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  • 1
    Online Resource
    Online Resource
    Assessment of the Impact of RNase in Patients With Severe Fatigue Related to Post-Acute Sequelae of SARS-CoV-2 Infection (PASC): A Randomized Phase 2 Trial of RSLV-132
    Oxford University Press (OUP) ; 2024
    In:  Clinical Infectious Diseases ( 2024-05-10)
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), ( 2024-05-10)
    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and RNA debris persist in viral reservoirs for weeks to months following infection, potentially triggering interferon production and chronic inflammation. RSLV-132 is a biologic drug composed of catalytically active human RNase1 fused to human IgG1 Fc and is designed to remain in circulation and digest extracellular RNA. We hypothesized that removal of SARS-CoV-2 viral RNA from latent reservoirs may improve inflammation, neuroinflammation, and fatigue associated with post-acute sequelae of SARS-CoV-2 infection (PASC). Methods This was a phase 2, double-blind, placebo-controlled randomized clinical trial in participants with a 24-week history of PASC and severe fatigue. The primary endpoint of the trial assessed the impact of 6 intravenous doses of RSLV-132 on the mean change from baseline at day 71 in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a). Results A statistically significant difference on day 71 was not observed with respect to the primary or secondary endpoints. This was likely due to a placebo response that increased during the trial. Statistically significant improvement in fatigue as measured by the PROMIS Fatigue SF 7a, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue), and Physicians Global Assessment (PGA) instruments were observed earlier in the trial, with women demonstrating greater responses to RSLV-132 than men. Conclusion While fatigue was not statistically significantly improved at Day 71, earlier timepoints revealed statistically significant improvement in fatigue and physician global assessment. The data suggest eliminating latent viral RNA by increasing serum RNase activity may improve fatigue in PASC patients. Women may respond better to this approach than men. Future studies will aim to confirm these findings.
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Article
    DOI: 10.1093/cid/ciae205
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 1099781-7
    detail.hit.zdb_id: 2002229-3
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  • 2
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    Online Resource
    Validation of Ligand Tetramers for the Detection of Antigen-Specific Lymphocytes
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 8 ( 2023-04-15), p. 1156-1165
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 8 ( 2023-04-15), p. 1156-1165
    Abstract: The study of Ag-specific lymphocytes has been a key advancement in immunology over the past few decades. The development of multimerized probes containing Ags, peptide:MHC complexes, or other ligands was one innovation allowing the direct study of Ag-specific lymphocytes by flow cytometry. Although these types of study are now common and performed by thousands of laboratories, quality control and assessment of probe quality are often minimal. In fact, many of these types of probe are made in-house, and protocols vary between laboratories. Although peptide:MHC multimers can often be obtained from commercial sources or core facilities, few such services exist for Ag multimers. To ensure high quality and consistency with ligand probes, we have developed an easy and robust multiplexed approach using commercially available beads able to bind Abs specific for the ligand of interest. Using this assay, we have sensitively assessed the performance of peptide:MHC and Ag tetramers and have found considerable batch-to-batch variability in performance and stability over time more easily than using murine or human cell-based assays. This bead-based assay can also reveal common production errors such as miscalculation of Ag concentration. This work could set the stage for the development of standardized assays for all commonly used ligand probes to limit laboratory-to-laboratory technical variation and experimental failure caused by probe underperformance.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200934
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 3
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    Online Resource
    The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients
    Oxford University Press (OUP) ; 2024
    In:  The Journal of Infectious Diseases ( 2024-05-14)
    Details
    In: The Journal of Infectious Diseases, Oxford University Press (OUP), ( 2024-05-14)
    Abstract: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics of the long-acting mAb sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients. Methods All participants received an intravenous infusion of sotrovimab within 1 week prior to initiating the pretransplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks posttransplant. Results Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease (GVHD) posttransplant. Conclusions These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased gastrointestinal clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
    URL: Article
    DOI: 10.1093/infdis/jiae236
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2024
    detail.hit.zdb_id: 3019-3
    detail.hit.zdb_id: 1473843-0
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  • 4
    Online Resource
    Online Resource
    Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 3 ( 2020-02-01), p. 498-509
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 3 ( 2020-02-01), p. 498-509
    Abstract: Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900799
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 5
    Online Resource
    Online Resource
    Arachidonic Acid Activates Phosphatidylinositol 3-Kinase Signaling and Induces Gene Expression in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 3 ( 2006-02-01), p. 1427-1433
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 3 ( 2006-02-01), p. 1427-1433
