scholarly journals Bioanalytical Challenges due to Prior Checkpoint Inhibitor Exposure: Interference and Mitigation in Drug Concentration and Immunogenicity Assays

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Andrew F. Dengler ◽  
Rachel Weiss ◽  
Tiffany Truong ◽  
Susan C. Irvin ◽  
Nidhi Gadhia ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Biologic Therapy ◽  
Positive Response ◽  
Checkpoint Inhibitor ◽  
Previous Treatment ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Target Capture ◽  
Immunogenicity Assays ◽  
The Impact

AbstractMonoclonal antibodies (mAbs) are a leading class of biotherapeutics. In oncology, patients often fail on early lines of biologic therapy to a specific target. Some patients may then enroll in a new clinical trial with a mAb specific for the same target. Therefore, immunoassays designed to quantify the current mAb therapy or assess immunogenicity to the drug may be susceptible to cross-reactivity or interference with residual prior biologics. The impact of two approved anti-PD-1 mAbs, pembrolizumab and nivolumab, was tested in several immunoassays for cemiplimab, another approved anti-PD-1 mAb. The methods included a target-capture drug concentration assay, a bridging anti-drug antibody (ADA) assay and a competitive ligand-binding neutralizing antibody (NAb) assay. We also tested bioanalytical strategies to mitigate cross-reactivity or interference in these assays from other anti-PD-1 biologics. Both pembrolizumab and nivolumab cross-reacted in the cemiplimab drug concentration assay. This was mitigated by addition of antibodies specific to pembrolizumab or nivolumab. ADA specific for pembrolizumab and nivolumab did not interfere in the cemiplimab ADA assay. However, pembrolizumab and nivolumab generated a false-positive response in a target-capture NAb assay. Our results demonstrate that similar exogenous pre-existing anti-PD-1 mAbs (biotherapeutics) such as pembrolizumab and nivolumab are detected and accurately quantified in the cemiplimab drug concentration assay. However, once steady state is achieved for the new therapy, prior biologics would likely not be detected. Cross-reactivity and interference in immunoassays from previous treatment with class-specific biotherapeutic(s) pose significant bioanalytical challenges, especially in immuno-oncology. Graphical abstract

scholarly journals 73. Improving Cephalosporin Utilization in the Emergency Department for Penicillin Allergic Patients

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S54-S55
Author(s):  
Arun Mattappallil ◽  
Debra Chew ◽  
Alyssa M Magan ◽  
Maryam Zaeem ◽  
Jaclyn Scalgione ◽  
...  
Keyword(s):  
Emergency Department ◽  
Previous Treatment ◽  
Patient Characteristics ◽  
Empiric Therapy ◽  
Cross Reactivity ◽  
Antibiotic Prescribing ◽  
Education Intervention ◽  
Prescribing Practices ◽  
Significant Difference ◽  
The Impact

Abstract Background Penicillin (PCN) allergies impact acute-care antibiotic prescribing practices, limit the use of first-line antibiotic agents and are associated with poor patient outcomes. Cephalosporins (CPN) are inconsistently prescribed to patients reporting PCN allergies despite reported low allergy cross-reactivity. The purpose of this study is to assess the impact of an education intervention on prescribing practices for CPN use in PCN allergic patients in the emergency department (ED). Methods This is a retrospective study evaluating all PCN allergic patients receiving a CPN in the ED from 07/01/2018 to 07/31/2019. The education intervention (consisting of circulating a locally developed guideline directing ED physicians to optimal CPN use given a designated PCN allergy along with lectures on suitable use of the guideline in recurring in-person sessions) occurred during 01/2019. We compared patient characteristics, CPN use, PCN allergy notation and adverse reactions between the “pre” (07/01/2018 – 12/31/2018) and “post” (02/01/2019 – 07/31/2019) groups. Antibiotic Allergy Cross Reactivity/Sensitivity Chart Results A total of 123 patients are included (53 “pre” vs. 70 “post”). Patient characteristics are similar (Table 1). 31 (12.1% vs. 13%, P = 0.5) received previous treatment with CPN with the most common choices being cefazolin (14, 11.3%), ceftriaxone (18, 14.6%) and cefepime (9, 7.3%). 14 (11.3%) received pretreatment prior to CPN use. CPN given to patients in the ED include cefazolin (6 vs. 7), cephalexin (4 vs. 3), ceftriaxone (32 vs. 45) and cefepime (11 vs. 11). Common indications for CPN use include “empiric therapy” (38, 30.8%), “UTI” (17, 13.8%) and “pelvic region infection” (15, 12.1%). CPN administration routes include oral (10, 8.1%), intravenous (91, 73.9%) and intramuscular (22, 17.8%). 80 patients (65%) received a single dose of a CPN (37 vs. 43). No significant difference is noted in CPN use between groups (P = 0.1). Increased PCN allergy notation on tolerance to CPN after CPN use is noted, but later use of CPN use did not increase after notation (Table 2). No adverse events occurred from any CPN use. Conclusion Education interventions on CPN use in PCN allergic patients require support with other strategies and tools. This intervention provides groundwork to initiate efforts to further improve CPN use in PCN allergic patients. Disclosures All Authors: No reported disclosures

