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  1. Article ; Online: HDACi promotes inflammatory remodeling of the tumor microenvironment to enhance epitope spreading and antitumor immunity.

    Nguyen, Andrew / Ho, Louisa / Hogg, Richard / Chen, Lan / Walsh, Scott R / Wan, Yonghong

    The Journal of clinical investigation

    2022  Volume 132, Issue 19

    Abstract: Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic ... ...

    Abstract Adoptive cell therapy (ACT) with tumor-specific memory T cells has shown increasing efficacy in regressing solid tumors. However, tumor antigen heterogeneity represents a longitudinal challenge for durable clinical responses due to the therapeutic selective pressure for immune escape variants. Here, we demonstrated that delivery of the class I histone deacetylase inhibitor MS-275 promoted sustained tumor regression by synergizing with ACT in a coordinated manner to enhance cellular apoptosis. We found that MS-275 altered the tumor inflammatory landscape to support antitumor immunoactivation through the recruitment and maturation of cross-presenting CD103+ and CD8+ DCs and depletion of Tregs. Activated endogenous CD8+ T cell responses against nontarget tumor antigens were critically required for the prevention of tumor recurrence. Importantly, MS-275 altered the immunodominance hierarchy by directing epitope spreading toward the endogenous retroviral tumor-associated antigen p15E. Our data suggest that MS-275 in combination with ACT multimechanistically enhanced epitope spreading and promoted long-term clearance of solid tumors.
    MeSH term(s) Antigens, Neoplasm/genetics ; Benzamides ; CD8-Positive T-Lymphocytes ; Epitopes ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Neoplasms/pathology ; Pyridines ; Tumor Microenvironment
    Chemical Substances Antigens, Neoplasm ; Benzamides ; Epitopes ; Histone Deacetylase Inhibitors ; Pyridines ; entinostat (1ZNY4FKK9H)
    Language English
    Publishing date 2022-10-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI159283
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  2. Article ; Online: Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

    Atkinson, Stephen J / Bagal, Sharan K / Argyrou, Argyrides / Askin, Sean / Cheung, Tony / Chiarparin, Elisabetta / Coen, Muireann / Collie, Iain T / Dale, Ian L / De Fusco, Claudia / Dillman, Keith / Evans, Laura / Feron, Lyman J / Foster, Alison J / Grondine, Michael / Kantae, Vasudev / Lamont, Gillian M / Lamont, Scott / Lynch, James T /
    Nilsson Lill, Sten / Robb, Graeme R / Saeh, Jamal / Schimpl, Marianne / Scott, James S / Smith, James / Srinivasan, Bharath / Tentarelli, Sharon / Vazquez-Chantada, Mercedes / Wagner, David / Walsh, Jarrod J / Watson, David / Williamson, Beth

    Journal of medicinal chemistry

    2024  Volume 67, Issue 6, Page(s) 4541–4559

    Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ' ... ...

    Abstract The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (
    MeSH term(s) Humans ; Neoplasms ; Entropy ; Methionine Adenosyltransferase/metabolism
    Chemical Substances MAT2A protein, human (EC 2.5.1.6) ; Methionine Adenosyltransferase (EC 2.5.1.6)
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c01860
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  3. Article ; Online: Molecular basis for processing of topoisomerase 1-triggered DNA damage by Apn2/APE2.

    Williams, Jessica S / Wojtaszek, Jessica L / Appel, Denise C / Krahn, Juno / Wallace, Bret D / Walsh, Evan / Kunkel, Thomas A / Williams, R Scott

    Cell reports

    2022  Volume 41, Issue 1, Page(s) 111448

    Abstract: Topoisomerase 1 (Top1) incises DNA containing ribonucleotides to generate complex DNA lesions that are resolved by APE2 (Apn2 in yeast). How Apn2 engages and processes this DNA damage is unclear. Here, we report X-ray crystal structures and biochemical ... ...

