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

Invasive candidiasis, including bloodstream infection (candidemia), encompasses the most severe forms of Candida 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. Serum samples from 14 patients with proven or probable invasive candidiasis, and from 10 control patients, were included in the analysis. A total of 50 serum samples were tested using C. albicans germ tube antibody (CAGTA) assay (Vircell), C. albicans IgM, C. albicans IgG and Candida mannan assays (Dynamiker Biotechnology). Among these samples, the ß-1-3-D-glucan (BDG) assay (Fungitell), a laboratory standard for the diagnosis of invasive candidiasis, was positive in 20 (40%), intermediate in five (10%) and negative in 25 (50%). In cases of proven or probable candidemia, the sensitivity and specificity of the BDG assay was 86% and 80%, respectively; the Candida mannan assay, 14% and 86%; the CAGTA test, 57% and 60%; the C. albicans IgM assay, 71% and 60%; and C. albicans IgG assay 29% and 90%. In 4/8 (50%) cases with multiple serum samples, C. albicans IgM was positive sooner than BDG. Thus, when used as a rule-out test for invasive candidiasis, our data suggest that the C. albicans IgM assay may assist antifungal stewardship (over serum BDG).

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 reference MBF was measured simultaneously on 13N-ammonia positron emission tomography (PET). METHODS: Sixteen patients with clinically confirmed myocardial ischemia were imaged in a clinical whole-body PET-MRI system. PET perfusion imaging was performed in a 10-min acquisition after the injection of 10 mCi of 13N-ammonia. The MRI perfusion acquisition started simultaneously with the start of the PET acquisition after the injection of a 0.075 mmol/kg gadolinium contrast agent. Cardiac stress imaging was initiated after the administration of regadenoson 20 s prior to PET-MRI scanning. The saturation part of the MRI AIF data was modeled as a gamma variate curve, which was then estimated for a true AIF by minimizing a cost function according to various boundary conditions. A standard AHA 16-segment model was used for comparative analysis of absolute MBF from PET and MRI. RESULTS: Overall, there were 256 segments in 16 patients, mean resting perfusion for PET was 1.06 ± 0.34 ml/min/g and 1.04 ± 0.30 ml/min/g for MRI (P = 0.05), whereas mean stress perfusion for PET was 2.00 ± 0.74 ml/min/g and 2.12 ± 0.76 ml/min/g for MRI (P < 0.01). Linear regression analysis in MBF revealed strong correlation (r = 0.91, slope = 0.96, P < 0.001) between PET and MRI. Myocardial perfusion reserve, calculated from the ratio of stress MBF over resting MBF, also showed a strong correlation between MRI and PET measurements (r = 0.82, slope = 0.81, P < 0.001). CONCLUSION: The results demonstrated the feasibility of the simplified AIF estimation method for the accurate quantification of MBF by MRI with single sequence and single contrast injection. The MRI MBF correlated strongly with PET MBF obtained simultaneously. This post-processing technique will allow easy transformation of clinical perfusion imaging data into quantitative information.

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

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. Hypothesizing that the E46K mutation impedes salt bridge formation and, therefore, exerts a selective pressure that can modulate α-synuclein strain propagation, we asked whether three distinct α-synuclein prion strains could propagate in TgM47+/- mice, which express human α-synuclein with the E46K mutation. Following intracranial injection of these strains, TgM47+/- mice were resistant to MSA prion transmission, whereas recombinant E46K preformed fibrils (PFFs) transmitted neurological disease to mice and induced the formation of phosphorylated α-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF-inoculation resulted in preclinical α-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human α-synuclein, with E46K PFFs, we observed delayed transmission kinetics with an incomplete attack rate. These findings suggest that the E46K mutation constrains the number of α-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact α-synuclein prion replication.

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. METHODS AND RESULTS: We studied data out-patients undergoing Bruce protocol stress echocardiograms (n = 11 086) and analyzed predictors of inappropriate early termination (defined as test duration < 8 min as per current practice guidelines) using logistic regression. A prediction model was constructed as follows: .5 points were given for each of hypertension, diabetes, smoking, and E/e' > 7.9 in the resting echocardiogram; .1 point was added for each 1-unit increment in body mass index; 1 point was added for patient age by decade; 2.0 points were subtracted for male sex (p for all < 0.001). In tests on held-out validation data, the model was well calibrated (in plots of predicted vs actual risk) and discriminated failure versus non-failure well (C-statistic .86 for a score of 6.0 points; p < 0.001). CONCLUSION: These data may help to standardize protocol selection in stress echocardiography, by identifying patients pre-hoc where Bruce protocol will be inappropriately steep.