scholarly journals Coronavirus Pseudotypes for All Circulating Human Coronaviruses for Quantification of Cross-Neutralizing Antibody Responses

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1579
Author(s):  
Alexander Thomas Sampson ◽  
Jonathan Heeney ◽  
Diego Cantoni ◽  
Matteo Ferrari ◽  
Maria Suau Sans ◽  
...  
Keyword(s):  
High Throughput ◽  
Natural Infection ◽  
Research Question ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Surface Proteins ◽  
Target Cells ◽  
Huh7 Cells ◽  
Human Coronaviruses ◽  
The Impact

The novel coronavirus SARS-CoV-2 is the seventh identified human coronavirus. Understanding the extent of pre-existing immunity induced by seropositivity to endemic seasonal coronaviruses and the impact of cross-reactivity on COVID-19 disease progression remains a key research question in immunity to SARS-CoV-2 and the immunopathology of COVID-2019 disease. This paper describes a panel of lentiviral pseudotypes bearing the spike (S) proteins for each of the seven human coronaviruses (HCoVs), generated under similar conditions optimized for high titre production allowing a high-throughput investigation of antibody neutralization breadth. Optimal production conditions and most readily available permissive target cell lines were determined for spike-mediated entry by each HCoV pseudotype: SARS-CoV-1, SARS-CoV-2 and HCoV-NL63 best transduced HEK293T/17 cells transfected with ACE2 and TMPRSS2, HCoV-229E and MERS-CoV preferentially entered HUH7 cells, and CHO cells were most permissive for the seasonal betacoronavirus HCoV-HKU1. Entry of ACE2 using pseudotypes was enhanced by ACE2 and TMPRSS2 expression in target cells, whilst TMPRSS2 transfection rendered HEK293T/17 cells permissive for HCoV-HKU1 and HCoV-OC43 entry. Additionally, pseudotype viruses were produced bearing additional coronavirus surface proteins, including the SARS-CoV-2 Envelope (E) and Membrane (M) proteins and HCoV-OC43/HCoV-HKU1 Haemagglutinin-Esterase (HE) proteins. This panel of lentiviral pseudotypes provides a safe, rapidly quantifiable and high-throughput tool for serological comparison of pan-coronavirus neutralizing responses; this can be used to elucidate antibody dynamics against individual coronaviruses and the effects of antibody cross-reactivity on clinical outcome following natural infection or vaccination.

Агрономическая эффективность промышленной (голландской) технологии возделывания картофеля

2018 ◽  
Author(s):  
C. Coy ◽  
A.V. Shuravilin ◽  
O.A. Zakharova
Keyword(s):  
Heavy Metals ◽  
Regression Analysis ◽  
Positive Response ◽  
Growth Yield ◽  
Correlation And Regression Analysis ◽  
Yield And Quality ◽  
Quality Of Products ◽  
High Degree ◽  
The Impact

Приведены результаты исследований по изучению влияния промышленной технологии возделывания картофеля на развитие, урожайность и качество продукции. Выявлена положительная реакция растений на подкормку K2SO4 в период посадки. Корреляционно-регрессионный анализ урожайности и качества клубней выявил высокую степень достоверности результатов опыта. Содержание нитратов и тяжелых металлов в клубнях было ниже допустимых величин.The results of studies on the impact of industrial technology of potato cultivation on growth, yield and quality of products. There was a positive response of plants to fertilizer K2SO4 in the period of planting. Correlation and regression analysis of yield and quality of tubers revealed a high degree of reliability of the results of experience. The contents of nitrates and heavy metals in tubers was below the permissible values.

scholarly journals Time-to-Treatment in Oral Cancer: Causes and Implications for Survival

