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Article ; Online: Early Recovery of Myeloid-Derived Suppressor Cells After Allogeneic Hematopoietic Transplant: Comparison of Post-Transplantation Cyclophosphamide to Standard Graft-Versus-Host Disease Prophylaxis.

Oshrine, Benjamin / Innamarato, Patrick / Branthoover, Holly / Nagle, Luz / Verdugo, Patrick / Pilon-Thomas, Shari / Beatty, Matthew

Transplantation and cellular therapy

2022 Volume 28, Issue 4, Page(s) 203.e1–203.e7

Abstract: Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor ... ...

Abstract	Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N = 11) and PTCy recipients (N = 11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II to IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
MeSH term(s)	Child ; Cyclophosphamide/pharmacology ; Graft vs Host Disease/prevention & control ; Hematopoietic Stem Cell Transplantation ; Humans ; Myeloid-Derived Suppressor Cells ; Transplantation Conditioning ; United States
Chemical Substances	Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2021.12.019
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Article ; Online: Targeting myeloid-derived suppressor cells with gemcitabine to enhance efficacy of adoptive cell therapy in bladder cancer.

Bazargan, Sarah / Bunch, Brittany / Ojwang', Awino Maureiq E / Blauvelt, Jamie / Landin, Annick / Ali, Johannes / Abrahams, Dominique / Cox, Cheryl / Hall, Amy M / Beatty, Matthew S / Poch, Michael / Rejniak, Katarzyna A / Pilon-Thomas, Shari

Frontiers in immunology

2023 Volume 14, Page(s) 1275375

Abstract: Background: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder ...

Abstract	Background: New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Methods: Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. Results: In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. Conclusion: MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.
MeSH term(s)	Humans ; Mice ; Animals ; Gemcitabine ; Myeloid-Derived Suppressor Cells/metabolism ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Immunotherapy, Adoptive ; Urinary Bladder Neoplasms/drug therapy ; Cytokines/metabolism ; Tumor Microenvironment
Chemical Substances	Gemcitabine ; Deoxycytidine (0W860991D6) ; Cytokines
Language	English
Publishing date	2023-10-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1275375
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Article ; Online: Digital health coaching to improve patient preparedness for elective lower limb arthroplasty: a quality improvement project.

Powley, Nicola / Tew, Garry A / Durrand, James / Carr, Esther / Nesbitt, Alexander / Hackett, Rhiannon / Gray, Joanne / McCarthy, Stephen / Beatty, Matthew / Huddleston, Robbie / Danjoux, Gerard

BMJ open quality

2023 Volume 12, Issue 4

Abstract: Major surgery carries high risks with comorbidities, frailty and health risk behaviours meaning patients are often unprepared for the physiological insult. Since 2018, the Prepwell programme at South Tees Hospitals NHS Foundation Trust has supported ... ...

Abstract	Major surgery carries high risks with comorbidities, frailty and health risk behaviours meaning patients are often unprepared for the physiological insult. Since 2018, the Prepwell programme at South Tees Hospitals NHS Foundation Trust has supported patients to improve their preoperative health and fitness. In April 2020, the face-to-face service was suspended due to the pandemic, leading to the team implementing a three-tiered remote digital support pathway, including digital health coaching via a mobile phone application. Methods: Patients scheduled for elective lower limb arthroplasty were offered 8 weeks of digital health coaching preoperatively. Following consent, participants were assigned a personal health coach to set individual behaviour change goals supported by online resources, alongside a digitally delivered exercise programme. Participants completed self-assessment questionnaires at Entry to, and Exit from, the programme, with outcome data collected 21 days postoperatively. The primary outcome was the change in Patient Activation Measure (PAM). Results: Fifty-seven of 189 patients (30.2%) consented to referral for digital health coaching. Forty participants completed the 8-week programme. Median PAM increased from 58.1 to 67.8 (p=0.002). Thirty-five per cent of participants were in a non-activated PAM level at Entry, reducing to 15% at Exit with no participants in PAM level 1 at completion. Seventy-one percent of non-activated participants improved their PAM by one level or more, compared with 45% for the whole cohort. Median LOS was 2 days, 1 day less than the Trust's arthroplasty patient population during the study period (unadjusted comparison). Conclusions: Digital health coaching was successfully implemented for patients awaiting elective lower limb arthroplasty. We observed significant improvements in participants' PAM scores after the programme, with the largest increase in participants with lower activation scores at Entry. Further study is needed to confirm the effects of digital health coaching in this and other perioperative groups.
MeSH term(s)	Humans ; Quality Improvement ; Mentoring ; Health Promotion ; Lower Extremity
Language	English
Publishing date	2023-12-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-6641
ISSN (online)	2399-6641
DOI	10.1136/bmjoq-2022-002244
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Article ; Online: The Factors Affecting Expansion of Reactive Tumor Infiltrating Lymphocytes (TIL) From Bladder Cancer and Potential Therapeutic Applications.

