enhancement data for most IDPs. While simulations with this revised force field still show deviations to experiments for some systems, our results suggest that it is overall a substantial improvement for coarse-grained simulations of soluble proteins.
TL;DR: In this paper , the authors explore two key contexts in which representations naturally arise: transfer learning and interpretable learning, and demonstrate that taking representation geometry into account significantly improves interpretability and lets the models reveal biological information that is otherwise obscured.
Abstract: How we choose to represent our data has a fundamental impact on our ability to subsequently extract information from them. Machine learning promises to automatically determine efficient representations from large unstructured datasets, such as those arising in biology. However, empirical evidence suggests that seemingly minor changes to these machine learning models yield drastically different data representations that result in different biological interpretations of data. This begs the question of what even constitutes the most meaningful representation. Here, we approach this question for representations of protein sequences, which have received considerable attention in the recent literature. We explore two key contexts in which representations naturally arise: transfer learning and interpretable learning. In the first context, we demonstrate that several contemporary practices yield suboptimal performance, and in the latter we demonstrate that taking representation geometry into account significantly improves interpretability and lets the models reveal biological information that is otherwise obscured.
TL;DR: In a prospective nationwide multicenter study from Denmark, myopericarditis after COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12-17 years of age as mentioned in this paper .
Abstract: In this prospective nationwide multicenter study from Denmark, myopericarditis after Pfizer-BioNTech mRNA COVID-19 vaccination was identified in 13 males and 2 females between May 15 and September 15, 2021, among 133,477 vaccinated males and 127,857 vaccinated females 12-17 years of age, equaling 97 males and 16 females per million. In conclusion, the incidence of myopericarditis after COVID-19 vaccination among males appears higher than reports from the United States.
DOI•
01 Feb 2022TL;DR: In this paper, a retrospective cohort study using claims data between 2007 and 2017 was conducted to investigate the effectiveness of AIT in respiratory allergy patients in the real world, with 46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort.
Abstract: Summary Background Allergen immunotherapy (AIT) is the only causal treatment for respiratory allergy. Long-term real-life effectiveness of AIT remains to be demonstrated beyond the evidence from randomised controlled trials (RCTs). Methods REACT (Real world effectiveness in allergy immunotherapy) is a retrospective cohort study using claims data between 2007 and 2017. Study eligibility was a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analysed as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up (ClinicalTrial.gov: NCT04125888). Findings 46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort. AIT-treated subjects were 29·5 (16·3) years and 53% were male. Compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in AR and asthma prescriptions, including both asthma controller and reliever prescriptions. Additionally, the AIT group had significantly greater likelihood of stepping down asthma treatment (P Interpretation The study extends the existing RCT evidence for AIT by demonstrating longer-term and sustained effectiveness of AIT in the real world. Additionally, in patients with concurrent asthma, AIT was associated with reduced likelihood of asthma exacerbations and pneumonia. Funding The study was funded by ALK A/S.
TL;DR: In this paper , the authors present a set of ab-initio numerical-relativity BNS merger simulations that show that an X-ray excess supports the presence of a high-velocity tail in the merger ejecta, and argues against the prompt collapse of the merger remnant into a black hole.
Abstract: For the first $\sim3$ years after the binary neutron star merger event GW 170817 the radio and X-ray radiation has been dominated by emission from a structured relativistic off-axis jet propagating into a low-density medium with n $< 0.01\,\rm{cm^{-3}}$. We report on observational evidence for an excess of X-ray emission at $\delta t>900$ days after the merger. With $L_x\approx5\times 10^{38}\,\rm{erg\,s^{-1}}$ at 1234 days, the recently detected X-ray emission represents a $\ge 3.2\,\sigma$ (Gaussian equivalent) deviation from the universal post jet-break model that best fits the multi-wavelength afterglow at earlier times. In the context of JetFit afterglow models, current data represent a departure with statistical significance $\ge 3.1\,\sigma$, depending on the fireball collimation, with the most realistic models showing excesses at the level of $\ge 3.7\,\sigma$. A lack of detectable 3 GHz radio emission suggests a harder broad-band spectrum than the jet afterglow. These properties are consistent with the emergence of a new emission component such as synchrotron radiation from a mildly relativistic shock generated by the expanding merger ejecta, i.e. a kilonova afterglow. In this context, we present a set of ab-initio numerical-relativity BNS merger simulations that show that an X-ray excess supports the presence of a high-velocity tail in the merger ejecta, and argues against the prompt collapse of the merger remnant into a black hole. Radiation from accretion processes on the compact-object remnant represents a viable alternative. Neither a kilonova afterglow nor accretion-powered emission have been observed before, as detections of BNS mergers at this phase of evolution are unprecedented.
