[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme.

Shaping of cutaneous function by encounters with commensals.

The skin is the largest organ in the human body and provides the first line of defence against environmental attack and pathogen invasion. It harbor multiple commensal microbial communities at different body sites, which play important roles in sensing the environment, protecting against colonization and infection of pathogens, and guiding the host immune system in response to foreign invasions. The skin microbiome is largely variable between individuals and body sites, with several core commensal members commonly shared among individuals at the healthy state.

ARAS: an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes.

Background: Automated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing a safe environment for radiation workers but also to ensure accuracy of dispensed radioactivity and an efficient workflow. For this purpose, we have designed ARAS, an automated radioactivity aliquoting system for dispensing solutions containing positron-emitting radioisotopes with particular focus on fluorine-18 ((18)F).

Methods: The key to the system is the combination of a radiation detector measuring radioactivity concentration, in line with a peristaltic pump dispensing known volumes.

Probing in Space and Time the Nuclear Motion Driven by Nonequilibrium Electronic Dynamics in Ultrafast Pumped N2.

An ultrafast electronic excitation of N2 in the vacuum ultraviolet creates a nonstationary coherent linear superposition of interacting valence and Rydberg states resulting in a net oscillating dipole moment. There is therefore a linear response to an electrical field that can be queried by varying the time delay between the pump and a second optical probe pulse. Both the pump and probe pulses are included in our computation as part of the Hamiltonian, and the time-dependent wave function for both electronic and nuclear dynamics is computed using a grid representation for the internuclear coordinate.

Quantum Nuclear Dynamics Pumped and Probed by Ultrafast Polarization Controlled Steering of a Coherent Electronic State in LiH.

The quantum wave packet dynamics following a coherent electronic excitation of LiH by an ultrashort, polarized, strong one-cycle infrared optical pulse is computed on several electronic states using a grid method. The coupling to the strong field of the pump and the probe pulses is included in the Hamiltonian used to solve the time-dependent Schrodinger equation. The polarization of the pump pulse allows us to control the localization in time and in space of the nonequilibrium coherent electronic motion and the subsequent nuclear dynamics.

MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4.

Monocarboxylate transporter 1 (MCT1) inhibition is thought to block tumor growth through disruption of lactate transport and glycolysis. Here, we show MCT1 inhibition impairs proliferation of glycolytic breast cancer cells co-expressing MCT1 and MCT4 via disruption of pyruvate rather than lactate export. MCT1 expression is elevated in glycolytic breast tumors, and high MCT1 expression predicts poor prognosis in breast and lung cancer patients.

Quantitative assessments of glycolysis from single cells.

The most common positron emission tomography (PET) radio-labeled probe for molecular diagnostics in patient care and research is the glucose analog, 2-deoxy-2-[F-18]fluoro-D-glucose (F-FDG). We report on an integrated microfluidics-chip/beta particle imaging system for F-FDG radioassays of glycolysis with single cell resolution. We investigated the kinetic responses of single glioblastoma cancer cells to targeted inhibitors of receptor tyrosine kinase signaling.

The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma.

Unlabelled: While prostatic adenocarcinomas are relatively indolent, some patients with advanced adenocarcinomas recur with small cell neuroendocrine carcinoma which is highly aggressive and lethal. Because glycolysis is a feature of malignancy and the degree of glycolysis generally correlates with tumor aggressiveness, we wanted to compare the metabolic differences and the molecular mechanisms involved between the two tumor types. In this study, and based on previous characterization, LNCaP and PC-3 prostate cancer cell lines were selected as models of prostatic adenocarcinoma and small cell neuroendocrine carcinoma, respectively.

A New Pulse Pileup Rejection Method Based on Position Shift Identification.

Pulse pileup events degrade the signal-to-noise ratio (SNR) of nuclear medicine data. When such events occur in multiplexed detectors, they cause spatial misposition, energy spectrum distortion and degraded timing resolution, which leads to image artifacts. Pulse pileup is pronounced in PETbox4, a bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice.

Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with -phenyl sydnone with the rate constant of up to 1.46 M s.

A High-Throughput Platform for Formulating and Screening Multifunctional Nanoparticles Capable of Simultaneous Delivery of Genes and Transcription Factors.

Simultaneous delivery of multiple genes and proteins (e.g., transcription factors; TFs) is an emerging issue surrounding therapeutic research due to their ability to regulate cellular circuitry.

Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma.

