Inhibition of insulin-like growth factors increases production of CXCL9/10 by macrophages and fibroblasts and facilitates CD8 cytotoxic T cell recruitment to pancreatic tumours.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of assays and preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8 cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8 T cell recruitment and trafficking towards the PDAC tumour.

Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12.

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad oncolytic activity and IL-12 transgene expression.

Trajectory Inspection: A Method for Iterative Clinician-Driven Design of Reinforcement Learning Studies.

Reinforcement learning (RL) has the potential to significantly improve clinical decision making. However, treatment policies learned via RL from observational data are sensitive to subtle choices in study design. We highlight a simple approach, trajectory inspection, to bring clinicians into an iterative design process for model-based RL studies.

Distinct Biomarker Profiles and TCR Sequence Diversity Characterize the Response to PD-L1 Blockade in a Mouse Melanoma Model.

Only a subset of patients responds to immune checkpoint blockade (ICB) in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgf;Cdk4 genetically engineered mouse (GEM) model to evaluate the efficacy of an anti-mouse PD-L1 antibody similar to the anti-human PD-L1 antibodies durvalumab and atezolizumab.

HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells.

We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2 and PD-L1 cells.

[Effect of a mobile room air filter on the aerosol burden in surgical examination rooms against the background of the COVID-19 pandemic].

Due to the airborne transmission of the coronavirus disease 2019 (COVID 19) via aerosols or microdroplets, this study investigated the effect of a mobile air filter system in a surgical examination room. The use of the air filter system led to a significant reduction of aerosols in the room. Therefore the use of a high efficiency air filtration device, in examination rooms with poor ventilation, e.

Activity of murine surrogate antibodies for durvalumab and tremelimumab lacking effector function and the ability to deplete regulatory T cells in mouse models of cancer.

Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function.

A decision algorithm to promote outpatient antimicrobial stewardship for uncomplicated urinary tract infection.

Antibiotic resistance is a major cause of treatment failure and leads to increased use of broad-spectrum agents, which begets further resistance. This vicious cycle is epitomized by uncomplicated urinary tract infection (UTI), which affects one in two women during their life and is associated with increasing antibiotic resistance and high rates of prescription for broad-spectrum second-line agents. To address this, we developed machine learning models to predict antibiotic susceptibility using electronic health record data and built a decision algorithm for recommending the narrowest possible antibiotic to which a specimen is susceptible.

Predicting human health from biofluid-based metabolomics using machine learning.

Biofluid-based metabolomics has the potential to provide highly accurate, minimally invasive diagnostics. Metabolomics studies using mass spectrometry typically reduce the high-dimensional data to only a small number of statistically significant features, that are often chemically identified-where each feature corresponds to a mass-to-charge ratio, retention time, and intensity. This practice may remove a substantial amount of predictive signal.

Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of patients with advanced solid malignancies.

Background: The safety, efficacy, pharmacokinetics, and pharmacodynamics of the anti-programmed cell death-1 antibody MEDI0680 were evaluated in a phase I, multicenter, dose-escalation study in advanced solid malignancies.

Methods: MEDI0680 was administered intravenously once every 2 weeks (Q2W) or once every 3 weeks at 0.1, 0.

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells.

MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential.

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is part of a system of signals involved in controlling T-cell activation. Targeting and agonizing GITR in mice promotes antitumor immunity by enhancing the function of effector T cells and inhibiting regulatory T cells. Here, we describe MEDI1873, a novel hexameric human GITR agonist comprising an IgG1 Fc domain, a coronin 1A trimerization domain and the human GITRL extracellular domain (ECD).

A Novel Murine GITR Ligand Fusion Protein Induces Antitumor Activity as a Monotherapy That Is Further Enhanced in Combination with an OX40 Agonist.

To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy. The EC value of the mGITRL-FP was compared with an anti-GITR antibody in an agonistic cell-based reporter assay. We assessed the impact of dose, schedule, and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model.

DACT2 silencing by promoter CpG methylation disrupts its regulation of epithelial-to-mesenchymal transition and cytoskeleton reorganization in breast cancer cells.