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. (Level of Difficulty: Advanced.).

Preprocedural valvuloarterial impedance as a predictor of left ventricular ejection fraction improvement after transcatheter aortic valve replacement in patients with reduced left ventricular ejection fraction.

BACKGROUND: Predictors of left ventricular ejection fraction (LVEF) improvement after transcatheter aortic valve replacement (TAVR) in patients with a preoperative reduced LVEF are limited. OBJECTIVES: This study aimed to investigate the relationship between preprocedural valuvuloarterial impedance (ZVa), which represents the global LV afterload, and LVEF improvement after TAVR. METHODS: This was a single-center, retrospective study, which included patients with symptomatic aortic valve stenosis (AS) with a reduced baseline LVEF (< 50%) underwent TAVR. Based on the difference in the LVEF before and 1 month after the procedure, they were divided into two groups: improved group (≥ 10% improvement) and non-improved group (< 10% improvement or worsening). Preprocedural ZVa and clinical outcomes were then compared. ZVa was calculated using preprocedural transthoracic echocardiography data. RESULTS: Among 473 cases of TAVR performed from May 2012 to July 2017 at Queen's Medical Center (Honolulu, HI, USA), 99 patients (improved group, n = 42; mean age 82.0 ± 8.6 years vs. non-improved group, n = 57, mean age 81.4 ± 9.5 years) were included. The improved group had a higher baseline ZVa {4.83 (4.15-6.89) mmHg/ml/m2 vs. 4.04 (3.56-4.63) mmHg/ml/m2, respectively, p = 0.0009} and prevalence of ZVa > 5 mmHg/ml/m2 (45.2% vs. 17.5%, respectively, p = 0.0028). Multivariable analysis of predictors of LVEF improvement ≥ 10% at 1 month identified ZVa > 5 mmHg/ml/m2 [odds ratio (OR): 3.31, 95% confidence interval (CI): 1.05-11.8] as a predictor. The improved group had a lower readmission rate due to heart failure than the non-improved group (log-rank test, p = 0.043). CONCLUSION: In conclusion, Zva is a simple, noninvasive marker that shows promise as a predictor of LVEF improvement after TAVR in reduced LVEF patients.

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 trans-cyclooctene (TCO)-modified antibodies. Noninvasive SPECT imaging of mice bearing HER2-expressing xenografts was performed both directly (111In-labeled antibody) and indirectly (pretargeted TCO-modified antibody followed by 111In-labeled tetrazine). Pharmacokinetic modulation of antibodies was achieved by two distinct methods: Fc engineering to reduce binding affinity to FcRn, and delayed administration of an antibody that competes with binding to FcRn. Tumor imaging with directly labeled antibodies was feasible in the absence of FcRn binding, rapidly attaining high tumor-to-blood ratios, but accompanied by moderate liver and spleen uptake. Pretargeted imaging of tumors with non-FcRn-binding antibody was also feasible, but systemic click reaction still occurred, albeit at lower levels than with parental antibody. Our findings demonstrate that FcRn binding impairment of full-length IgG antibodies moderately lowers tumor accumulation of radioactivity, and shifts background activity from blood pool to liver and spleen. Furthermore, reduction of FcRn binding did not eliminate systemic click reaction, but yielded greater improvements in tumor-to-blood ratio when imaging with directly labeled antibodies than with pretargeting.

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. Here, combination of in vivo (genetics and ChIP-seq), in vitro (surface plasmon resonance) and phylogenetic analyses identified an astonishing plasticity of CBC:HapX:DNA interaction. DNA motifs recognized by the CBC:HapX protein complex comprise a bipartite DNA binding site 5'-CSAATN12RWT-3' and an additional 5'-TKAN-3' motif positioned 11-23 bp downstream of the CCAAT motif, i.e. occasionally overlapping the 3'-end of the bipartite binding site. Phylogenetic comparison taking advantage of 20 resolved Aspergillus species genomes revealed that DNA recognition by the CBC:HapX complex shows promoter-specific cross-species conservation rather than regulon-specific conservation. Moreover, we show that CBC:HapX interaction is absolutely required for all known functions of HapX. The plasticity of the CBC:HapX:DNA interaction permits fine tuning of CBC:HapX binding specificities that could support adaptation of pathogens to their host niches.