Aydin, Ahmet Murat / Bunch, Brittany L / Beatty, Matthew / Hajiran, Ali / Dhillon, Jasreman / Sarnaik, Amod A / Pilon-Thomas, Shari / Poch, Michael A

Frontiers in immunology

2021 Volume 12, Page(s) 628063

Abstract: Tumor infiltrating lymphocytes (TIL) therapy was shown to provide durable objective response in patients with metastatic melanoma. As a fundamental first step to bring TIL therapy to clinical use, identification of patients whose tumors yield optimal ... ...

Abstract	Tumor infiltrating lymphocytes (TIL) therapy was shown to provide durable objective response in patients with metastatic melanoma. As a fundamental first step to bring TIL therapy to clinical use, identification of patients whose tumors yield optimal numbers of reactive TIL is indispensable. We have previously shown that expansion of tumor reactive TIL from primary bladder tumors and lymph node metastases is feasible. Here, we performed TIL harvesting from additional surgical specimens (additional 31 primary tumors and 10 lymph nodes) to generate a heterogenous cohort of 53 patients with bladder cancer (BC) to evaluate the tumor characteristics that lead to tumor-reactive TIL expansion. Among a total of 53 patients, overall TIL growth from tumor samples were 37/53 (69.8%) and overall anti-tumor reactive TIL were 26/35 (74.3%). Mixed urothelial carcinoma is associated with higher anti-tumor reactivity of expanded TIL than pure urothelial carcinoma (89.5% vs. 56.3%, p=0.049). The anti-tumor reactivity of expanded TIL from primary tumors previously treated with BCG immunotherapy were lower (33.3% vs. 82.6%, p=0.027) although T-cell phenotype (CD3+, CD4+, CD8+, and CD56+) was similar regardless prior of BCG therapy. Addition of agonistic 4-1BB antibody in culture media with IL-2 improved the number of expanded TIL from primary tumors previously treated with BCG immunotherapy. There was no significant difference between basal and luminal subtype tumors in terms of viable and reactive TIL growth. Our study demonstrates that TIL expansion is feasible across all BC patients and BC subtypes, and we suggest that TIL therapy can be a reasonable treatment strategy for various manifestations of BC.
MeSH term(s)	Aged ; Cancer Vaccines/immunology ; Cell Proliferation ; Cells, Cultured ; Cohort Studies ; Female ; Humans ; Immunotherapy, Adoptive/methods ; Interleukin-2/metabolism ; Lymphatic Metastasis ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating/physiology ; Male ; Middle Aged ; Mycobacterium bovis ; Tumor Necrosis Factor Receptor Superfamily, Member 9/agonists ; Urinary Bladder Neoplasms/immunology ; Urinary Bladder Neoplasms/therapy ; Urothelium/pathology
Chemical Substances	Cancer Vaccines ; Interleukin-2 ; Tumor Necrosis Factor Receptor Superfamily, Member 9
Language	English
Publishing date	2021-02-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.628063
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Article: L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.

Biomedicines

2024 Volume 12, Issue 2

Abstract: Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor ...

Abstract	Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO
Language	English
Publishing date	2024-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines12020461
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Article ; Online: Chapter two--Adenovirus strategies for tissue-specific targeting.

Beatty, Matthew S / Curiel, David T

Advances in cancer research

2012 Volume 115, Page(s) 39–67

Abstract: Cancer gene therapy approaches have benefited greatly from the utilization of molecular-based therapeutics. Of these, adenovirus-based interventions hold much promise as a platform for targeted therapeutic delivery to tumors. However, a barrier to this ... ...