Wnt signaling plays an important role in breast carcinogenesis. DAPPER2 (DACT2) functions as an inhibitor of canonical Wnt signaling and plays distinct roles in different cell contexts, with its role in breast tumorigenesis unclear. We investigated DACT2 expression in breast cancer cell lines and primary tumors, as well as its functions and molecular mechanisms.

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas.

Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers.

Novel endoscopic sacroiliac screw removal technique: reduction of intraoperative radiation exposure.

Objective: We report in the following on our technique of endoscopic sacroiliacal screw removal as a new extra-articular endoscopic method in soft tissue surgery, aimed at the reduction of radiation exposure for both the patient and the surgical teams. Patients who underwent endoscopic implant removal from the dorsal pelvic ring (Group A) were retrospectively compared with a control group, in which the screws were removed via the conventional approach (Group B). The parameters of interest were the extent of x-ray exposure in seconds and surgical duration in minutes as well as approach related peri- and postoperative complications.

Periprosthetic joint infection--effect on quality of life.

Purpose: Relatively little is known about the extent to which periprosthetic joint infections (PJI) affect the patient's long-term quality of life (QoL). Our study aim was to assess the effect of a periprosthetic infection on our patients' QoL.

Methods: We collected data retrospectively of patients who had undergone surgery in our institution between 2006 and 2011.

Effect of 2 different thoracolumbar orthoses on the stability of the spine during various body movements.

Study Design: Biomechanical volunteer study.

Objective: To quantify the stabilizing effect of 2 different semirigid thoracolumbar orthoses during various body movements.

Summary Of Background Data: Various spinal diseases need to be treated by immobilization.

DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer.

Introduction: Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in breast tumorigenesis remains unclear.

Methods: We examined DACT1 expression in breast cancer cell lines and primary tumors with semiquantitative or quantitative RT-PCR and immunochemistry, and further evaluated the promoter methylation of DACT1 with methylation-specific PCR (MSP).

Effects of three-dimensional navigation on intraoperative management and early postoperative outcome after open reduction and internal fixation of displaced acetabular fractures.

Background: This study was conducted to evaluate whether intraoperative procedure and/or early postoperative results after open reduction and internal fixation (ORIF) of displaced acetabulum fractures are influenced by the use of a three-dimensional (3D) image intensifier in combination with a navigation system.

Methods: From January 2004 until December 2008, all patients with acetabular fractures were followed prospectively. From January 2004 until October 2006, all operations were performed under fluoroscopic control using a conventional two-dimensional image intensifier.

The CEA/CD3-bispecific antibody MEDI-565 (MT111) binds a nonlinear epitope in the full-length but not a short splice variant of CEA.

MEDI-565 (also known as MT111) is a bispecific T-cell engager (BiTE®) antibody in development for the treatment of patients with cancers expressing carcinoembryonic antigen (CEA). MEDI-565 binds CEA on cancer cells and CD3 on T cells to induce T-cell mediated killing of cancer cells. To understand the molecular basis of human CEA recognition by MEDI-565 and how polymorphisms and spliced forms of CEA may affect MEDI-565 activity, we mapped the epitope of MEDI-565 on CEA using mutagenesis and homology modeling approaches.

The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.

Background: Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear.

Internal fixation of dorsally comminuted fractures of the distal part of the radius: a biomechanical analysis of volar plate and intramedullary nail fracture stability.

Introduction: The purpose of the present study was to carry out biomechanical testing of "new generation" volar plates and an intramedullary nail.

Methods: Four volar locking plates (Column Plate, VariAx distal radius, 2.4 mm-LCP and 3.

The effect of intramedullary bone endoscopy on the endosteal blood supply in long bones. An experimental study in sheep.

This study investigated whether the Intramedullary Bone Endoscopy (IBE) procedure within the cavity of an intact long bone will interfere with the local endosteal blood supply. In a sheep model, 10 animals underwent the IBE procedure with complete perioperative anaesthesiology monitoring. After the femora were harvested, histological analysis was performed to examine destruction of the endosteum and consecutive reduction in perfusion.