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. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings.

The ribosomal maturation factor P from Mycobacterium smegmatis 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 Escherichia coli Because of its central importance in bacterial metabolism, RimP represents a good potential target for drug design to combat human pathogens such as Mycobacterium tuberculosis However, to date, the only RimP structure available is the NMR structure of the ortholog in another bacterial pathogen, Streptococcus pneumoniae Here, we report a 2.2 Å resolution crystal structure of MSMEG_2624, the RimP ortholog in the close M. tuberculosis relative Mycobacterium smegmatis, and using in vitro 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. However, neither of the two domains alone was sufficient to form strong interactions with RpsL. More importantly, the linker region was essential for in vivo ribosomal biogenesis. Our study provides critical mechanistic insights into the role of RimP in ribosome biogenesis. We anticipate that the MSMEG_2624 crystal structure has the potential to be used for drug design to manage M. tuberculosis infections.

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. The effect of stoichiometry on tissue distribution was assessed for pretargeting TCO-modified antibodies (monitored by 125I) and subsequent accumulation of an 111In-labeled tetrazine in a therapeutically relevant HER2+tumor-bearing mouse model. Single photon emission computed tomography (SPECT) imaging was also employed to assess tumor imaging at various TCO-to-monoclonal antibody (mAb) ratios. Increasing TCO-to-mAb molar ratios correlated with increased in vivo click reaction efficiency evident by increased tumor distribution and systemic exposure of 111In-labeled tetrazines. The pharmacokinetics of TCO-modified antibodies did not vary with stoichiometry. Pretargeted SPECT imaging of HER2-expressing tumors using 111In-labeled tetrazine demonstrated robust click reaction with circulating antibody at ~2 hours and good tumor delineation for both the 2 and 6 TCO-to-mAb ratio variants at 24 hours, consistent with a limited cell-surface pool of pretargeted antibody and benefit from further distribution and internalization. To our knowledge, this represents the first reported systematic analysis of how pretargeted imaging is affected solely by variation in click reaction stoichiometry through site-specific conjugation chemistry.

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. It also offers fascinating possibilities in imaging other cardiovascular-related disease states, such as tumor imaging and vascular imaging. In this review, we begin with a general overview of the potentials of PET-MRI in cardiovascular imaging, followed by a discussion of the technical challenges unique to cardiovascular PET-MRI. We then discuss PET-MRI in various cardiovascular disease imaging applications. Potential limitations of PET-MRI and future directions are also considered.

Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers.

Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 µg/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.

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. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro. However, we observed metabolism of a critical acetate ester of the drug in vivo, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

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. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.

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. METHODS AND RESULTS: Evaluation was performed in both phantom and patient data. A chest phantom containing heart, lungs, and a lesion insert was scanned by both PET/MR and PET/CT. In addition, 30 patients underwent whole-body 18F-fluorodeoxyglucose PET/CT followed by simultaneous cardiac PET/MR. Phantom study showed 3% reduction of activity values in the myocardium due to the non-inclusion of the phased array coil in the AC. In patient scans, average standardized uptake values (SUVs) obtained by PET/CT and PET/MR showed no significant difference (n = 30, 4.6 ± 3.5 vs 4.7 ± 2.8, P = 0.47). There was excellent per patient correlation between the values acquired by PET/CT and PET/MR (R 2 = 0.97). CONCLUSIONS: Myocardial SUVs PET imaging using MR for AC shows excellent correlation with myocardial SUVs obtained by standard PET/CT imaging. The 2-point Dixon VIBE MR technique can be used for AC in simultaneous PET/MR data acquisition.

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. Nevertheless, PET/MR examination has unique promises in several areas of cardiovascular medicine, and in recent years more and more research publications have become available to lend us insight into its utility in cardiovascular imaging. Here we review the existing literature on simultaneous cardiovascular PET/MR imaging, with an emphasis on organizing the current literature into disease-specific discussions. These areas include coronary artery disease (CAD), carotid atherosclerosis, various infiltrative, inflammatory and hereditary heart diseases, myocarditis, vasculitis, and cardiac mass assessment. The purpose of this review is to provide an overview of the current understanding of cardiovascular PET/MR clinical imaging, in a disease-specific manner, from a clinician's perspective. Potential limitations of simultaneous PET/MR, such as cost effectiveness, artifacts, contraindications, and radiation exposure, are briefly discussed.

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. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR.