Product-specific Differences Research Articles

CAR-T Phenotype and Efficacy Is Impaired By Lymphoma-Associated CD39 + T Cells

Background: Autologous chimeric antigen receptor (CAR) T-cell therapy is standard of care for patients with relapsed or refractory Large B cell Lymphoma (R/R LBCL). Each patient's CAR T product is unique, and the patient-specific determinants of CAR T-cell quality are poorly understood. CD39 is an ectonucleosidase that participates in the conversion of ATP and ADP and is upregulated in cancer. On T-cells, CD39 is expressed on CD4+ Tregs and on exhausted CD8+ T-cells that are prone to apoptosis. Methods: This is a retrospective single-center cohort study (N=72) of patients who received CD19 CAR T-cell therapy for LBCL (axi-cel n=52; tisa-cel n=20). Leukapheresis material was obtained from n=51 patients and flow cytometry was performed to phenotype CD4+ and CD8+ stem-central memory, memory, and effector T-cell subsets (using CCR7 and CD45RO), and for immune checkpoint expression (PD-1, LAG3, TIGIT, and CD39). 10x multiome (ATAC and RNA) single cell sequencing (scRNA-seq) was performed on n=8 leukapheresis products for deeper characterization. Serum metabolomics was performed on paired samples from n=21 patients. 10X Genomics Chromium scRNAseq was also performed on n=57 CAR T-cell infusion products, including n=36 with paired leukapheresis material previously phenotyped by flow cytometry. In vitro CAR T-cells were manufactured from starting patient T-cells and analyzed for CAR T-cell phenotype and function. Results: In the leukapheresis material of patients that did not achieve long-term remission after CAR T-cell therapy, and in those with high tumor burden, we found higher numbers of CD4+CD39+ and CD8+CD39+ T-cells ( Figs. 1 and 2). 10X multiome sequencing confirmed that CD39+ T-cells exhibit characteristics of exhaustion. Recent platinum-based chemotherapy did not affect CD39+ T-cell levels. In n=21 patients with paired serum analyzed by metabolomics, high CD8+CD39+ T-cells associated with reduced metabolites in the inosine-hypoxanthine pathway, which are downstream of the ectonucleotidase function of CD39 (inosine; P=0.006; hypoxanthine P=0.07). Increased numbers of CD39+ T-cells in the starting leukapheresis material translated into manufactured CAR T-cells having less favorable product characteristics, including higher CD39 expression and fewer memory cells in both paired patient samples and in experiments of in vitro CAR T-cell manufacturing. ScRNA-seq of the infused CAR T-cell product revealed differential gene signatures, both globally and in association with response, between axi-cel and tisa-cel CAR T-cell products, highlighting the profound product-specific differences. Nonetheless, both products were adversely affected by high CD39+ T-cells in the leukapheresis material used for manufacture. Conclusions: CD39+ T-cells, found in patients with high lymphoma tumor burden and an unfavourable immunometabolic environment, associate with poor CAR T-cell quality and adverse patient outcomes in R/R LBCL. Strategies are needed to improve patient T-cell quality prior to leukapheresis and/or improve CAR T-cell manufacturing from patients with high levels of exhausted CD39+ T-cells. Figure 1: Progression-free survival (PFS) stratified by leukapheresis CD8+CD39+ T-cells in the leukapheresis product. Blue - below cohort median percentage of CD8+T-cells that are CD39+ (low); Red - above median percentage of CD8+T-cells that are CD39+ (high). P-value by Log-Rank test. Overall survival (not shown) P-value 0.01. Figure 2: Proportion of CD8+CD39+ T-cells found in patients with low or high baseline metabolic tumor volume (MTV) based on a previously established cutoff (Dean et al. Blood Adv. 2020). MTV was measured on the pre-CAR T-cell PET/CT. P-value by T-test. MDJ, XY, and RMA are co-first authors with equal contribution.

Lactoferrin-based food supplements trigger toxin production of enteropathogenic Bacillus cereus.