Malignant gliomas are intractable and among the most lethal human malignancies. Like other cancers, metabolic reprogramming is a key feature of glioma and is thought to accommodate the heightened nutrient requirements for tumor cell proliferation, growth, and survival. This metabolic rewiring, driven by oncogenic signaling and molded by the unique environment of the brain, may impose vulnerabilities that could be exploited therapeutically for increased tumor control.

Understanding temperatures and pressures during short radiochemical reactions.

Automated radiosynthesizers are critical for the reliable, routine production of PET tracers. To perform reactions in these systems, the temperature of the reactor heater is controlled, and the liquid temperature within the reaction vessel is presumed to closely follow. In reality, the liquid temperature can lag by several minutes and generally does not reach the heater temperature.

AEG-1 activates Wnt/PCP signaling to promote metastasis in tongue squamous cell carcinoma.

Despite advances in therapy, survival among patients with locally advanced squamous cell carcinoma of tongue (TSCC) and cervical lymph node metastasis remains dismal. Here, we estimated the functional effect of AEG-1 on TSCC metastasis and explored the molecular mechanism by which AEG-1 stimulates epithelial-mesenchymal transition (EMT). We initially found that AEG-1 mRNA levels were much higher in metastatic TSCC than in non-metastatic TSCC and that AEG-1 expression strongly correlates with EMT status.

An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy.

The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys-diabody ((89)Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8(+) T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti-PD-L1).

MYC-induced reprogramming of glutamine catabolism supports optimal virus replication.

Viruses rewire host cell glucose and glutamine metabolism to meet the bioenergetic and biosynthetic demands of viral propagation. However, the mechanism by which viruses reprogram glutamine metabolism and the metabolic fate of glutamine during adenovirus infection have remained elusive. Here, we show MYC activation is necessary for adenovirus-induced upregulation of host cell glutamine utilization and increased expression of glutamine transporters and glutamine catabolism enzymes.

Fluorescent Image-Guided Surgery with an Anti-Prostate Stem Cell Antigen (PSCA) Diabody Enables Targeted Resection of Mouse Prostate Cancer Xenografts in Real Time.

Purpose: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery.

A DOI Detector With Crystal Scatter Identification Capability for High Sensitivity and High Spatial Resolution PET Imaging.

A new phoswich detector is being developed at the Crump Institute, aiming to provide improvements in sensitivity, and spatial resolution for PET. The detector configuration is comprised of two layers of pixelated scintillator crystal arrays, a glass light guide and a light detector. The annihilation photon entrance (top) layer is a 48 × 48 array of 1.

High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis.

Collagen triple helix repeat-containing 1 (CTHRC1) is aberrantly overexpressed in multiple malignant tumors. However, the expression characteristics and function of CTHRC1 in epithelial ovarian cancer (EOC) remain unclear. We found that CTHRC1 expression was up-regulated in the paraffin-embedded EOC tissues compared to borderline or benign tumor tissues.

Development and characterization of an αvβ6-specific diabody and a disulfide-stabilized αvβ6-specific cys-diabody.

Introduction: This work describes the development and characterization of two antibody fragments that specifically target the α(v)β(6) integrin, a non-covalent diabody and a disulfide-stabilized cys-diabody. The diabodies were analyzed for their ability to bind both immobilized and cell surface-bound α(v)β(6). Radiolabeling was done using non-site-specific and site-specific conjugation approaches with N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]-SFB) and the bifunctional chelator 1,4,7-triazacyclononane-triacetic acid maleimide (NOTA-maleimide) and copper-64 ([(64)Cu]), respectively.

Statistical thermodynamics of transcription profiles in normal development and tumorigeneses in cohorts of patients.

Experimental biology is providing the distribution of numerous different biological molecules inside cells and in body fluids of patients. Statistical methods of analysis have very successfully examined these rather large databases. We seek to use a thermodynamic analysis to provide a physical understanding and quantitative characterization of human cancers and other pathologies within a molecule-centered approach.

On-demand generation and mixing of liquid-in-gas slugs with digitally-programmable composition and size.

Microscopic droplets or slugs of mixed reagents provide a convenient platform for performing large numbers of isolated biochemical or chemical reactions for many screening and optimization applications. Myriad microfluidic approaches have emerged for creating droplets or slugs with controllable size and composition, generally using an immiscible carrier fluid to assist with the formation or merging processes. We report a novel device for generation of liquid slugs in air when the use of a carrier liquid is not compatible with the application.

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan.

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases.

Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis.

Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, we aimed to understand the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. Metatranscriptomic analysis revealed that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals.