PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer.

Purpose: While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands.

Analysis of the Porphyrin Peak Shift and Fluorescence Lifetime in Gliomas with Different Tumor Grades, Intratumoral Regions, and Visible Fluorescence Status.

5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence shows high sensitivity in detecting the tumor core of high-grade gliomas (HGG) but poor sensitivity for tissue of low-grade gliomas (LGG) and the margins of HGG. The characteristic emission peak for PpIX is known to be located at 635 nm. Recently, a second emission peak was described at 620 nm wavelength in LGG and the tumor infiltration zone of HGG.

Creating a plasma coordination center to support COVID-19 outpatient trials across a national network of hospital blood banks.

Introduction: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

Methods: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

Development and Use of Human Recombinant Cu-rHCF as a Kidney Glomerulus-Targeted Contrast Agent for Positron Emission Tomography.

In this work, we develop recombinant human cationic ferritin (rHCF) as a contrast agent to detect glomeruli in the kidney using positron emission tomography (PET). We first expressed recombinant human ferritin (rHF) in and then functionalized and radiolabeled it with Copper-64 (Cu) to form Cu-rHCF. Intravenously injected Cu-rHCF bound to kidney glomeruli and was detected by PET.

Localization of protoporphyrin IX during glioma-resection surgery via paired stimulated Raman histology and fluorescence microscopy.

The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions.

Synthesis and Expression of a Targeted, Ferritin-Based Tracer for PET Imaging of Kidney Glomeruli.

Cationic ferritin (CF) has been developed as a multimodal, targeted imaging tracer to directly detect and map nephrons in the kidney in vivo. Direct detection of functional nephrons provides a unique, sensitive biomarker to predict or monitor kidney disease progression. CF has been developed to map functional nephron number from magnetic resonance imaging (MRI) or positron emission tomography (PET).

Flavin fluorescence lifetime and autofluorescence optical redox ratio for improved visualization and classification of brain tumors.

Purpose: Modern techniques for improved tumor visualization have the aim to maximize the extent of resection during brain tumor surgery and thus improve patient prognosis. Optical imaging of autofluorescence is a powerful and non-invasive tool to monitor metabolic changes and transformation in brain tumors. Cellular redox ratios can be retrieved from fluorescence emitted by the coenzymes reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD).

Fluorescence Lifetime Imaging and Spectroscopic Co-Validation for Protoporphyrin IX-Guided Tumor Visualization in Neurosurgery.

Maximal safe resection is a key strategy for improving patient prognosis in the management of brain tumors. Intraoperative fluorescence guidance has emerged as a standard in the surgery of high-grade gliomas. The administration of 5-aminolevulinic acid prior to surgery induces tumor-specific accumulation of protoporphyrin IX, which emits red fluorescence under blue-light illumination.

Validation of Trifluoromethylphenyl Diazirine Cholesterol Analogues As Cholesterol Mimetics and Photolabeling Reagents.

Aliphatic diazirine analogues of cholesterol have been used previously to elaborate the cholesterol proteome and identify cholesterol binding sites on proteins. Cholesterol analogues containing the trifluoromethylphenyl diazirine (TPD) group have not been reported. Both classes of diazirines have been prepared for neurosteroid photolabeling studies and their combined use provided information that was not obtainable with either diazirine class alone.

Intrasubunit and Intersubunit Steroid Binding Sites Independently and Additively Mediate 122L GABA Receptor Potentiation by the Endogenous Neurosteroid Allopregnanolone.

Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABA receptor. The sites are located in the membrane-spanning domains of the receptor at the - subunit interface (site I) and within the (site II) and subunits (site III). Here, we have investigated the effects of mutations to these sites on potentiation of the rat 122L GABA receptor by the endogenous neurosteroid allopregnanolone (35P).

Mapping nephron mass in vivo using positron emission tomography.

Nephron number varies widely in humans. A low nephron endowment at birth or a loss of functioning nephrons is strongly linked to increased susceptibility to chronic kidney disease. In this work, we developed a contrast agent, radiolabeled cationic ferritin (RadioCF), to map functioning glomeruli in vivo in the kidney using positron emission tomography (PET).

Macroscopic fluorescence-lifetime imaging of NADH and protoporphyrin IX improves the detection and grading of 5-aminolevulinic acid-stained brain tumors.