Lactoferrin is an iron-binding glycoprotein exhibiting antibacterial, antiviral, antifungal, antiparasitic, antiinflammatory, antianaemic and anticarcinogenic properties. While its inhibitory effects against bacterial pathogens are well investigated, little is known about its influence on the production and/or mode of action of bacterial toxins. Thus, the present study aimed to determine the impact of food supplements based on bovine lactoferrin on Bacillus cereus enterotoxin production. First, strain-specific growth inhibition of three representative isolates was observed in minimal medium with 1 or 10 mg/mL of a lactoferrin-based food supplement, designated as product no. 1. Growth inhibition did not result from iron deficiency. In contrast to that, all three strains showed increased amounts of enterotoxin component NheB in the supernatant, which corresponded with cytotoxicity. Moreover, lactoferrin product no. 1 enhanced NheB production of further 20 out of 28 B. cereus and Bacillus thuringiensis strains. These findings again suggested a strain-specific response toward lactoferrin. Product-specific differences also became apparent comparing the influence of further six products on highly responsive strain INRA C3. Highest toxin titres were detected after exposure to products no. 7, 1 and 2, containing no ingredients except pure bovine lactoferrin. INRA C3 was also used to determine the transcriptional response toward lactoferrin exposure via RNA sequencing. As control, iron-free medium was also included, which resulted in down-regulation of eight genes, mainly involved in amino acid metabolism, and in up-regulation of 52 genes, mainly involved in iron transport, uptake and utilization. In contrast to that, 153 genes were down-regulated in the presence of lactoferrin, including genes involved in flagellar assembly, motility, chemotaxis and sporulation as well as genes encoding regulatory proteins, transporters, heat and cold shock proteins and virulence factors. Furthermore, 125 genes were up-regulated in the presence of lactoferrin, comprising genes involved in sporulation and germination, nutrient uptake, iron transport and utilization, and resistance. In summary, lactoferrin exposure of B. cereus strain-specifically triggers an extensive transcriptional response that considerably exceeds the response toward iron deficiency and, despite down-regulation of various genes belonging to the PlcR-regulon, ultimately leads to an increased level of secreted enterotoxin by a mechanism, which has yet to be elucidated.

Product Choice Affects Risk of False-Positive Hepatitis B Virus Serology During Immunoglobulin Replacement Therapy.

Hepatitis B virus (HBV) core antigen antibodies passively transferred from immunoglobulin products used for replacement or immunomodulation may lead to unnecessary antiviral treatment for patients who are also starting immunosuppressive treatment. We have systematically assessed the contents of 93 commercial immunoglobulin batches and show that there are consistent product-specific differences in the levels of HBV core antigen antibodies and that choice of immunoglobulin product may have an impact on false-positivity rates.

The Impact of Product-Dependent Policyholder Risk Sensitivities in Life Insurance: Insights from Experiments and Model-Based Simulation Analyses

Abstract In contrast to previous work, this paper studies the product-dependent risk sensitivities of policyholders toward the reported safety levels of a life insurer in a long-term multi-period setting. With this aim, we first conduct two choice-based conjoint analyses using a German survey panel to investigate the effect of an insurer’s reported default probability on individuals’ willingness to pay for annuities and term life insurances. Our experimental results suggest that individuals (sharply) reduce their willingness to pay for probabilistic life insurance products, with (strong) product-specific differences. In light of these observations, the paper then revisits the impact of these differing risk sensitivities on a life insurer’s risk situation in a simulation study based on an asset-liability model with a specific focus on a life insurer offering annuities and term life insurances. The results reveal the potentially strong impact of such product-dependent risk sensitivities on risk-reducing portfolio compositions. One main driver is the deviation between risk sensitivities depending on the respective product (annuities vs. term life).

Physicochemical characterization and functionality comparison of Humira®(adalimumab), Remicade®(infliximab) and Simponi Aria® (golimumab)

FDA-approved anti-TNFα biopharmaceuticals are successful in treating a range of autoimmune diseases. However, not all anti-TNFα products are identical in their patient outcomes, suggesting that there may be product-specific differences stemming from protein structural differences, doses and routes of administration. In this work, we focus only on structural and functional differences across three full-length anti-TNFα mAbs (Humira®, Remicade®, and Simponi Aria®) to better understand the implications of such differences on the products’ efficacy. For structural characterization, we quantified N-glycans using mass spectrometry and fluorescence labeling. From these studies, we observed that Remicade® had the highest percent of afucosylated glycans (15.5 ± 1.3 %) and the largest number of unique glycans, 28. While Humira® had the fewest unique glycans, 15, and 11.4 ± 0.8 % of afucosylated, high-mannose glycans. For the functional studies we tested TNFα binding via ELISA, FcγRIIIa binding via AlphaLISA and effector function using an ADCC bioreporter assay. Humira® had a significantly lower EC50 (1.9 ± 0.1 pM) for ELISA and IC50 (10.5 ± 1.1 nM) for AlphaLISA, suggesting that Humira® has higher TNFα and FcγRIIIa binding affinity than Remicade® and Simponi Aria®. Humira® was also the most potent in the bioreporter assay with an EC50 value of 0.55 ± 0.03 nM compared to Remicade® (0.64 ± 0.04 nM) and Simponi Aria® (0.67 ± 0.03 nM). This comparison is significant as it highlights functional differences between mAbs with shared mechanisms of action when examined in a single laboratory and under one set of conditions.

