Innovative Approaches To The Management of Acute Arterial Hypertension - Clevidipine Butyrate

Acute arterial hypertension is one of the major concerns in many clinical settings including but not limited to operating room, intensive care and emergency care units. Perioperative hypertension is one of the major reasons for cancellation of elective surgeries, and also increases the perioperative morbidity. We would like to discuss pathophysiology, evaluation of the patients with acute hypertension, management of these patients and future considerations of the current intravenous antihypertensive medications

Multi-messenger observations of thunderstorm-related bursts of cosmic rays

We present the facilities of the Aragats Space Environmental Center in Armenia used during multi-year observations of the thunderstorm ground enhancements (TGEs) and corresponding environmental parameters. We analyze the characteristics of the scintillation detectors, operated on Aragats, and describe the coordinated detection of TGEs by the network of scintillation detectors, field meters, and environmental parameters. By using a fast synchronized data acquisition system we reveal correlations of the multivariate data on time scales from second to nanosecond which allow us to gain insight into the TGE and lightning origin and their interrelations

Thunderstorm ground enhancements: Multivariate analysis of 12 years of observations

We present a survey of more than a half-thousand thunderstorm ground enhancements (TGEs, fluxes of electrons, and gamma rays associated with thunderstorms) registered in 2008–2022 at Aragats space environmental center (ASEC). We analyze correlations between various measured parameters characterizing TGEs measured on Aragats. Two special cases of TGE events are considered: one, terminated by nearby lightning flashes, and another one—with a sufficiently large ratio of electrons to gamma rays. On the basis of the analysis, we summarize the most important results obtained during 12 years of TGE study, which include the following statements: (i) TGEs originated from multiple relativistic runaway electron avalanches starting with seed electrons from the ambient population of cosmic rays, which enter an extended region of the electric field with strength exceeding the critical value; (ii) quite frequently, TGEs occur prior to lightning flashes and are terminated by them; (iii) the energy spectra of avalanche electrons observed on Aragats indicate that the strong electric field region can extend very low above the ground covering a large area on the earth’s surface

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC

Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI

Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an ironmimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/ phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors