Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria.

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice.

Pharmaceutical compounding and storage of faricimab in a syringe for intravitreal injection do not impair stability and bi-specific binding properties.

Background: Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.

Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells.

Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9.

New insertable cardiac monitors show high diagnostic yield and good safety profile in real-world clinical practice: results from the international prospective observational SMART Registry.

Aims: Insertable cardiac monitors (ICMs) are indicated for long-term monitoring of unexplained syncope or palpitations, and for detection of bradycardia, ventricular tachycardia, and/or atrial fibrillation (AF). The aim of our study was to evaluate the safety and clinical value associated with a new generation ICM (Confirm Rx™, Abbott, Illinois, USA), featuring a new remote monitoring system based on smartphone patient applications.

Methods And Results: The SMART Registry is an international prospective observational study.

A Silicone Oil-Free Syringe Tailored for Intravitreal Injection of Biologics.

Intravitreal injections (IVI) of biologics targeting vascular endothelial growth factor (anti-VEGF) led to a paradigm shift in the management and prognosis of prevalent retinal conditions. Yet, IVI are typically performed with syringes that are neither developed nor approved for this purpose. Notably, syringes lubricated with silicone oil (SiO) are extensively used despite multiple reports showing that such syringes can cause deposition of SiO droplets in the vitreous body and patient discomfort.

Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life.

Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells.

Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn and .

Albumin has a serum half-life of 3 weeks in humans. This feature can be used to improve the pharmacokinetics of shorter-lived biologics. For instance, an albumin-binding domain (ABD) can be used to recruit albumin.

The neonatal Fc receptor in mucosal immune regulation.

The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism.

Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy.

The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non-coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome-wide structural genomic variants (SVs) and their association with gene expression in the human heart.

Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure.

Background: Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls.

Methods: Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands.

[Analysis of mortality and its predictors in patients with contralateral hip fracture after femoral neck fracture].

Introduction: There is a high mortality with not well understood risk factors after the second hip fracture.

Aim: Analysis of the 30- and 365-day mortality and its risk factors in patients with contralateral hip fracture.

Method: Patients with contralateral hip fracture between 01 Jan 2000 and 31 Dec 2008 were identified among those who suffered their primary hip fracture in Hungary in 2000.

The Role of Quality Control in Targeted Next-generation Sequencing Library Preparation.

Next-generation sequencing (NGS) is getting routinely used in the diagnosis of hereditary diseases, such as human cardiomyopathies. Hence, it is of utter importance to secure high quality sequencing data, enabling the identification of disease-relevant mutations or the conclusion of negative test results. During the process of sample preparation, each protocol for target enrichment library preparation has its own requirements for quality control (QC); however, there is little evidence on the actual impact of these guidelines on resulting data quality.

Wintertime surgery increases the risk of conversion to hip arthroplasty after internal fixation of femoral neck fracture.

Unlabelled: The study demonstrates that wintertime surgeries are associated with impaired fracture healing and increases the risk of conversion to hip arthroplasty after osteosynthesis of femoral neck fracture. Furthermore, the results raise the possibility of association between seasonal changes in vitamin D levels and impaired fracture healing of femoral neck fracture.

Introduction: Although the changes of vitamin D level and calcitropic hormones influencing bone metabolism are seasonal, the effect of seasons on hip fracture healing is unknown.

Factors influencing pacemaker generator longevity: results from the complete automatic pacing threshold utilization recorded in the CAPTURE Trial.

Objectives: The CAPTURE study evaluated the accuracy of automated atrial and right ventricular (RV) threshold algorithms.

Background: Modern pacemakers include many added features designed to improve the ease of patient follow-up, as well as algorithms to reduce pacing outputs and/or reduce the atrial or ventricular pacing percentages, thus improving longevity.

Methods: Automated atrial and RV threshold measurements were assessed versus manual measurements at 6 months.

Positioning of the wrist for scaphoid radiography.

Purpose: The purpose of this cadaver study was to determine the ideal position of the wrist for scaphoid radiography.

Materials And Methods: Four cadaver wrists were rotated around their longitudinal axis in 15 degrees increments and exposures were taken. Seven postero-anterior images were taken as well.

Biomechanics of the membranous flexor tendon sheath: the role of Grayson's ligaments.

Background: The biomechanical integrity of the tendon sheath of the fingers has a significant effect on the success of flexor tendon surgery. As nonweightbearing elements, the membranous parts of the sheath have received little attention, and their contribution to sheath movement is still obscure. The authors presumed that Grayson's ligaments, which have been described as force-transmitting elements, might play a role in the biomechanics of the membranous flexor tendon sheath.

Modified carpal box technique in the diagnosis of suspected scaphoid fractures.

Purpose: To establish and test the clinical efficacy of a new diagnostic algorithm with the extensive utilization of modified carpal box radiography (mX-CB) in the detection of scaphoid fractures.

Material And Methods: Initial and early follow-up radiographic evaluation of 146 suspected scaphoid fractures were carried out by mX-CB. Patients with unconfirmed diagnosis were referred to CT.

Transcatheter closure of residual atrial septal defect after cardiac transplantation.

A 55-year-old male patient experienced 2 acute neurologic events 3 weeks after orthotopic cardiac transplantation. Transesophageal echocardiography demonstrated a patent foramen ovale in the native portion of the interatrial septum with bidirectional shunting by Doppler and microbubble contrast. The defect was closed successfully with a CardioSeal transcatheter septal closure device.

Biomechanics of the human flexor tendon sheath investigated by tenography.

Tenography has been performed on eight detached fingers and two intact hands of cadavers. Bulging and overlapping of synovial pockets between the ligamentous structures during flexion, their flattening during extension and the continuous change in expansion of the proximal cul de sac suggests a possible mixing mechanism for the synovial fluid. During flexion and extension a physiological joint-type bowstringing of the flexor tendons was observed at the PIP and DIP joints.

Complications of endoscopic sinus surgery: analysis of 2108 patients--incidence and prevention.

The incidence of complications of endoscopic sinus surgery (ESS) in a combined experience with 2108 total patients is compared to complications in 11 other series of patients (2583 total) who underwent ESS and 6 series of patients (2110 total) who underwent traditional endonasal sinus surgery. The incidence of major perioperative complications was 0.85%, with cerebrospinal fluid (CSF) leak being the most common.

Endoscopic sinus surgery: 4-year follow-up on the first 100 patients.

Endoscopic sinus surgery has been reported to be successful, but lack of a standardized classification system hampers comparison of results between studies, and long-term results of surgery have not been reported in a series of consecutive patients. The results of our first 100 endoscopic sinus surgery procedures, reported previously after an average 9-month follow-up, were reviewed with the application of a new classification scheme and in light of a longer (4-year) follow-up. Surgery was successful in all patients whose sinus symptoms resulted from anatomical variations or suppurative infection, but failed in some patients with hyperplastic disease or polyps.