Pesticide residues in food and drinking water from the consumerʼs perspective: The relevance of maximum residue levels and product-specific differences

One disadvantage of pesticide use in agriculture are the residues that remain in food and drinking water. In addition to analyzing consumer intolerance to pesticide residues for various food groups (fruit/vegetables, cereals/cereal products, and potatoes) according to the degree of product processing, the present study investigates consumer knowledge and attitudes regarding the EU's regulations on maximum residue levels (comparatively) for both food and drinking water. A survey of 1,195 German consumers was conducted by means of an online questionnaire. Different statistical analysis methods were used for the data analysis. The results show that EU regulations on maximum residue levels were known to 62.7% of respondents regarding food, and to 60.9% of the respondents regarding drinking water. Both pesticide residues in general and those exceeding the maximum residue levels were considered rather problematic. There was an ambivalent attitude towards the maximum residue levels. The attitudinal differences between food and drinking water were small to marginal. The analyses of pesticide residue intolerance with respect to degree of food processing showed that the highest intolerance was found with unprocessed/minimally processed products, followed by food products with higher processing degrees. Overall, these findings underline the consumer-sided general importance of the residue issue and argue for more sustainable agricultural systems characterized by pesticide use reduction or avoidance.

Cemented conical stems can be removed more easily than cylindrical stems, regardless of cone angle in revision knee arthroplasty.

According to literature, more than 30% of revised knee arthroplasties will require at least one re-revision. Practical experience has shown that there are considerable product-specific differences in the explantability of cemented long-stem prostheses. In the registers of successful implants, stem geometry varies considerably between the manufacturers. However, comparative data on explantability of the respective stems are missing. Objective of the present study was to identify a correlation between the geometry of a smooth cemented long stem and the necessary explantation energy required until failure of the implant-cement interface occurs. Eight cemented stems with different conical profile angles (0°-3°) were explanted in a reproducible biomechanical setup each six times to evaluate the correlation between the stem design and the required explantation energy. The average explantation energy was highest in the case of the cylindrical stem, at 18.1 ± 3.6J. At a cone angle of 0.25°, it was just 12.1 ± 2.1J (p < 0.001) and dropped beyond 0.5° to an average of 5.7 ± 1.8J(p<0.001). Between 0.5° and 3°, no significant difference in the required extraction energy was observed. Whereas smooth conical stems can mostly be removed easily, an early decision in favour of osteotomy or fenestration can be taken in the case of cylindrical cemented stems.

Adhesive Durability Inside the Root Canal Using Self-adhesive Resin Cements for Luting Fiber Posts.

The aim of the study was to investigate the effects of various self-adhesive resin cements on the push-out bond strengths and nanoleakage expression at the luting interfaces of fiber posts immediately and after one year of aging. One hundred forty-four extracted human anterior teeth were endodontically treated. After post space preparation, fiber posts were luted using five commercially available self-adhesive resin (SAR) cements and a core build-up material applied with a self-etch adhesive (BF: Bifix SE/Rebilda Post, VOCO; CSA: Clearfil SA Cement/Rely X Fiber Post, 3M ESPE; RX: RelyX Unicem 2/Rely X Fiber Post, 3M ESPE; SPC: Speed Cem/FRC Postec, Ivoclar Vivadent; SMC: Smart Cem/X Post, Dentsply; RB: Rebilda DC-Futurabond/Rebilda Post; n=22). For each group, half of the specimens were subjected to thermocycling (TC) (5°C-55°C, 10,000 cycles) and stored humid for one year at 37°C. Push-out bond strength data of six slices (thickness 1 mm) per root and nanoleakage expression of representative specimens were evaluated after 24 hours (baseline) and after TC and storage for one year (aging), respectively. Bond strength differed significantly among resin cements (p<0.0005) and the location inside the root canal (p<0.0005), but not by aging (p=0.390; repeated-measures analysis of variance). SMC (14.6±5.8 MPa) and RX (14.1±6.8 MPa) revealed significantly higher bond strength compared to BF (10.6±5.4 MPa) and RB (10.0±4.6 MPa) but differed not significantly from SPC (12.8±4.8) MPa; CSA (6.1±4.6 MPa) revealed significantly lower bond strength compared to all other investigated materials (p<0.05; Tukey Honestly Significantly Different). Qualitative nanoleakage analysis revealed more silver deposits at the interface in all groups after aging. For CSA, a large amount of silver deposits inside the cement was also observed at baseline and after aging. Fiber post luting using SAR cements demonstrated reliable bond strengths. Product-specific differences and initial degradation effects could be demonstrated.

