A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8(N)/(C)EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy

Explaining Satisfaction in Double Deviation Scenario's: The Effect of Anger and Distributive Justice

Purpose – research has shown that more than half of attempted recovery efforts only reinforce dissatisfaction, producing a “double deviation” effect. Surprisingly, these double deviation effects have received little attention in service marketing literature. To fill this gap, this paper aims to develop and empirically test a model of how customers form satisfaction judgments in double deviation scenarios. The paper seeks to propose that emotions have a distinct and separate influence from perceived justice in explaining satisfaction with failed recovery.design/methodology/approach – the paper employs the critical incident technique to obtain data from banking customers and apply latent variable path analysis to test the proposed model.findings – the results of the study support the model and highlight the important role of specific recovery-related emotions in double deviation contexts.research limitations/implications – future research should try to determine whether different specific negative emotions and/or the interactional and procedural components of justice affect post-recovery judgments in double deviation scenarios.practical implications – the results show that specific emotions such as anger play an important role in explaining satisfaction with service recovery. The paper proposes that in future, customer satisfaction surveys could include items measuring specific emotions. This could increase their efficiency as managerial tools.originality/value – to the authors' knowledge, this has been the first attempt to model the effect of specific emotions triggered by the service recovery on satisfaction with service recovery and to empirically test a model of satisfaction with service recovery in double deviation scenarios. Furthermore, this study is based on the analysis of real service failures and recovery strategies

Long-term follow-up of axillary recurrences after negative sentinel lymph node biopsy: effect on prognosis and survival.

Contains fulltext : 118739pub.pdf (publisher's version ) (Closed access) Contains fulltext : 118739pos.pdf (postprint version ) (Open Access)As axillary recurrence (AR) after a negative sentinel lymph node biopsy (SLNB) is rare, the prognosis of these patients is unknown. Since treatment paradigms for patients with breast cancer are shifting toward less axillary surgery, the number of ARs might increase. In this study, we evaluated primary and salvage treatment as well as long-term survival of patients diagnosed with an AR. A retrospective analysis of the cancer registry of 16 breast cancer units in the Netherlands was used to identify patients who developed an AR after a negative SLNB performed between 2002 and 2004. Using local hospital records we recorded primary patient-, tumor-, and treatment-characteristics, as well as salvage treatment. We identified 54 patients with an AR, median 30 months (range 3-79) after SLNB. Eighteen patients (33 %) were initially treated with breast conserving therapy, 15 of whom received external beam radiation therapy (EBRT). Thirty-three patients (61 %) did not receive adjuvant systemic treatment. In 45 of the 54 (83 %) patients, a salvage axillary lymph node dissection was performed showing a median of three positive nodes (range 1-24). Nine patients (17 %) were not treated surgically: three were treated with salvage EBRT and six with salvage systemic therapy only. At time of detection of the AR, a total of 7 patients (13 %) had proven distant metastases. After a median follow-up of 47 months (range 3-118), the 5-year "post-recurrence" distant metastasis free survival was 50 % and overall survival was 58 %. Significant negative predictors of survival were negative estrogen receptor (ER) status and receiving adjuvant chemotherapy at initial treatment. AR following a negative SLNB is associated with a 58 % 5-year OS. Prognostic factors are ER- primary tumor and receiving adjuvant chemotherapy as a part of initial treatment, reflecting an aggressive phenotype. Adequate regional and systemic salvage therapy constitute a chance for long-term survival after AR.01 juli 201

Recyclinggerechte Befestigungstechnik bei Bauteilen aus thermoplastischen Kunststoffen Abschlussbericht

Available from TIB Hannover: RA 2383(248) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEArbeitsgemeinschaft Industrieller Forschungsvereinigungen 'Otto von Guericke' e.V. (AIF), Koeln (Germany); Bundesministerium fuer Wirtschaft, Bonn (Germany)DEGerman

Binding of CML-Modified as Well as Heat-Glycated β-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity

Intake of dietary advanced glycation end products (AGEs) is associated with inflammation-related health problems. Nε-carboxymethyl lysine (CML) is one of the best characterised AGEs in processed food. AGEs have been described as ligands for receptors present on antigen presenting cells. However, changes in protein secondary and tertiary structure also induce binding to AGE receptors. We aimed to discriminate the role of different protein modifications in binding to AGE receptors. Therefore, β-lactoglobulin was chemically modified with glyoxylic acid to produce CML and compared to β-lactoglobulin glycated with lactose. Secondary structure was monitored with circular dichroism, while hydrophobicity and formation of β-sheet structures was measured with ANS-assay and ThT-assay, respectively. Aggregation was monitored using native-PAGE. Binding to sRAGE, CD36, and galectin-3 was measured using inhibition ELISA. Even though no changes in secondary structure were observed in all tested samples, binding to AGE receptors increased with CML concentration of CML-modified β-lactoglobulin. The negative charge of CML was a crucial determinant for the binding of protein bound CML, while binding of glycated BLG was determined by increasing hydrophobicity. This shows that sRAGE, galectin-3, and CD36 bind to protein bound CML and points out the role of negatively charged AGEs in binding to AGE receptors.</p

Differential Effects of Dry vs. Wet Heating of β-Lactoglobulin on Formation of sRAGE Binding Ligands and sIgE Epitope Recognition

<p>The effect of glycation and aggregation of thermally processed β-lactoglobulin (BLG) on binding to sRAGE and specific immunoglobulin E (sIgE) from cow milk allergic (CMA) patients were investigated. BLG was heated under dry conditions (water activity &lt; 0.7) and wet conditions (in phosphate buffer at pH 7.4) at low temperature (&lt;73 °C) and high temperatures (&gt;90 °C) in the presence or absence of the milk sugar lactose. Nε-(carboxymethyl)-l-lysine (CML) western blot and glycation staining were used to directly identify glycation structures on the protein fractions on SDS-PAGE. Western blot was used to specify sRAGE and sIgE binding fractions. sRAGE binding was highest under wet-heated BLG independent of the presence of the milk sugar lactose. Under wet heating, high-molecular-weight aggregates were most potent and did not require the presence of CML to generate sRAGE binding ligands. In the dry system, sRAGE binding was observed only in the presence of lactose. sIgE binding affinity showed large individual differences and revealed four binding profiles. Dependent on the individual, sIgE binding decreased or increased by wet heating independent of the presence of lactose. Dry heating required the presence of lactose to show increased binding to aggregates in most individuals. This study highlights an important role of heating condition-dependent protein aggregation and glycation in changing the immunogenicity and antigenicity of cow's milk BLG.</p