    Abstract Topoisomerase 1 (Top1) incises DNA containing ribonucleotides to generate complex DNA lesions that are resolved by APE2 (Apn2 in yeast). How Apn2 engages and processes this DNA damage is unclear. Here, we report X-ray crystal structures and biochemical analysis of Apn2-DNA complexes to demonstrate how Apn2 frays and cleaves 3' DNA termini via a wedging mechanism that facilitates 1-6 nucleotide endonucleolytic cleavages. APN2 deletion and DNA-wedge mutant Saccharomyces cerevisiae strains display mutator phenotypes, cell growth defects, and sensitivity to genotoxic stress in a ribonucleotide excision repair (RER)-defective background harboring a high density of Top1-incised ribonucleotides. Our data implicate a wedge-and-cut mechanism underpinning the broad-specificity Apn2 nuclease activity that mitigates mutagenic and genome instability phenotypes caused by Top1 incision at genomic ribonucleotides incorporated by DNA polymerase epsilon.
    MeSH term(s) DNA ; DNA Damage ; DNA Polymerase II/genetics ; DNA Repair ; DNA Topoisomerases, Type I/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Ribonucleotides/chemistry ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Ribonucleotides ; Saccharomyces cerevisiae Proteins ; DNA (9007-49-2) ; DNA Polymerase II (EC 2.7.7.7) ; APN2 protein, S cerevisiae (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; TOP1 protein, S cerevisiae (EC 5.99.1.1) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
    Language English
    Publishing date 2022-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.111448
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  4. Article ; Online: Large-scale optical characterization of solid-state quantum emitters.

    Sutula, Madison / Christen, Ian / Bersin, Eric / Walsh, Michael P / Chen, Kevin C / Mallek, Justin / Melville, Alexander / Titze, Michael / Bielejec, Edward S / Hamilton, Scott / Braje, Danielle / Dixon, P Benjamin / Englund, Dirk R

    Nature materials

    2023  Volume 22, Issue 11, Page(s) 1338–1344

    Abstract: Solid-state quantum emitters have emerged as a leading quantum memory for quantum networking applications. However, standard optical characterization techniques are neither efficient nor repeatable at scale. Here we introduce and demonstrate ... ...

    Abstract Solid-state quantum emitters have emerged as a leading quantum memory for quantum networking applications. However, standard optical characterization techniques are neither efficient nor repeatable at scale. Here we introduce and demonstrate spectroscopic techniques that enable large-scale, automated characterization of colour centres. We first demonstrate the ability to track colour centres by registering them to a fabricated machine-readable global coordinate system, enabling a systematic comparison of the same colour centre sites over many experiments. We then implement resonant photoluminescence excitation in a widefield cryogenic microscope to parallelize resonant spectroscopy, achieving two orders of magnitude speed-up over confocal microscopy. Finally, we demonstrate automated chip-scale characterization of colour centres and devices at room temperature, imaging thousands of microscope fields of view. These tools will enable the accelerated identification of useful quantum emitters at chip scale, enabling advances in scaling up colour centre platforms for quantum information applications, materials science and device design and characterization.
    Language English
    Publishing date 2023-08-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2088679-2
    ISSN 1476-4660 ; 1476-1122
    ISSN (online) 1476-4660
    ISSN 1476-1122
    DOI 10.1038/s41563-023-01644-8
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  5. Article ; Online: HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden-induced T-cell Exhaustion.

    Nguyen, Andrew / Brown, Dominique / Krishnan, Ramya / Bastin, Donald / Deng, Li / Chen, Lan / Salem, Omar / Walsh, Scott R / Bramson, Jonathan L / Wan, Yonghong

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2023  Volume 29, Issue 20, Page(s) 4289–4305

    Abstract: Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified ...

    Abstract Purpose: T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness.
    Experimental design: We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis.
    Results: ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation.
    Conclusions: Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.
    Language English
    Publishing date 2023-08-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-22-2181
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    Zs.A 4223: Show issues Location:
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  6. Article ; Online: High-throughput screening for prescribing cascades among real world statin initiators.