Abstract	Cancer gene therapy approaches have benefited greatly from the utilization of molecular-based therapeutics. Of these, adenovirus-based interventions hold much promise as a platform for targeted therapeutic delivery to tumors. However, a barrier to this progression is the lack of native adenovirus receptor expression on a variety of cancer types. As such, any adenovirus-based cancer therapy must take into consideration retargeting the vector to nonnative cellular surface receptors. Predicated upon the knowledge gained in native adenovirus biology, several strategies to transductionally retarget adenovirus have emerged. Herein, we describe the biological hurdles as well as strategies utilized in adenovirus transductional targeting, covering the progress of both adapter-based and genetic manipulation-based targeting. Additionally, we discuss recent translation of these targeting strategies into a clinical setting.
MeSH term(s)	Adenoviridae/genetics ; Animals ; Capsid ; Disease Progression ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Models, Genetic ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/therapy ; Peptides/chemistry ; Signal Transduction ; Transduction, Genetic
Chemical Substances	Immunoglobulin Fab Fragments ; Peptides
Language	English
Publishing date	2012-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/B978-0-12-398342-8.00002-1
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Article ; Online: Development and Validation of Risk Scores for All-Cause Mortality for a Smartphone-Based "General Health Score" App: Prospective Cohort Study Using the UK Biobank.

Clift, Ashley K / Le Lannou, Erwann / Tighe, Christian P / Shah, Sachin S / Beatty, Matthew / Hyvärinen, Arsi / Lane, Stephen J / Strauss, Tamir / Dunn, Devin D / Lu, Jiahe / Aral, Mert / Vahdat, Dan / Ponzo, Sonia / Plans, David

JMIR mHealth and uHealth

2021 Volume 9, Issue 2, Page(s) e25655

Abstract: Background: Given the established links between an individual's behaviors and lifestyle factors and potentially adverse health outcomes, univariate or simple multivariate health metrics and scores have been developed to quantify general health at a ... ...

Abstract	Background: Given the established links between an individual's behaviors and lifestyle factors and potentially adverse health outcomes, univariate or simple multivariate health metrics and scores have been developed to quantify general health at a given point in time and estimate risk of negative future outcomes. However, these health metrics may be challenging for widespread use and are unlikely to be successful at capturing the broader determinants of health in the general population. Hence, there is a need for a multidimensional yet widely employable and accessible way to obtain a comprehensive health metric. Objective: The objective of the study was to develop and validate a novel, easily interpretable, points-based health score ("C-Score") derived from metrics measurable using smartphone components and iterations thereof that utilize statistical modeling and machine learning (ML) approaches. Methods: A literature review was conducted to identify relevant predictor variables for inclusion in the first iteration of a points-based model. This was followed by a prospective cohort study in a UK Biobank population for the purposes of validating the C-Score and developing and comparatively validating variations of the score using statistical and ML models to assess the balance between expediency and ease of interpretability and model complexity. Primary and secondary outcome measures were discrimination of a points-based score for all-cause mortality within 10 years (Harrell c-statistic) and discrimination and calibration of Cox proportional hazards models and ML models that incorporate C-Score values (or raw data inputs) and other predictors to predict the risk of all-cause mortality within 10 years. Results: The study cohort comprised 420,560 individuals. During a cohort follow-up of 4,526,452 person-years, there were 16,188 deaths from any cause (3.85%). The points-based model had good discrimination (c-statistic=0.66). There was a 31% relative reduction in risk of all-cause mortality per decile of increasing C-Score (hazard ratio of 0.69, 95% CI 0.663-0.675). A Cox model integrating age and C-Score had improved discrimination (8 percentage points; c-statistic=0.74) and good calibration. ML approaches did not offer improved discrimination over statistical modeling. Conclusions: The novel health metric ("C-Score") has good predictive capabilities for all-cause mortality within 10 years. Embedding the C-Score within a smartphone app may represent a useful tool for democratized, individualized health risk prediction. A simple Cox model using C-Score and age balances parsimony and accuracy of risk predictions and could be used to produce absolute risk estimations for app users.
MeSH term(s)	Biological Specimen Banks ; Cohort Studies ; Humans ; Mobile Applications ; Prospective Studies ; Risk Factors ; Smartphone ; United Kingdom/epidemiology
Language	English
Publishing date	2021-02-16
Publishing country	Canada
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2719220-9
ISSN	2291-5222 ; 2291-5222
ISSN (online)	2291-5222
ISSN	2291-5222
DOI	10.2196/25655
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Article ; Online: Systemic and intravesical adoptive cell therapy of tumor-reactive T cells can decrease bladder tumor growth in vivo.

Bunch, Brittany L / Morse, Jennifer / Asby, Sarah / Blauvelt, Jamie / Aydin, Ahmet M / Innamarato, Patrick / Hajiran, Ali / Beatty, Matthew / Poch, Michael / Pilon-Thomas, Shari

Journal for immunotherapy of cancer

2021 Volume 8, Issue 2

Abstract: Background: The therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment ... ...

