Comparison of β-1-3-D-Glucan and Mannan Biomarker Assays with Serological Tests for the Diagnosis of Candidemia.

Invasive candidiasis, including bloodstream infection (candidemia), encompasses the most severe forms of infection. Several species-specific and non-specific serological assays are commercially available to aid in diagnosis. This study compared the performance of five such biomarker assays.

A simplified method to correct saturation of arterial input function for cardiac magnetic resonance first-pass perfusion imaging: validation with simultaneously acquired PET.

Background: First-pass perfusion imaging in magnetic resonance imaging (MRI) is an established method to measure myocardial blood flow (MBF). An obstacle for accurate quantification of MBF is the saturation of blood pool signal intensity used for arterial input function (AIF). The objective of this project was to validate a new simplified method for AIF estimation obtained from single-bolus and single sequence perfusion measurements.

The E46K mutation modulates α-synuclein prion replication in transgenic mice.

In multiple system atrophy (MSA), the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the E46K mutation in α-synuclein causes familial Parkinson's disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that α-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80.

Predicting premature termination of exercise during Bruce protocol stress echocardiography.

Aims: Clinical guidelines recommend that the exercise protocol of a stress echocardiogram is selected to induce volitional exhaustion after a target duration of at least 8 minutes. While the Bruce protocol is very commonly used for clinical stress tests, it is known to be "steep", and many patients therefore fail to reach 8 minutes. We studied predictors of failure and developed a method for identifying patients not suitable for Bruce protocol which was accurate and yet simple enough to be used as a point-of-care decision support tool.

Fibroelastic Tissue Ring Causing ECMO Catheter Obstruction: An Unusual Complication of Avalon Elite Catheter Insertion.

The Avalon Elite catheter (Maquet Cardiopulmonary, Rastatt, Germany) is a bicaval catheter for single-site cannulation that can be used in the initiation of venovenous extracorporeal membrane oxygenation (ECMO) or as a transition from venoarterial ECMO. We report a unique complication of tissue obstructing the outflow aperture during insertion. ().

The fungal CCAAT-binding complex and HapX display highly variable but evolutionary conserved synergetic promoter-specific DNA recognition.

To sustain iron homeostasis, microorganisms have evolved fine-tuned mechanisms for uptake, storage and detoxification of the essential metal iron. In the human pathogen Aspergillus fumigatus, the fungal-specific bZIP-type transcription factor HapX coordinates adaption to both iron starvation and iron excess and is thereby crucial for virulence. Previous studies indicated that a HapX homodimer interacts with the CCAAT-binding complex (CBC) to cooperatively bind bipartite DNA motifs; however, the mode of HapX-DNA recognition had not been resolved.

Effect of Modulating FcRn Binding on Direct and Pretargeted Tumor Uptake of Full-length Antibodies.

Full-length antibodies lack ideal pharmacokinetic properties for rapid targeted imaging, prompting the pursuit of smaller peptides and fragments. Nevertheless, studying the disposition properties of antibody-based imaging agents can provide critical insight into the pharmacology of their therapeutic counterparts, particularly for those coupled with potent payloads. Here, we evaluate modulation of binding to the neonatal Fc receptor (FcRn) as a protein engineering-based pharmacologic strategy to minimize the overall blood pool background with directly labeled antibodies and undesirable systemic click reaction of radiolabeled tetrazine with circulating pretargeted -cyclooctene (TCO)-modified antibodies.

Antibody-Drug Conjugates Derived from Cytotoxic seco-CBI-Dimer Payloads Are Highly Efficacious in Xenograft Models and Form Protein Adducts In Vivo.

This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species.

The ribosomal maturation factor P from facilitates the ribosomal biogenesis by binding to the small ribosomal protein S12.

The ribosomal maturation factor P (RimP) is a highly conserved protein in bacteria and has been shown to be important in ribosomal assembly in Because of its central importance in bacterial metabolism, RimP represents a good potential target for drug design to combat human pathogens such as However, to date, the only RimP structure available is the NMR structure of the ortholog in another bacterial pathogen, Here, we report a 2.2 Å resolution crystal structure of MSMEG_2624, the RimP ortholog in the close relative , and using binding assays, we show that MSMEG_2624 interacts with the small ribosomal protein S12, also known as RpsL. Further analyses revealed that the conserved residues in the linker region between the N- and C-terminal domains of MSMEG_2624 are essential for binding to RpsL.

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging.

Antibody pretargeting is a promising strategy for improving molecular imaging, wherein the separation in time of antibody targeting and radiolabeling can lead to rapid attainment of high contrast, potentially increased sensitivity, and reduced patient radiation exposure. The inverse electron demand Diels-Alder 'click' reaction between trans-cyclooctene (TCO) conjugated antibodies and radiolabeled tetrazines presents an ideal platform for pretargeted imaging due to rapid reaction kinetics, bioorthogonality, and potential for optimization of both slow and fast clearing components. Herein, we evaluated a series of anti-human epidermal growth factor receptor 2 (HER2) pretargeting antibodies containing distinct molar ratios of site-specifically incorporated TCO.

Cardiac Positron Emission Tomography-Magnetic Resonance Imaging: Current Status and Future Directions.

Simultaneous acquisition positron emission tomography-magnetic resonance imaging (PET-MRI) has the ability to combine anatomic information derived from cardiac MRI with quantitative capabilities of cardiac PET and MRI and the promise of molecular imaging by specific PET tracers. This combination of cardiac PET and MRI delivers a robust and comprehensive clinical examination. It has the potential to assess various cardiovascular conditions, including assessment of myocardial ischemia, infarction, and function, as well as specific characterization of inflammatory and infiltrative heart diseases such as cardiac sarcoid and amyloid.

Stabilizing a Tubulysin Antibody-Drug Conjugate To Enable Activity Against Multidrug-Resistant Tumors.

The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody-drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity.

Cardiac Applications of PET/MR Imaging.

Simultaneous acquisition PET/MR imaging combines the anatomic capabilities of cardiac MR imaging with quantitative capabilities of both PET and MR imaging. Cardiac PET/MR imaging has the potential not only to assess cardiac tumors but also to provide thorough assessment of myocardial ischemia, infarction, and function and specific characterization of cardiomyopathies, such as cardiac sarcoid. In this article, the authors start with a discussion of the technical challenges specific to cardiovascular PET/MR imaging followed by a discussion of the use of PET/MR imaging in various cardiovascular conditions.

Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers.

A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC.

Disease-specific cardiovascular positron emission tomography/magnetic resonance imaging: a brief review of the current literature.

The hybrid positron emission tomography/magnetic resonance (PET/MR) is a new imaging tool that has garnered immense research interest for its potentials to assist clinical investigations. PET/MR combines the quantitative measurement of PET with dynamic functional and anatomic assessment of MR and can deliver a robust clinical examination. Currently, simultaneous cardiovascular PET/MR imaging remains in the pre-clinical research stage, and most institutions have not adopted a clinical PET/MR clinical imaging service.

A runaway sternal wire: A rare case and outcome of sternal wire intravascular embolization.

We present a case of a 56-year-old man with history of coronary artery disease and prior two coronary bypass surgeries, who presented with chronic chest pain and was found to have a fractured sternal wire that migrated through the right ventricle and embolized to the right lower pulmonary artery without evident hemodynamic consequences. The sternal wire migration process, in part due to patient's poor medical compliance, was captured on serial computed tomography scans over a period of several years. < Recognize potential sternotomy complications on imaging.

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells.

ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1.

The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96.

Evaluation of attenuation correction in cardiac PET using PET/MR.

Background: Simultaneous acquisition Positron emission tomography/magnetic resonance (PET/MR) is a new technology that has potential as a tool both in research and clinical diagnosis. However, cardiac PET acquisition has not yet been validated using MR imaging for attenuation correction (AC). The goal of this study is to evaluate the feasibility of PET imaging using a standard 2-point Dixon volume interpolated breathhold examination (VIBE) MR sequence for AC.

Characteristics of the electrocardiogram in patients with continuous-flow left ventricular assist devices.

Background: Electrocardiograms (ECGs) are routinely obtained in patients with advanced congestive heart failure (CHF) before and after surgical implantation with a left-ventricular assist device (LVAD). As the number of patients with CHF is increasing, it is necessary to characterize the changes present in the ECG of patients with LVADs.

Methods: ECGs of 43 patients pre- and postimplantation of a HeartMate II LVAD were compared to characterize the presence of an LVAD using the following six criteria (LVADS2 ): low limb-lead voltage, ventricular pacing, artifact (electrical), duration of the QRS > 120 milliseconds, ST-elevation in the lateral leads, and splintering of the QRS complex.

Patient characteristics and risk of subsequent contralateral hip fracture after surgical management of first fracture.

Background: Sequential hip fractures are associated with increased morbidity and mortality. Understanding of risk factors is important for secondary prevention. Although hip fractures have a multifactorial aetiology related to falls, it is unknown whether fracture management approach influences the risk of sequential hip fractures.