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1321
Author(s):  
Constanza Saka-Herrán ◽  
Enric Jané-Salas ◽  
Antoni Mari-Roig ◽  
Albert Estrugo-Devesa ◽  
José López-López
Keyword(s):  
Oral Cancer ◽  
Previous Treatment ◽  
Diagnostic Procedures ◽  
Original Data ◽  
Primary Treatment ◽  
Medical Attention ◽  
Time Interval ◽  
Pre Treatment ◽  
The Impact ◽  
Lack Of Knowledge

The purpose of this review was to identify and describe the causes that influence the time-intervals in the pathway of diagnosis and treatment of oral cancer and to assess its impact on prognosis and survival. The review was structured according to the recommendations of the Aarhus statement, considering original data from individual studies and systematic reviews that reported outcomes related to the patient, diagnostic and pre-treatment intervals. The patient interval is the major contributor to the total time-interval. Unawareness of signs and/or symptoms, denial and lack of knowledge about oral cancer are the major contributors to the process of seeking medical attention. The diagnostic interval is influenced by tumor factors, delays in referral due to higher number of consultations and previous treatment with different medicines or dental procedures and by professional factors such as experience and lack of knowledge related to the disease and diagnostic procedures. Patients with advanced stage disease, primary treatment with radiotherapy, treatment at an academic facility and transitions in care are associated with prolonged pre-treatment intervals. An emerging body of evidence supports the impact of prolonged pre-treatment and treatment intervals with poorer survival from oral cancer.

scholarly journals Outcomes Related to Percutaneous Nephrostomies (PCN) in Malignancy-Associated Ureteric Obstruction: A Systematic Review of the Literature

2021 ◽  
Vol 10 (11) ◽  
pp. 2354
Author(s):  
Francesca J. New ◽  
Sally J. Deverill ◽  
Bhaskar K. Somani
Keyword(s):  
Quality Of Life ◽  
Advanced Cancer ◽  
Previous Treatment ◽  
Cochrane Library ◽  
Cancer Type ◽  
Ureteric Obstruction ◽  
Survival Times ◽  
Advanced Malignancies ◽  
The Impact

Background: Malignant ureteric obstruction occurs in a variety of cancers and has been typically associated with a poor prognosis. Percutaneous nephrostomy (PCN) can potentially help increase patient longevity by establishing urinary drainage and treating renal failure. Our aim was to look at the outcomes of PCN in patients with advanced cancer and the impact on the patients’ lifespan and quality of life. Materials and Methods: A literature review was carried out for articles from 2000 to 2020 on PCN in patients with advanced malignancies, using MEDLINE, EMBASE, Scopus, CINAHL, Cochrane Library, clinicaltrials.gov, and Google Scholar. All English-language articles reporting on a minimum of 20 patients who underwent PCN for malignancy-associated ureteric obstruction were included. Results: A total of 21 articles (1674 patients) met the inclusion criteria with a mean of 60.2 years (range: 21–102 years). PCN was performed for ureteric obstruction secondary to urological malignancies (n = −633, 37.8%), gynaecological malignancies (n = 437, 26.1%), colorectal and GI malignancies (n = 216, 12.9%), and other specified malignancies (n = 205, 12.2%). The reported mean survival times varied from 2 to 8.5 months post PCN insertion, with an average survival time of 5.6 months, which depended on the cancer type, stage, and previous treatment. Conclusions: Patients with advanced malignancies who need PCN tend to have a survival rate under 12 months and spend a large proportion of this time in the hospital. Although the advent of newer chemotherapy and immunotherapy options has changed the landscape of managing advanced cancer, decisions on nephrostomy must be balanced with their survival and quality of life, which must be discussed with the patient.

scholarly journals A Whole Virion Vaccine for COVID-19 Produced via a Novel Inactivation Method and Preliminary Demonstration of Efficacy in an Animal Challenge Model

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 340
Author(s):  
Izabela K Ragan ◽  
Lindsay M Hartson ◽  
Taru S Dutt ◽  
Andres Obregon-Henao ◽  
Rachel M Maison ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Rapid Development ◽  
Neutralizing Antibody ◽  
Emerging Diseases ◽  
Effective Vaccine ◽  
Preliminary Evaluation ◽  
Sequencing Data ◽  
Post Challenge ◽  
Vaccine Candidates ◽  
The Impact

The COVID-19 pandemic has generated intense interest in the rapid development and evaluation of vaccine candidates for this disease and other emerging diseases. Several novel methods for preparing vaccine candidates are currently undergoing clinical evaluation in response to the urgent need to prevent the spread of COVID-19. In many cases, these methods rely on new approaches for vaccine production and immune stimulation. We report on the use of a novel method (SolaVAX) for production of an inactivated vaccine candidate and the testing of that candidate in a hamster animal model for its ability to prevent infection upon challenge with SARS-CoV-2 virus. The studies employed in this work included an evaluation of the levels of neutralizing antibody produced post-vaccination, levels of specific antibody sub-types to RBD and spike protein that were generated, evaluation of viral shedding post-challenge, flow cytometric and single cell sequencing data on cellular fractions and histopathological evaluation of tissues post-challenge. The results from this preliminary evaluation provide insight into the immunological responses occurring as a result of vaccination with the proposed vaccine candidate and the impact that adjuvant formulations, specifically developed to promote Th1 type immune responses, have on vaccine efficacy and protection against infection following challenge with live SARS-CoV-2. This data may have utility in the development of effective vaccine candidates broadly. Furthermore, the results of this preliminary evaluation suggest that preparation of a whole virion vaccine for COVID-19 using this specific photochemical method may have potential utility in the preparation of one such vaccine candidate.

scholarly journals Towards Quantitative and Standardized Serological and Neutralization Assays for COVID-19

2021 ◽  
Vol 22 (5) ◽  
pp. 2723
Author(s):  
Linhua Tian ◽  
Elzafir B. Elsheikh ◽  
Paul N. Patrone ◽  
Anthony J. Kearsley ◽  
Adolfas K. Gaigalas ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Epidemiologic Studies ◽  
Cross Reactivity ◽  
Receptor Binding Domain ◽  
Proof Of Concept ◽  
Reference Standard ◽  
Improve Measurement ◽  
Antibody Titers

Quantitative and robust serology assays are critical measurements underpinning global COVID-19 response to diagnostic, surveillance, and vaccine development. Here, we report a proof-of-concept approach for the development of quantitative, multiplexed flow cytometry-based serological and neutralization assays. The serology assays test the IgG and IgM against both the full-length spike antigens and the receptor binding domain (RBD) of the spike antigen. Benchmarking against an RBD-specific SARS-CoV IgG reference standard, the anti-SARS-CoV-2 RBD antibody titer was quantified in the range of 37.6 µg/mL to 31.0 ng/mL. The quantitative assays are highly specific with no correlative cross-reactivity with the spike proteins of MERS, SARS1, OC43 and HKU1 viruses. We further demonstrated good correlation between anti-RBD antibody titers and neutralizing antibody titers. The suite of serology and neutralization assays help to improve measurement confidence and are complementary and foundational for clinical and epidemiologic studies.

scholarly journals Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations

2021 ◽  
Author(s):  
Billy J Gardner ◽  
A. Marm Kilpatrick
Keyword(s):  
Vaccine Coverage ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Reproductive Number ◽  
Vaccine Protection ◽  
Contact Rates ◽  
Previous Infection ◽  
Antibody Titers ◽  
Protection Against Infection ◽  
The Impact

Background Vaccines have greatly reduced the impact of COVID-19 globally. Unfortunately, evidence indicates that immunity wanes following vaccination, especially with the Delta variant (B.1.617.2). Protection against severe disease and death remain high, but protection against milder disease and infection have dropped significantly. A third booster dose of two-dose vaccines has been approved in several countries to individuals at higher risk of severe disease to protect those individuals, but the benefit to boosting immunity in younger healthy individuals and the effects on transmission are less clear. Methods Here we use relationships between neutralizing antibody titers and vaccine protection against infection and transmission, combined with data on waning and boosting of neutralizing antibody titers to examine the impact of a third dose of the Pfizer vaccine on infection and transmission and its impact on the pathogen effective reproductive number Rt. Findings Eight months of waning reduced protection of the Pfizer vaccine against all infections from 80.0% (95% CI: 77% to 83%) to 60.4% (95% CI: 53% to 67%); a third dose (which increased neutralizing antibody titers 25.9- fold relative to levels after 8 months of waning) increased protection to 87.2% (95% CI: 83% to 91%). Increased protection against infection and transmission from third doses reduced Rt by 21% to 66% depending on vaccine coverage and previous infection and reduced Rt below 1 when vaccination coverage was high or contact rates were well below pre-pandemic levels. Interpretation A third dose of the Pfizer vaccine could reduce transmission of SARS-CoV-2, which would reduce infection in unvaccinated individuals and breakthrough infections in vaccinated individuals. While vaccination of unvaccinated individuals, especially in developing countries, would be more effective for reducing disease than providing a third dose to vaccinated individuals, the benefit of a third dose in reducing transmission is sizeable and increases with vaccine coverage and contact rates among individuals.

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