Key Features Relevant to Select Antigens and TCR From the MHC-Mismatched Repertoire to Treat Cancer.

Adoptive transfer of T cells transgenic for tumor-reactive T-cell receptors (TCR) is an attractive immunotherapeutic approach. However, clinical translation is so far limited due to challenges in the identification of suitable target antigens as well as TCRs that are concurrent safe and efficient. Definition of key characteristics relevant for effective and specific tumor rejection is essential to improve current TCR-based adoptive T-cell immunotherapies.

Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers.

Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8 T central memory cells (CD8 T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity.

T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target.

Cancer immunotherapy has proven high efficacy in treating diverse cancer entities by immune checkpoint modulation and adoptive T-cell transfer. However, patterns of treatment response differ substantially from conventional therapies, and reliable surrogate markers are missing for early detection of responders versus non-responders. Current imaging techniques using F-fluorodeoxyglucose-positron-emmission-tomograpy (F-FDG-PET) cannot discriminate, at early treatment times, between tumor progression and inflammation.

Galectin-3 Targeting in Thyroid Orthotopic Tumors Opens New Ways to Characterize Thyroid Cancer.

Preoperative characterization of thyroid nodules is challenging since thyroid scintigraphy fails to distinguish between benign and malignant lesions. Galectin-3 (gal-3) is expressed in well-differentiated and in undifferentiated thyroid cancer types but not in normal thyrocytes and benign thyroid lesions. Herein, we aimed to validate gal-3 targeting as a specific method to detect non-radioiodine-avid thyroid cancer in thyroid orthotopic tumor models.

User Evaluation Indicates High Quality of the Surveillance Outbreak Response Management and Analysis System (SORMAS) After Field Deployment in Nigeria in 2015 and 2018.

During the West African Ebola virus disease outbreak in 2014-15, health agencies had severe challenges with case notification and contact tracing. To overcome these, we developed the Surveillance, Outbreak Response Management and Analysis System (SORMAS). The objective of this study was to measure perceived quality of SORMAS and its change over time.

Effects on Clinical Outcomes of a 5-Year Surgical Safety Checklist Implementation Experience: A Large-scale Population-Based Difference-in-Differences Study.

The adoption of a surgical checklist is strongly recommended worldwide as an effective practice to improve patient safety; however, several studies have reported mixed results and a number of issues are still unresolved. The main objective of this study was to explore the impact of the first 5-year period of a surgical checklist-based intervention in a large regional health care system in Italy (4 500 000 inhabitants). We conducted a retrospective longitudinal study on 1 166 424 patients who underwent surgery in 48 public hospitals between 2006 and 2014.

In-depth Characterization of a TCR-specific Tracer for Sensitive Detection of Tumor-directed Transgenic T Cells by Immuno-PET.

A number of different technologies have been developed to monitor the distribution of gene-modified T cells used in immunotherapy. Nevertheless, in-depth characterization of novel approaches with respect to sensitivity and clinical applicability are so far missing. We have previously described a novel method to track engineered human T cells in tumors using Zr-Df-aTCRmu-F(ab') targeting the murinized part of the TCR beta domain (TCRmu) of a transgenic TCR.

Immuno-PET Imaging of Engineered Human T Cells in Tumors.

Sensitive in vivo imaging technologies applicable to the clinical setting are still lacking for adoptive T-cell-based immunotherapies, an important gap to fill if mechanisms of tumor rejection or escape are to be understood. Here, we propose a highly sensitive imaging technology to track human TCR-transgenic T cells in vivo by directly targeting the murinized constant TCR beta domain (TCRmu) with a zirconium-89 ((89)Zr)-labeled anti-TCRmu-F(ab')2 fragment. Binding of the labeled or unlabeled F(ab')2 fragment did not impair functionality of transgenic T cells in vitro and in vivo Using a murine xenograft model of human myeloid sarcoma, we monitored by Immuno-PET imaging human central memory T cells (TCM), which were transgenic for a myeloid peroxidase (MPO)-specific TCR.

Optimized Lentiviral Transduction Protocols by Use of a Poloxamer Enhancer, Spinoculation, and scFv-Antibody Fusions to VSV-G.

Lentiviral vectors (LV) are widely used to successfully transduce cells for research and clinical applications. This optimized LV infection protocol includes a nontoxic poloxamer-based adjuvant combined with antibody-retargeted lentiviral particles. The novel poloxamer P338 demonstrates superior characteristics for enhancing lentiviral transduction over the best-in-class polybrene-assisted transduction.

Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T cells specifically inhibit Ewing sarcoma growth in vitro and in vivo.

The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES.

Effectiveness of a community-based positive prevention intervention for people living with HIV who are not receiving antiretroviral treatment: a prospective cohort study.

Background: We report effectiveness of an HIV-prevention intervention delivered by community health workers (CHWs) in Mombasa, Kenya, to PLHIV who have not initiated or who have discontinued ART-an often difficult-to-reach population because they fall outside the ambit of health care and prevention services.

Methods: A 2-arm cohort study assessed a structured risk-reduction intervention involving at least 4 one-to-one counseling sessions and personalized support. The control group received standard prevention services.

Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity.

Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4(+) T cells have been described to be highly important for tumour elimination although TCR derived from CD4(+) T cells with anti-tumour reactivity have been only rarely described.

Poloxamer synperonic F108 improves cellular transduction with lentiviral vectors.

Background: Although lentiviral transduction methods are widely used, their broader application is dependent upon the optimization of lentiviral transduction efficiency for a broad range of cell types. In the present study, we focus on the evaluation of two chemical classes with respect to their ability to increase lentiviral transduction without cytotoxicity.

Methods: We compared the activity of adjuvants that are already used for lentivirus delivery with that of novel adjuvants selected on the basis of their chemical and physical characteristics.

A large outbreak of influenza B-associated benign acute childhood myositis in Germany, 2007/2008.

Background: Benign acute childhood myositis (BACM) is a rare syndrome associated with various viral infections. Bilateral calve pain may lead to inability to walk. During winter 2007/2008, we investigated a nationwide outbreak of influenza-associated BACM (IA-BACM) to identify etiologic (sub)type, describe the course of disease, and explore how well the syndrome is known among physicians.

A human model of epithelial to mesenchymal transition to monitor drug efficacy in hepatocellular carcinoma progression.

The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation.

Using pharmacy data to identify those with chronic conditions in Emilia Romagna, Italy.

Background And Objectives: Automated pharmacy data have been used to develop a measure of chronic disease status in the general population. The objectives of this project were to refine and apply a model of chronic disease identification using Italian automated pharmacy data; to describe how this model may identify patterns of morbidity in Emilia Romagna, a large Italian region; and to compare estimated prevalence rates using pharmacy data with those available from a 2000 Emilia Romagna disease surveillance study.

Methods: Using the Chronic Disease Score, a list of chronic conditions related to the consumption of drugs under the Italian pharmaceutical dispensing system was created.