Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure.

Optimization of the highly potent and selective, yet metabolically unstable and poorly soluble hRXFP1 agonist AZ7976 led to the identification of the clinical candidate, AZD5462. Assessment of RXFP1-dependent cell signaling demonstrated that AZD5462 activates a highly similar panel of downstream pathways as relaxin H2 but does not modulate relaxin H2-mediated cAMP second messenger responsiveness. The therapeutic potential of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model.

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists.

Relaxin H2 is a clinically relevant peptide agonist for relaxin family peptide receptor 1 (RXFP1), but a combination of this hormone's short plasma half-life and the need for injectable delivery limits its therapeutic potential. We sought to overcome these limitations through the development of a potent small molecule (SM) RXFP1 agonist. Although two large SM HTS campaigns failed in identifying suitable hit series, we uncovered novel chemical space starting from the only known SM RXFP1 agonist series, represented by ML290.

Microwave and Antenna Systems in Medical Applications.

The non-ionizing nature of microwave radiation and the low cost of microwave electronics offer innovative solutions for medical diagnosis, treatment, and health monitoring [...

A wearable microwave instrument can detect and monitor traumatic abdominal injuries in a porcine model.

Abdominal injury is a frequent cause of death for trauma patients, and early recognition is essential to limit fatalities. There is a need for a wearable sensor system for prehospital settings that can detect and monitor bleeding in the abdomen (hemoperitoneum). This study evaluates the potential for microwave technology to fill that gap.

Discrete Dipole Approximation-Based Microwave Tomography for Fast Breast Cancer Imaging.

This paper describes a fast microwave tomography reconstruction algorithm based on the two-dimensional discrete dipole approximation. Synthetic data from a finite-element based solver and experimental data from a microwave imaging system are used to reconstruct images and to validate the algorithm. The microwave measurement system consists of 16 monopole antennas immersed in a tank filled with lossy coupling liquid and a vector network analyzer.

Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip.

Antisense oligonucleotides (ASOs) are a promising therapeutic modality. However, failure to predict acute kidney injury induced by SPC5001 ASO observed in a clinical trial suggests the need for additional preclinical models to complement the preceding animal toxicity studies. To explore the utility of in vitro systems in this space, we evaluated the induction of nephrotoxicity and kidney injury biomarkers by SPC5001 in human renal proximal tubule epithelial cells (HRPTEC), cultured in 2D, and in a recently developed kidney proximal tubule-on-a-chip.

Expansion of the Nodal-Adjoint Method for Simple and Efficient Computation of the 2D Tomographic Imaging Jacobian Matrix.

This paper focuses on the construction of the Jacobian matrix required in tomographic reconstruction algorithms. In microwave tomography, computing the forward solutions during the iterative reconstruction process impacts the accuracy and computational efficiency. Towards this end, we have applied the discrete dipole approximation for the forward solutions with significant time savings.

A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization-Dependent Cisplatin Toxicity.

Drug-induced kidney injury is a major clinical problem and causes drug attrition in the pharmaceutical industry. To better predict drug-induced kidney injury, kidney in vitro cultures with enhanced physiologic relevance are developed. To mimic the proximal tubule, the main site of adverse drug reactions in the kidney, human-derived renal proximal tubule epithelial cells (HRPTECs) were injected in one of the channels of dual-channel Nortis chips and perfused for 7 days.

Investigation of an Ultra Wideband Noise Sensor for Health Monitoring.

Quick on-scene assessment and early intervention is the key to reduce the mortality of stroke and trauma patients, and it is highly desirable to develop ambulance-based diagnostic and monitoring devices in order to provide additional support to the medical personnel. We developed a compact and low cost ultra wideband noise sensor for medical diagnostics and vital sign monitoring in pre-hospital settings. In this work, we demonstrated the functionality of the sensor for respiration and heartbeat monitoring.

Hyperthermia Treatment Planning Including Convective Flow in Cerebrospinal Fluid for Brain Tumour Hyperthermia Treatment Using a Novel Dedicated Paediatric Brain Applicator.

Hyperthermia therapy (40-44 °C) is a promising option to increase efficacy of radiotherapy/chemotherapy for brain tumours, in particular paediatric brain tumours. The Chalmers Hyperthermia Helmet is developed for this purpose. Hyperthermia treatment planning is required for treatment optimisation, but current planning systems do not involve a physically correct model of cerebrospinal fluid (CSF).

Airborne contamination and surgical site infection: Could a thirty-year-old idea help solve the problem?

Surgical site infection (SSI) is a most serious postoperative complication, associated with increased morbidity and mortality, as well as extended therapy and elevated healthcare costs. In open clean surgery, e.g.

3D Simulations of Intracerebral Hemorrhage Detection Using Broadband Microwave Technology.

Early, preferably prehospital, detection of intracranial bleeding after trauma or stroke would dramatically improve the acute care of these large patient groups. In this paper, we use simulated microwave transmission data to investigate the performance of a machine learning classification algorithm based on subspace distances for the detection of intracranial bleeding. A computational model, consisting of realistic human head models of patients with bleeding, as well as healthy subjects, was inserted in an antenna array model.