TL;DR: In this article , a continuous pyrolysis system (auger reactor) at 525 °C was used for pinewood biochar to study phenol biodegradation from synthetic effluents.
TL;DR: In this paper, the co-selection of heavy metal/biocide and antibiotic resistance genes (ARGs) has been suggested as one potential mechanism promoting the proliferation of antimicrobial resistance (AMR).
TL;DR: In this article , the authors investigated the ability of the Sentinel-1 mission to monitor snow depth at sub-kilometer (100 m, 500 m, and 1 km) resolutions over the European Alps for 2017-2019.
Abstract: Abstract. Seasonal snow is an essential water resource in many mountain regions. However, the spatio-temporal variability in mountain snow depth or snow water equivalent (SWE) at regional to global scales is not well understood due to the lack of high-resolution satellite observations and robust retrieval algorithms. We investigate the ability of the Sentinel-1 mission to monitor snow depth at sub-kilometer (100 m, 500 m, and 1 km) resolutions over the European Alps for 2017–2019. The Sentinel-1 backscatter observations, especially in cross-polarization, show a high correlation with regional model simulations of snow depth over Austria and Switzerland. The observed changes in radar backscatter with the accumulation or ablation of snow are used in an empirical change detection algorithm to retrieve snow depth. The algorithm includes the detection of dry and wet snow conditions. Compared to in situ measurements at 743 sites in the European Alps, dry snow depth retrievals at 500 m and 1 km resolution have a spatio-temporal correlation of 0.89. The mean absolute error equals 20 %–30 % of the measured values for snow depths between 1.5 and 3 m. The performance slightly degrades for retrievals at the finer 100 m spatial resolution as well as for retrievals of shallower and deeper snow. The results demonstrate the ability of Sentinel-1 to provide snow estimates in mountainous regions where satellite-based estimates of snow mass are currently lacking. The retrievals can improve our knowledge of seasonal snow mass in areas with complex topography and benefit a number of applications, such as water resource management, flood forecasting, and numerical weather prediction. However, future research is recommended to further investigate the physical basis of the sensitivity of Sentinel-1 backscatter observations to snow accumulation.
01 Sep 2022
TL;DR: In this paper , the authors conducted a cohort study using Cox regression to compare SARS-CoV-2 infection rates before and after a primary infection among still unvaccinated individuals, adjusting for sex, age, comorbidity and residency region.
Abstract: The level of protection after a SARS-CoV-2 infection against reinfection and COVID-19 disease remains important with much of the world still unvaccinated. Analysing nationwide, individually referable, Danish register data including RT-PCR-test results, we conducted a cohort study using Cox regression to compare SARS-CoV-2 infection rates before and after a primary infection among still unvaccinated individuals, adjusting for sex, age, comorbidity and residency region. Estimates of protection against infection were calculated as 1 minus the hazard ratio. Estimates of protection against symptomatic infections and infections leading to hospitalisation were also calculated. The prevalence of infections classified as symptomatic or asymptomatic was compared for primary infections and reinfections. The study also assessed protection against each of the main viral variants after a primary infection with an earlier variant by restricting follow-up time to distinct, mutually exclusive periods during which each variant dominated. Until 1 July 2021 the estimated protection against reinfection was 83.4% (95%CI: 82.2–84.6%); but lower for the 65+ year-olds (72.2%; 95%CI: 53.2–81.0%). Moderately higher estimates were found for protection against symptomatic disease, 88.3% overall (95%CI: 85.9–90.3%). First-time cases who reported no symptoms were more likely to experience a reinfection (odds ratio: 1.48; 95%CI: 1.35–1.62). By autumn 2021, when infections were almost exclusively caused by the Delta variant, the estimated protection following a recent first infection was 91.3% (95%CI: 89.7–92.7%) compared to 71.4% (95%CI: 66.9–75.3%) after a first infection over a year earlier. With Omicron, a first infection with an earlier variant in the past 3-6 months gave an estimated 51.0% (95%CI: 50.1–52.0%) protection, whereas a first infection longer than 12 months earlier provided only 19.0% (95%CI: 17.2–20.5%) protection. Protection by an earlier variant-infection against hospitalisation due to a new infection was estimated at: 86.6% (95%CI: 46.3–96.7%) for Alpha, 97.2% (95%CI: 89.0–99.3%) for Delta, and 69.8% (95%CI: 51.5–81.2%) for the Omicron variant. SARS-CoV-2 infection offered a high level of sustained protection against reinfection, comparable with that offered by vaccines, but decreased with the introduction of new main virus variants; dramatically so when Omicron appeared. Protection was lower among the elderly but appeared more pronounced following symptomatic compared to asymptomatic infections. The level of estimated protection against serious disease was somewhat higher than that against infection and possibly longer lasting. Decreases in protection against reinfection, seemed primarily to be driven by viral evolution. None.
TL;DR: In this article , the authors employed continuous sulfate and sulfur records from three Greenland and three Antarctic ice cores to estimate the emission strength, the frequency and the climatic forcing of large volcanic eruptions that occurred during the second half of the last glacial period and the early Holocene, 60-9 kyr before 2000 CE (b2k).
Abstract: Abstract. Large volcanic eruptions occurring in the last glacial period can be detected by their accompanying sulfuric acid deposition in continuous ice cores. Here we employ continuous sulfate and sulfur records from three Greenland and three Antarctic ice cores to estimate the emission strength, the frequency and the climatic forcing of large volcanic eruptions that occurred during the second half of the last glacial period and the early Holocene, 60–9 kyr before 2000 CE (b2k). Over most of the investigated interval the ice cores are synchronized, making it possible to distinguish large eruptions with a global sulfate distribution from eruptions detectable in one hemisphere only. Due to limited data resolution and large variability in the sulfate background signal, particularly in the Greenland glacial climate, we only list Greenland sulfate depositions larger than 20 kg km−2 and Antarctic sulfate depositions larger than 10 kg km−2. With those restrictions, we identify 1113 volcanic eruptions in Greenland and 737 eruptions in Antarctica within the 51 kyr period – for which the sulfate deposition of 85 eruptions is found at both poles (bipolar eruptions). Based on the ratio of Greenland and Antarctic sulfate deposition, we estimate the latitudinal band of the bipolar eruptions and assess their approximate climatic forcing based on established methods. A total of 25 of the identified bipolar eruptions are larger than any volcanic eruption occurring in the last 2500 years, and 69 eruptions are estimated to have larger sulfur emission strengths than the Tambora, Indonesia, eruption (1815 CE). Throughout the investigated period, the frequency of volcanic eruptions is rather constant and comparable to that of recent times. During the deglacial period (16–9 ka b2k), however, there is a notable increase in the frequency of volcanic events recorded in Greenland and an obvious increase in the fraction of very large eruptions. For Antarctica, the deglacial period cannot be distinguished from other periods. This confirms the suggestion that the isostatic unloading of the Northern Hemisphere (NH) ice sheets may be related to the enhanced NH volcanic activity. Our ice-core-based volcanic sulfate records provide the atmospheric sulfate burden and estimates of climate forcing for further research on climate impact and understanding the mechanism of the Earth system.
TL;DR: In this paper , a facile stirring cross-linking method was used to construct polyethylenimine (PEI) cross-linked P84 nanofiltration membranes with high positive charge and hydrophilic surface.
TL;DR: The DELIVER trial as mentioned in this paper investigated the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures, but benefits in the subpopulations of patients with previous treatment failures were not examined.