Asymmetric cost pass-through? Empirical evidence on the role of market power, search and menu costs

We estimate cost pass-through rates based on data for store-level retail prices and wholesale costs for up to 90 different brands of milk sold in 327 retail stores across Germany. The abundance of the data allows us to identify heterogeneity in pass-through across retailers and relate it to underlying explanatory factors such as retailer market power, measures of consumer search and menu costs. Results from a threshold-error-correction-process clearly provide empirical support for the ‘rockets and feathers’ phenomenon: prices increase more quickly than they decrease. In contrast to much of the existing literature, which explains the ‘rockets and feathers’ phenomenon as a result of retailers exercising market power, we find the opposite result: the degree of asymmetry in prices is negatively related to market power (decreases with the Lerner-Index). Our measure of (cross-product) search costs does not account for observable differences in asymmetric cost pass-through rates between products. The ‘rockets and feathers’ observation is better explained by product-specific differences in menu costs (‘mistake costs’) and costs associated with stock-outs which can lead to a loss of consumer goodwill.

Does shelf-labeling of organic foods increase sales? Results from a natural experiment

Can a simple point-of-purchase (POP) shelf-label increase sales of organic foods? We use a random-effects׳, random-coefficients׳ model, including a time adjustment variable, to test data from a natural experiment in a hypermarket in Gävle, Sweden. Our model incorporates both product specific heterogeneity in the effects of labeling and consumer adjustment to the labels over time. We find that the introduction of POP displays leads to an increase in sales of organic coffee and olive oil, but a reduction in sales of organic flour. All targeted products became less price-sensitive. The results reveal that product specific differences have to be accounted for, and in some cases consumers adjusted to labeling over time.

Pharmacodynamic Differences in the Two Generic Brands of Enoxaparin

Abstract 1251Several generic versions of enoxaparin have recently become available. While these generic versions of enoxaparin exhibit similar molecular profiles and comparable anti-Xa activities; product specific differences in global anticoagulant (APTT, Heptest and thrombin generation inhibition) have been reported. The purpose of this study was to compare a generic version of enoxaparin Sandoz from Argentina (Fibrinox lot 002) and from the US (enoxaparin lot 914786) in various in vitro whole blood and plasma based clotting tests. Despite comparable molecular profile and anti-Xa potency, product specific differences were noted between the products and the US generic enoxaparin showed a cumulatively stronger activity in most of the assays. To further test the pharmacodynamic profile of these products, individual groups of monkeys (n=4–8) were administered with each product at a 1 mg/kg SC and blood samples were collected for up to 28 hours. Clot based assays such as the APTT, Heptest, thrombin time, amidolytic anti-Xa and anti-IIa activities were carried out. In addition, tissue factor pathway inhibitor (TFPI) antigen, thrombin activatable fibrinolysis inhibitor (TAFI) activity and thrombin generation assays were also performed. Variable differences were noted in the clot based and amidolytic assays. Interestingly, the US generic product exhibited a lower release in the TFPI antigen whereas in the thrombin generation assays it produced a stronger inhibition of thrombin in terms of the AUC. TAFI activity profile also showed wide variations. These differences were more prevalent during the 1–4 hour time period. No differences were noted at >6 hours. The hysterisis PK/PD plots revealed marked differences between the two products. These results indicate that the products for the same generic suppliers may exhibit variations according to market places. Moreover, these observations underscore the need for a more stringent pharmacodynamic profile to demonstrate product equivalence. Disclosures:No relevant conflicts of interest to declare.

Development of a Quality Index Method (QIM) for Maatjes Herring Stored in Air and Under Modified Atmosphere

ABSTRACT The aim of the study was to develop a Quality Index Method (QIM) scheme for maatjes herring stored in air and under a modified atmosphere at 4°C and 10°C. The attributes included in this new scheme are: appearance of skin side and bone side, color of the blood, odor (rancidity and other), taste (rancidity and other), aftertaste and texture. The QIM scheme developed proved to be potentially useful in evaluating and defining the quality of maatjes herring stored in air and under modified atmosphere. Since natural variations and processing of maatjes herring limit the use of the QIM scheme, the scheme must be specified taking the product-specific differences and storage conditions more in detail into account.

Free Competition and the Optimal Amount of Fraud

THIS paper explores the reasons for and determinants of the provision by a firm of false information to a consumer so as to induce purchases which would not be made if the consumer possessed full information about the qualities of his purchase. Market responses to potential for fraud are analyzed in detail. It is shown that fraud and related practices follow from significant costs both in the determination of quality of a particular good or service and in the effective vertical integration of seller and buyer through some exchange of property rights. Much of our discussion focuses on the key problem of the joint provision of diagnosis and services-such as the choice and execution of an automobile repair or taxicab route--but the model developed will be seen to have general applicability whenever the seller provides information which influences purchases, as through advertising or salesmen's promises. In the context of the repair problem, we explore the reasons for and the determinants of the provision of repair services in amounts greater than would be economically efficient, given the price of the services and their marginal product in terms of the service flow from the repaired commodity.' The possibility of this situation is suggested by the observation that in a considerable number of cases involving medical, automotive, and other repair services, contrary to the basic assumption of conventional demand theory, the consumer is unaware of the ability of the repair service to satisfy a given want.2