Application of Two-Dimensional Discrete Dipole Approximation in Simulating Electric Field of a Microwave Breast Imaging System.

The two-dimensional electric field distribution of the microwave imaging system is numerically simulated for a simplified breast tumour model. The proposed two-dimensional discrete dipole approximation (DDA) has the potential to improve computational speed compared to other numerical methods while retaining comparable accuracy. We have modeled the field distributions in COMSOL Multiphysics as baseline results to benchmark the DDA simulations.

A Discrete Dipole Approximation Solver Based on the COCG-FFT Algorithm and Its Application to Microwave Breast Imaging.

We introduce the discrete dipole approximation (DDA) for efficiently calculating the two-dimensional electric field distribution for our microwave tomographic breast imaging system. For iterative inverse problems such as microwave tomography, the forward field computation is the time limiting step. In this paper, the two-dimensional algorithm is derived and formulated such that the iterative conjugate orthogonal conjugate gradient (COCG) method can be used for efficiently solving the forward problem.

Effects of the Plastic of the Realistic GeePS-L2S-Breast Phantom.

A breast phantom developed at the Supelec Institute was interrogated to study its suitability for microwave tomography measurements. A microwave measurement system based on 16 monopole antennas and a vector network analyzer was used to study how the S-parameters are influenced by insertion of the phantom. The phantom is a 3D-printed structure consisting of plastic shells that can be filled with tissue mimicking liquids.

A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery.

Drug-induced nephrotoxicity is a major concern in the clinic and hampers the use of available treatments as well as the development of innovative medicines. It is typically discovered late during drug development, which reflects a lack of in vitro nephrotoxicity assays available that can be employed readily in early drug discovery, to identify and hence steer away from the risk. Here, we report the development of a high content screening assay in ciPTEC-OAT1, a proximal tubular cell line that expresses several relevant renal transporters, using five fluorescent dyes to quantify cell health parameters.

Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized.

Clinical Evaluation of a Microwave-Based Device for Detection of Traumatic Intracranial Hemorrhage.

Traumatic brain injury (TBI) is the leading cause of death and disability among young persons. A key to improve outcome for patients with TBI is to reduce the time from injury to definitive care by achieving high triage accuracy. Microwave technology (MWT) allows for a portable device to be used in the pre-hospital setting for detection of intracranial hematomas at the scene of injury, thereby enhancing early triage and allowing for more adequate early care.

Compact self-grounded Bow-Tie antenna design for an UWB phased-array hyperthermia applicator.

Using UWB hyperthermia systems has the potential to improve the heat delivery to deep seated tumours. In this paper, we present a novel self-grounded Bow-Tie antenna design which is to serve as the basis element in a phased-array applicator. The UWB operation in the frequency range of 0.

Asymmetric cationic liposomes designed for heat-activated association with cells.

Improved anticancer drugs and drug carriers are needed in combination therapies, such as hyperthermia-assisted chemotherapy. Liposomal drug carriers with advanced functions are attractive candidates for targeted accumulation and drug release in response to heat stimulus. We report on the design of liposomes with a heat-activated surface function.

Advances in Predictive Toxicology for Discovery Safety through High Content Screening.

High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile.

Microwave technology for detecting traumatic intracranial bleedings: tests on phantom of subdural hematoma and numerical simulations.

Traumatic brain injury is the leading cause of death and severe disability for young people and a major public health problem for elderly. Many patients with intracranial bleeding are treated too late, because they initially show no symptoms of severe injury and are not transported to a trauma center. There is a need for a method to detect intracranial bleedings in the prehospital setting.

In vitro toxicity of cationic micelles and liposomes in cultured human hepatocyte (HepG2) and lung epithelial (A549) cell lines.

The aim of this study was to compare the effects of cationic micelle and liposome drug delivery systems on liver and lung cells in a toxicological in vitro screening model, with observations on cytotoxicity and genotoxicity. A screening battery was established for assessment of a broad range of parameters related to adverse effects. Clear concentration response effects were observed related to impairment of mitochondrial function, membrane integrity and oxidative stress markers, but no effect was observed on genotoxicity.

MRBrainS Challenge: Online Evaluation Framework for Brain Image Segmentation in 3T MRI Scans.

Many methods have been proposed for tissue segmentation in brain MRI scans. The multitude of methods proposed complicates the choice of one method above others. We have therefore established the MRBrainS online evaluation framework for evaluating (semi)automatic algorithms that segment gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) on 3T brain MRI scans of elderly subjects (65-80 y).

Heat-activated liposome targeting to streptavidin-coated surfaces.

There is a great need of improved anticancer drugs and corresponding drug carriers. In particular, liposomal drug carriers with heat-activated release and targeting functions are being developed for combined hyperthermia and chemotherapy treatments of tumors. The aim of this study is to demonstrate the heat-activation of liposome targeting to biotinylated surfaces, in model experiments where streptavidin is used as a pretargeting protein.