    Abstract: Essential fatty acids are not only energy-rich molecules; they are also an important component of the membrane bilayer and recently have been implicated in induction of fatty acid synthase and other genes. Using gene chip analysis, we have found that arachidonic acid, an ω-6 fatty acid, induced 11 genes that are regulated by nuclear factor-κB (NF-κB). We verified gene induction by ω-6 fatty acid, including COX-2, IκBα, NF-κB, GM-CSF, IL-1β, CXCL-1, TNF-α, IL-6, LTA, IL-8, PPARγ, and ICAM-1, using quantitative reverse transcription-PCR. Prostaglandin E2 (PGE2) synthesis was increased within 5 minutes of addition of arachidonic acid. Analysis of upstream signal transduction showed that within 5 minutes of fatty acid addition, phosphatidylinositol 3-kinase (PI3K) was significantly activated followed by activation of Akt at 30 minutes. Extracellular signal-regulated kinase 1 and 2, p38 and stress-activated protein kinase/c-Jun-NH2-kinase were not phosphorylated after ω-6 fatty acid addition. Thirty minutes after fatty acid addition, we found a significant 3-fold increase in translocation of NF-κB transcription factor to the nucleus. Addition of a nonsteroidal anti-inflammatory drug (NSAID) caused a decrease in COX-2 protein synthesis, PGE2 synthesis, as well as inhibition of PI3K activation. We have previously shown that NSAIDs cause an inhibition of arachidonic acid–induced proliferation; here, we have shown that arachidonic acid–induced proliferation is also blocked (P & lt; 0.001) by PI3K inhibitor LY294002. LY294002 also significantly inhibited the arachidonic acid–induced gene expression of COX-2, IL-1β, GM-CSF, and ICAM1. Taken together, the data suggest that arachidonic acid via conversion to PGE2 plays an important role in stimulation of growth-related genes and proliferation via PI3K signaling and NF-κB translocation to the nucleus. (Cancer Res 2006; 66(3): 1427-33)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-0914
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
    Online Resource
    Online Resource
    Predictive Value of Respiratory Viral Detection in the Upper Respiratory Tract for Infection of the Lower Respiratory Tract With Hematopoietic Stem Cell Transplantation
    Oxford University Press (OUP) ; 2019
    In:  The Journal of Infectious Diseases ( 2019-09-21)
    Details
    In: The Journal of Infectious Diseases, Oxford University Press (OUP), ( 2019-09-21)
    Abstract: Hematopoietic cell transplant (HCT) recipients are frequently infected with respiratory viruses (RVs) in the upper respiratory tract (URT), but the concordance between URT and lower respiratory tract (LRT) RV detection is not well characterized. Methods Hematopoietic cell transplant candidates and recipients with respiratory symptoms and LRT and URT RV testing via multiplex PCR from 2009 to 2016 were included. Logistic regression models were used to analyze risk factors for LRT RV detection. Results Two-hundred thirty-five HCT candidates or recipients had URT and LRT RV testing within 3 days. Among 115 subjects (49%) positive for a RV, 37% (42 of 115) had discordant sample pairs. Forty percent (17 of 42) of discordant pairs were positive in the LRT but negative in the URT. Discordance was common for adenovirus (100%), metapneumovirus (44%), rhinovirus (34%), and parainfluenza virus type 3 (28%); respiratory syncytial virus was highly concordant (92%). Likelihood of LRT detection was increased with URT detection (oods ratio [OR] = 73.7; 95% confidence interval [CI] , 26.7–204) and in cytomegalovirus-positive recipients (OR = 3.70; 95% CI, 1.30–10.0). Conclusions High rates of discordance were observed for certain RVs. Bronchoalveolar lavage sampling may provide useful diagnostic information to guide management in symptomatic HCT candidates and recipients.
    Type of Medium: Online Resource
    ISSN: 0022-1899 , 1537-6613
    URL: Article
    DOI: 10.1093/infdis/jiz470
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 3019-3
    detail.hit.zdb_id: 1473843-0
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  • 7
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    Online Resource
    The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity
    Oxford University Press (OUP) ; 2012
    In:  Journal of Leukocyte Biology Vol. 92, No. 6 ( 2012-12-01), p. 1133-1145
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 92, No. 6 ( 2012-12-01), p. 1133-1145
    Abstract: Transactivation of immediate early genes, especially targets of the Rel/NFκB pathway, is disrupted in T cells activated in microgravity. This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in μg. Immunosuppression during spaceflight is a major barrier to safe, long-term human space habitation and travel. The goals of these experiments were to prove that μg was the cause of impaired T cell activation during spaceflight, as well as understand the mechanisms controlling early T cell activation. T cells from four human donors were stimulated with Con A and anti-CD28 on board the ISS. An on-board centrifuge was used to generate a 1g simultaneous control to isolate the effects of μg from other variables of spaceflight. Microarray expression analysis after 1.5 h of activation demonstrated that μg- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly, differentially down-regulated in μg. Importantly, several key immediate early genes were inhibited in μg. In particular, transactivation of Rel/NF-κB, CREB, and SRF gene targets were down-regulated. Expression of cREL gene targets were significantly inhibited, and transcription of cREL itself was reduced significantly in μg and upon anti-CD3/anti-CD28 stimulation in simulated μg. Analysis of gene connectivity indicated that the TNF pathway is a major early downstream effector pathway inhibited in μg and may lead to ineffective proinflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that μg was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes.
    Type of Medium: Online Resource
    ISSN: 1938-3673 , 0741-5400
    URL: Article
    DOI: 10.1189/jlb.0312157
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
    detail.hit.zdb_id: 605722-6
    detail.hit.zdb_id: 2026833-6
    SSG: 12
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