    Vouri, Scott M / Morris, Earl J / Walsh, Marta / Agalliu, Jessica / Dempsey, Alyssa / Hochleitner, Leonie / Muschett, Matthew R / Schmidt, Stephan / Pepine, Carl J / Smith, Steven M

    Pharmacoepidemiology and drug safety

    2023  Volume 32, Issue 7, Page(s) 773–782

    Abstract: Purpose: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been ... ...

    Abstract Purpose: Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge.
    Methods: We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed.
    Results: We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n = 57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246).
    Conclusions: Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.
    MeSH term(s) Aged ; Adult ; Humans ; Female ; United States ; Middle Aged ; Male ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; High-Throughput Screening Assays ; Medicare ; Simvastatin/adverse effects ; Atorvastatin
    Chemical Substances Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Simvastatin (AGG2FN16EV) ; Atorvastatin (A0JWA85V8F)
    Language English
    Publishing date 2023-03-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1099748-9
    ISSN 1099-1557 ; 1053-8569
    ISSN (online) 1099-1557
    ISSN 1053-8569
    DOI 10.1002/pds.5607
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    Zs.A 3395: Show issues Location:
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  7. Article: Porphyromonas somerae

    Crooks, Taylor A / Madison, Joseph D / Walsh, Dana M / Herbert, William G / Jeraldo, Patricio R / Chia, Nicholas / Cliby, William A / Kaufmann, Scott H / Walther-Antonio, Marina R S

    Frontiers in microbiology

    2021  Volume 12, Page(s) 674835

    Abstract: Recent evidence suggests an association between endometrial cancer and the understudied bacterial ... ...

    Abstract Recent evidence suggests an association between endometrial cancer and the understudied bacterial species
    Language English
    Publishing date 2021-07-23
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2021.674835
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  8. Article ; Online: Burden of mental health symptoms and perceptions of their management in in-centre hemodialysis care: a mixed methods study.

    Schick-Makaroff, Kara / Wozniak, Lisa A / Short, Hilary / Davison, Sara N / Klarenbach, Scott / Buzinski, Robert / Walsh, Michael / Johnson, Jeffrey A

    Journal of patient-reported outcomes

    2021  Volume 5, Issue 1, Page(s) 111

    Abstract: ... used to understand patients' and nurses' perceptions of managing these symptoms using the ESAS-r: Renal ... responses (n = 779) and nurses' chart notes (n = 84), we discerned that PROMs (ESAS-r: Renal/EQ-5D-5L) had ...

    Abstract Background: We aimed to describe (1) depressive and anxiety symptom burdens reported by adults on in-centre hemodialysis in Northern Alberta, Canada and (2) patients' and nurses' perceptions of managing such symptoms using routine patient-reported outcome measures (PROMs).
    Methods: A longitudinal mixed methods approach was employed. Cluster randomized controlled trial data exposed the prevalence of positive screens (scores ≥ 3) for depressive (PHQ-2) and anxiety (GAD-2) symptoms. A descriptive qualitative approach was used to understand patients' and nurses' perceptions of managing these symptoms using the ESAS-r: Renal and EQ-5D-5L. Using purposeful sampling, patients and nurses were invited for interviews. Field notes were documented from 6 dialysis unit observations. Patients' responses to open-ended survey questions and nurses' electronic chart notes related to mental health were compiled. Thematic and content analyses were used.
    Results: Average age of patients (n = 408) was 64.0 years (SD 15.4), 57% were male, and 87% were not working; 29% screened positive for depressive symptoms, 21% for anxiety symptoms, and 16% for both. From patient (n = 10) and nurse (n = 8) interviews, unit observations, patient survey responses (n = 779) and nurses' chart notes (n = 84), we discerned that PROMs (ESAS-r: Renal/EQ-5D-5L) had the potential to identify and prompt management of mental health concerns. However, opinions differed about whether mental health was within kidney care scope. Nonetheless, participants agreed there was a lack of mental health resources.
    Conclusions: Prevalence of depressive and anxiety symptoms aligned with existing literature. Tensions regarding mental health management highlight the need for systemic decisions about how routine PROM use, including mental health assessment, may be optimized to meet patients' needs.
    Language English
    Publishing date 2021-10-28
    Publishing country Germany
    Document type Journal Article
    ISSN 2509-8020
    ISSN (online) 2509-8020
    DOI 10.1186/s41687-021-00385-z
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  9. Article ; Online: Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.