Maximal safe tumor resection remains the key prognostic factor for improved prognosis in brain tumor patients. Despite 5-aminolevulinic acid-based fluorescence guidance the neurosurgeon is, however, not able to visualize most low-grade gliomas (LGG) and infiltration zone of high-grade gliomas (HGG). To overcome the need for a more sensitive visualization, we investigated the potential of macroscopic, wide-field fluorescence lifetime imaging of nicotinamide adenine dinucleotide (NADH) and protoporphyrin IX (PPIX) in selected human brain tumors.

Site-specific effects of neurosteroids on GABA receptor activation and desensitization.

This study examines how site-specific binding to three identified neurosteroid-binding sites in the αβ GABA receptor (GABAR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β(+)-α(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β subunit, promoting receptor desensitization and the α subunit promoting effects that vary between neurosteroids.

Analysis of Modulation of the 1 GABA Receptor by Combinations of Inhibitory and Potentiating Neurosteroids Reveals Shared and Distinct Binding Sites.

The 1 GABA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the 1 receptor is insensitive to many anesthetic drugs that modulate the heteromeric GABA receptor, it maintains a rich and multifaceted steroid pharmacology. The receptor is negatively modulated by 5-reduced steroids, sulfated or carboxylated steroids, and -estradiol, whereas many 5-reduced steroids potentiate the receptor.

Towards real-time wide-field fluorescence lifetime imaging of 5-ALA labeled brain tumors with multi-tap CMOS cameras.

Fluorescence guided neurosurgery based on 5-aminolevulinic acid (5-ALA) has significantly increased maximal safe resections. Fluorescence lifetime imaging (FLIM) of 5-ALA could further boost this development by its increased sensitivity. However, neurosurgeons require real-time visual feedback which was so far limited in dual-tap CMOS camera based FLIM.

Surgical microscope with integrated fluorescence lifetime imaging for 5-aminolevulinic acid fluorescence-guided neurosurgery.

Significance: 5-Aminolevulinic acid (5-ALA)-based fluorescence guidance in conventional neurosurgical microscopes is limited to strongly fluorescent tumor tissue. Therefore, more sensitive, intrasurgical 5-ALA fluorescence visualization is needed.

Aim: Macroscopic fluorescence lifetime imaging (FLIM) was performed ex vivo on 5-ALA-labeled human glioma tissue through a surgical microscope to evaluate its feasibility and to compare it to fluorescence intensity imaging.

The molecular determinants of neurosteroid binding in the GABA(A) receptor.

Neurosteroids positively modulate GABA-A receptor (GABAR) channel activity by binding to a transmembrane domain intersubunit site. Understanding the interactions in this site that determine neurosteroid binding and its effect is essential for the design of neurosteroid-based therapeutics. Using photo-affinity labeling and an ELIC-α1GABAR chimera, we investigated the impact of mutations (Q242L, Q242W and W246L) within the intersubunit site on neurosteroid binding.

Assessment of Copper Nanoclusters for Accurate in Vivo Tumor Imaging and Potential for Translation.

Nanoparticles have been widely used for preclinical cancer imaging. However, their successful clinical translation is largely hampered by potential toxicity, unsatisfactory detection of malignancy at early stages, inaccurate diagnosis of tumor biomarkers, and histology for imaging-guided treatment. Herein, a targeted copper nanocluster (CuNC) is reported with high potential to address these challenges for future translation.

Multiple functional neurosteroid binding sites on GABAA receptors.

Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites.

Neural scene representation and rendering.

Scene representation-the process of converting visual sensory data into concise descriptions-is a requirement for intelligent behavior. Recent work has shown that neural networks excel at this task when provided with large, labeled datasets. However, removing the reliance on human labeling remains an important open problem.

"Click Chip" Conjugation of Bifunctional Chelators to Biomolecules.

There is a growing demand for diagnostic procedures including in vivo tumor imaging. Radiometal-based imaging agents are advantageous for tumor imaging because radiometals (i) have a wide range of half-lives and (ii) are easily incorporated into imaging probes via a mild, rapid chelation event with a bifunctional chelator (BFC). Microfluidic platforms hold promise for synthesis of radiotracers because they can easily handle minute volumes, reduce consumption of expensive reagents, and minimize personnel exposure to radioactive compounds.

A Clickable Analogue of Ketamine Retains NMDA Receptor Activity, Psychoactivity, and Accumulates in Neurons.

Ketamine is a psychotomimetic and antidepressant drug. Although antagonism of cell-surface NMDA receptors (NMDARs) may trigger ketamine's psychoactive effects, ketamine or its major metabolite norketamine could act intracellularly to produce some behavioral effects. To explore the viability of this latter hypothesis, we examined intracellular accumulation of novel visualizable analogues of ketamine/norketamine.