Abstract	Background: The therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment responses and duration of responses are still less than expected. Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has potential to treat bladder cancer, as previously demonstrated by successful expansion of tumor reactive T cells from human bladder tumors. Methods: A model system using OT-I T cells and an ovalbumin expressing MB49 tumor cell line (MB49OVA) was developed to study ACT in bladder cancer. Systemic ACT-treated mice were given T cells intravenously after lymphodepleting chemotherapy and followed by interleukin (IL)-2 administration. Intravesical ACT treated mice were given T cells directly into the bladder, without chemotherapy or IL-2. TILs were isolated from MB49 orthotopic tumors and expanded ex vivo in IL-2. Immune cell infiltrates were analyzed by flow cytometry. T cell infiltration was studied using a CXCR3 blocking antibody. Results: Systemic ACT-treated mice had a decrease in tumor growth, increase in T cell infiltration and long-term immune protection compared with control-treated mice. OT-I T cells delivered intravesically were able to control tumor growth without lymphodepleting chemotherapy or IL-2 in MB49OVA orthotopic tumors. Intravesical delivery of TIL expanded from MB49 tumors was also able to decrease tumor growth in mice with MB49 orthotopic tumors. Blocking CXCR3 on OT-I T cells prior to intravesical delivery decreased T cell infiltration into the tumor and prevented the control of tumor growth. Conclusions: This study demonstrates how TIL therapy can be used in treating different stages of bladder cancer.
Language	English
Publishing date	2021-05-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-001673
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Article ; Online: SARS-CoV-2 antibody response duration and neutralization following natural infection.

Dukes, Christopher W / Rossetti, Renata Am / Hensel, Jonathan A / Snedal, Sebastian / Cubitt, Christopher L / Schell, Michael J / Abrahamsen, Martha / Isaacs-Soriano, Kimberly / Kennedy, Kayoko / Mangual, Leslie N / Whiting, Junmin / Martinez-Brockhus, Veronica / Islam, Jessica Y / Rathwell, Julie / Beatty, Matthew / Hall, Amy M / Abate-Daga, Daniel / Giuliano, Anna R / Pilon-Thomas, Shari

Journal of clinical virology plus

2023 Volume 3, Issue 3

Abstract: Background: The role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) neutralizing antibody response from natural infection and vaccination, and the potential determinants of this response are poorly understood. Characterizing this ... ...

Abstract	Background: The role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) neutralizing antibody response from natural infection and vaccination, and the potential determinants of this response are poorly understood. Characterizing this antibody response and the factors associated with neutralization can help inform future prevention efforts and improve clinical outcomes in those infected. Objectives: The goals of this study were to prospectively evaluate SARS-CoV-2 antibody levels and the neutralizing antibody responses among naturally infected adults and to determine demographic and behavioral factors independently associated with these responses. Methods: Serum was collected from seropositive individuals at baseline, four-weeks, and three-months following their first study visit to be evaluated for antibody levels. Detection of neutralizing antibodies was performed at baseline. Participant demographic and behavioral information was collected via web questionnaire prior to their first visit. Results: At baseline, higher antibody levels were associated with better neutralization capacity, with 83% of participants having detectable neutralizing antibodies. We found an age-dependent effect on antibody level and neutralization capacity with participants over 65 years having significantly higher levels. Ethnicity, heart disease, autoimmune disease, and COVID symptoms were associated with higher antibody levels, but not with increased neutralization capacity. Work environment during the pandemic correlated with increased neutralization capacity, while kidney or liver disease and traveling out of state after February 2020 correlated with decreased neutralization capacity, however neither correlated with antibody levels. Conclusions: Our data show that natural infection by SARS-CoV-2 can induce a humoral response reflected by high antibody levels and neutralization capacity.
Language	English
Publishing date	2023-07-01
Publishing country	England
Document type	Journal Article
ISSN	2667-0380
ISSN (online)	2667-0380
DOI	10.1016/j.jcvp.2023.100158
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Article: L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor.

Jardim-Perassi, Bruna Victorasso / Irrera, Pietro / Abrahams, Dominique / Estrella, Veronica C / Ordway, Bryce / Byrne, Samantha R / Ojeda, Andrew A / Whelan, Christopher J / Kim, Jongphil / Beatty, Matthew S / Damgaci-Erturk, Sultan / Longo, Dario Livio / Gaspar, Kim J / Siegers, Gabrielle M / Centeno, Barbara A / Lau, Justin Y C / Ibrahim-Hashim, Arig / Pilon-Thomas, Shari A / Gillies, Robert J

bioRxiv : the preprint server for biology

2023

Abstract	Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds CEACAM6, a cell surface protein highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.
Language	English
Publishing date	2023-08-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.28.555194
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