    Barry, Elly / Walsh, Jaimie A / Weinrich, Scott L / Beaupre, Darrin / Blasi, Eileen / Arenson, Daniel R / Jacobs, Ira A

    Paediatric drugs

    2021  Volume 23, Issue 4, Page(s) 381–394

    Abstract: Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer ... ...

    Abstract Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.
    MeSH term(s) Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/therapeutic use ; Child ; Clinical Trials as Topic/legislation & jurisprudence ; Clinical Trials as Topic/methods ; Drug Delivery Systems/methods ; Drug Development/legislation & jurisprudence ; Drug Development/methods ; European Union ; Expert Testimony/legislation & jurisprudence ; Expert Testimony/methods ; Humans ; Medical Oncology/legislation & jurisprudence ; Medical Oncology/methods ; Neoplasms/drug therapy ; Neoplasms/epidemiology ; United States ; United States Food and Drug Administration/legislation & jurisprudence
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2021-06-26
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1492748-2
    ISSN 1179-2019 ; 1174-5878
    ISSN (online) 1179-2019
    ISSN 1174-5878
    DOI 10.1007/s40272-021-00455-1
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    Zs.A 5205: Show issues Location:
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  10. Article ; Online: Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine.

    Falsey, Ann R / Walsh, Edward E / Scott, Daniel A / Gurtman, Alejandra / Zareba, Agnieszka / Jansen, Kathrin U / Gruber, William C / Dormitzer, Philip R / Swanson, Kena A / Jiang, Qin / Gomme, Emily / Cooper, David / Schmoele-Thoma, Beate

    The Journal of infectious diseases

    2021  Volume 225, Issue 12, Page(s) 2056–2066

    Abstract: Background: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults and adults with comorbidities. An effective vaccine is needed. An investigational bivalent prefusion F vaccine (RSVpreF) was assessed in healthy ... ...

    Abstract Background: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults and adults with comorbidities. An effective vaccine is needed. An investigational bivalent prefusion F vaccine (RSVpreF) was assessed in healthy adults.
    Methods: This phase 1/2 study randomized adults 18-85 years old to receive placebo or 60, 120, or 240 µg RSVpreF (with or without aluminum hydroxide) alone or concomitantly with seasonal inactivated influenza vaccine (SIIV). Safety and immunogenicity were assessed.
    Results: In older adults, reactogenicity events were predominantly mild or moderate among RSVpreF recipients; adverse events through 1 month postvaccination were similar across formulations. Coadministration with SIIV did not appear to affect safety among younger or older adults. All RSVpreF formulations with or without concomitant SIIV elicited robust RSV serum-neutralizing responses in adults aged 50-85 years 1 month postvaccination. Neutralizing titers 1 and 12 months postvaccination were 6.9-14.9 and 2.9-4.5 times, respectively, those before vaccination. SIIV immune responses trended lower when coadministered with RSVpreF.
    Conclusions: RSVpreF formulations administered alone or with SIIV were well tolerated and highly immunogenic in older adults, supporting the potential for RSVpreF to protect older adults from RSV disease.
    Clinical trials registration: NCT03529773.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Neutralizing ; Antibodies, Viral ; Humans ; Immunogenicity, Vaccine ; Influenza Vaccines/administration & dosage ; Influenza, Human/epidemiology ; Middle Aged ; Respiratory Syncytial Virus Infections/epidemiology ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/adverse effects ; Respiratory Syncytial Virus, Human ; Vaccines, Inactivated/administration & dosage ; Young Adult
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Influenza Vaccines ; Respiratory Syncytial Virus Vaccines ; Vaccines, Inactivated
    Language English
    Publishing date 2021-12-21
    Publishing country United States
    Document type Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiab611
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