Abstract: Background The monoclonal antibody eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined. We aimed to investigate the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures. Methods DELIVER was a multicentre, multi-arm, phase 3b trial comprising a 24-week double-blind, placebo-controlled period and a 48-week dose-blinded extension. We recruited adults with episodic or chronic migraine with at least 4 monthly migraine days (as per International Headache Society guidelines) and documented evidence of two-to-four previous preventive treatment failures within the past 10 years, from 96 study locations across Europe (n=93) and the USA (n=3). Patients were randomly assigned (1:1:1) via a centralised randomisation system, stratified by baseline monthly headache days and country, to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1–12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. The dose-blinded extension period is ongoing. The trial is registered with ClinicalTrials.gov, NCT04418765, and EudraCT, 2019-004497-25. Findings Between June 1, 2020, and Oct 7, 2021, 891 individuals were randomly assigned and received at least one dose of study drug (safety population; eptinezumab 100 mg n=299 [34%], eptinezumab 300 mg n=294 [33%], placebo n=298 [33%]). 865 patients completed the placebo-controlled period. The change from baseline to weeks 1–12 in mean monthly migraine days was –4·8 (SE 0·37) with eptinezumab 100 mg, –5·3 (0·37) with eptinezumab 300 mg, and –2·1 (0·38) with placebo. The difference from placebo in change in mean monthly migraine days from baseline was significant with eptinezumab 100 mg (–2·7 [95% CI –3·4 to –2·0]; p<0·0001) and eptinezumab 300 mg (–3·2 [–3·9 to –2·5]; p<0·0001). Treatment-emergent adverse events occurred in 127 (42%) of 299 patients in the eptinezumab 100 mg group, in 120 (41%) of 294 in the eptinezumab 300 mg group, and in 119 (40%) of 298 in the placebo group. The most common treatment-emergent adverse event was COVID-19 (20 [7%] of 299 patients in the eptinezumab 100 mg group, 17 [6%] of 294 in the eptinezumab 300 mg group, and 16 [5%] of 298 in the placebo group). Serious adverse events were uncommon (five [2%] of 299 in the eptinezumab 100 mg group, seven [2%] of 294 in the eptinezumab 300 mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1). Interpretation In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The dose-blinded extension period will provide additional long-term safety data in patients with migraine and previous preventive treatment failures. Funding H Lundbeck. The monoclonal antibody eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined. We aimed to investigate the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures. DELIVER was a multicentre, multi-arm, phase 3b trial comprising a 24-week double-blind, placebo-controlled period and a 48-week dose-blinded extension. We recruited adults with episodic or chronic migraine with at least 4 monthly migraine days (as per International Headache Society guidelines) and documented evidence of two-to-four previous preventive treatment failures within the past 10 years, from 96 study locations across Europe (n=93) and the USA (n=3). Patients were randomly assigned (1:1:1) via a centralised randomisation system, stratified by baseline monthly headache days and country, to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1–12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. The dose-blinded extension period is ongoing. The trial is registered with ClinicalTrials.gov, NCT04418765, and EudraCT, 2019-004497-25. Between June 1, 2020, and Oct 7, 2021, 891 individuals were randomly assigned and received at least one dose of study drug (safety population; eptinezumab 100 mg n=299 [34%], eptinezumab 300 mg n=294 [33%], placebo n=298 [33%]). 865 patients completed the placebo-controlled period. The change from baseline to weeks 1–12 in mean monthly migraine days was –4·8 (SE 0·37) with eptinezumab 100 mg, –5·3 (0·37) with eptinezumab 300 mg, and –2·1 (0·38) with placebo. The difference from placebo in change in mean monthly migraine days from baseline was significant with eptinezumab 100 mg (–2·7 [95% CI –3·4 to –2·0]; p<0·0001) and eptinezumab 300 mg (–3·2 [–3·9 to –2·5]; p<0·0001). Treatment-emergent adverse events occurred in 127 (42%) of 299 patients in the eptinezumab 100 mg group, in 120 (41%) of 294 in the eptinezumab 300 mg group, and in 119 (40%) of 298 in the placebo group. The most common treatment-emergent adverse event was COVID-19 (20 [7%] of 299 patients in the eptinezumab 100 mg group, 17 [6%] of 294 in the eptinezumab 300 mg group, and 16 [5%] of 298 in the placebo group). Serious adverse events were uncommon (five [2%] of 299 in the eptinezumab 100 mg group, seven [2%] of 294 in the eptinezumab 300 mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1). In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The dose-blinded extension period will provide additional long-term safety data in patients with migraine and previous preventive treatment failures.
TL;DR: In this paper , the authors derived spurious pole-free, all-spin opposite-helicity Compton amplitudes in the classical limit for QED, QCD, and gravity.
Abstract: A bstract The classical scattering of spinning objects is well described by the spinor-helicity formalism for heavy particles. Using these variables, we derive spurious-pole-free, all-spin opposite-helicity Compton amplitudes (factorizing on physical poles to the minimal, all-spin three-point amplitudes) in the classical limit for QED, QCD, and gravity. The cured amplitudes are subject to deformations by contact terms, the vast majority of whose contributions we can fix by imposing a relation between spin structures — motivated by lower spin multipoles of black hole scattering — at the second post-Minkowskian (2PM) order. For QED and gravity, this leaves a modest number of unfixed coefficients parametrizing contact-term deformations, while the QCD amplitude is uniquely determined. Our gravitational Compton amplitude allows us to push the state-of-the-art of spinning-2PM scattering to any order in the spin vectors of both objects; we present results here and in the supplementary material file 2PMSpin8Aux.nb up to eighth order in the spin vectors. Interestingly, despite leftover coefficients in the Compton amplitude, imposing the aforementioned relation between spin structures uniquely fixes some higher-spin parts of the 2PM amplitude.