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In oncology, the feasibility of Cerenkov luminescence imaging (CLI) has been assessed by imaging superficial lymph nodes in a few patients undergoing diagnostic

The application of nanomaterials made of rare earth elements within biomedical sciences continues to make significant progress. The rare earth elements, also called the lanthanides, play an essential role in modern life through materials and electronics. As we learn more about their utility, function, and underlying physics, we can contemplate extending their applications to biomedicine. This particularly applies to diagnosis and radiation therapy due to their relatively unique features, such as an ultra-wide Stokes shift in the luminescence, variable magnetism and potentially tunable properties, due to the library of lanthanides available and their multivalent oxidation state chemistry. The ability to prepare nanomaterials of relatively smaller sizes has increased the likelihood of use in vivo. In this review, we summarize the different emerging applications of nanoparticles with rare earth elements as the host or doped elements for biomedical applications in the past three to four years, especially in the area of imaging and disease diagnosis. Researchers have made progress in utilizing surfactants and polymers to modify the surface of lanthanide nanoparticles to enhance biocompatibility. At the same time, specific antibodies and proteins can also be conjugated to these nanoparticles to increase targeting efficiency for specific tumor models. Finally, in the near-infrared II imaging window, lanthanide nanoparticles have been shown to exhibit extraordinary bright emission, which is an exciting development for image-guided surgery.

Cerenkov (or Cherenkov) luminescence occurs when charged particles exceed the phase velocity of a given medium. Cerenkov has gained interest in preclinical space as well as in clinical trials for optical visualization of numerous radionuclides. However, Cerenkov intensity has to be inferred from alternative databases with energy emission spectra, or theoretical fluence estimates. Here we present the largest experimental dataset of Cerenkov emitting isotopes recorded using the IVIS optical imaging system. We report Cerenkov measurements spanning orders of magnitude normalized to the activity concentration for 21 Cerenkov emitting isotopes, covering electron, alpha, beta minus, and positron emissions. Isotopes measured include Carbon-11, Fluorine-18, Phosphorous-32, Scandium-47, Copper-64, Copper-67, Gallium-68, Arsenic-72, Bromine-76, Yttrium-86, Zirconium-89, Yttrium-90, Iodine-124, Iodine-131, Cerium-134, Lutetium-177, Lead-203, Lead-212, Radium-223, Actinium-225, and Thorium-227. We hope this updating resource will serve as a rank ordering for comparing isotopes for Cerenkov luminescence in the visible window and serve as a rule of thumb for comparing Cerenkov intensities in vitro and in vivo.MethodsAll Cerenkov emitting radionuclides were either produced at Memorial Sloan Kettering Cancer Center (Carbon-11,11C; Fluorine-18,18F; Iodine-124,124I), from commercial sources such as Perkin Elmer (Phosphorous-32,32P; Yttrium-90,90Y), Bayer (Radium-223,223Ra, Xofigo), 3D-Imaging (Zirconium-89,89Zr), Nuclear Diagnostic Products (Iodine-131,131I), or from academic collaborators at Washington University at St. Louis (Copper-64,64Cu), University of Wisconsin (Bromine-76,76Br), MD Anderson Cancer Center (Yttrium-86,86Y), Brookhaven National Laboratory (Arsenic-72,72As; Thorium-227,227Th), or Oak Ridge National Laboratory (Cerium-134,134Ce, Actinium-225,225Ac), and Viewpoint Molecular Targeting (Lead-203,203Pb; Lead 212,212Pb). All isotopes were diluted in triplicate on a black bottomed corning 96 well plate to several activity concentrations ranging from 0.1-250 μCi in 100-200 μL of Phosphate Buffered Saline. Cerenkov imaging was acquired on a single Perkin-Elmer Spectrum In-Vivo Imaging System (IVIS) at field of view c with exposures ranging up to 15 minutes or lower provided no part of the image intensity was saturated, or that the activity significantly changed during the exposure. Experimental radiances on the IVIS were calculated from regions of interest drown over each 96 well, and then normalized for the activity present in the well, and the volume the isotope was diluted into.

Organ-on-chip systems recapitulate the form and function of biological organs in highly controlled in vitro conditions and have already been used for testing a variety of nanoparticles. Can they unlock the translational potential of nanomedicine?

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There is a critical need to improve optical imaging that will lead to its widespread acceptance for routine clinical procedures. Shortwave infrared (SWIR, 900–1700nm) imaging has demonstrated clear advantages over visible and near-infrared imaging (reduced autofluorescence with improved contrast, resolution, and sensitivity at tissue depth). Here we show that the previously reported compound, pH low insertion peptide (pHLIP) conjugated to indocyanine green (ICG, pHLIP ICG) currently in clinical trials, serves as an excellent candidate for SWIR imaging protocols. SWIR’s increased sensitivity enabled preclinical tumor screening and resection at exposure times as low as 0.1 ms with acceptable signal-to-noise and contrast-to-noise ratios. Imaging was performed under ambient lighting conditions, and SWIRs sensitivity enabled an extended surgical resection window up to 96 hrs post injection in an orthotopic breast cancer mouse model. This work provides a direct precedent for the clinical translation of SWIR pHLIP ICG imaging for cancer resection.One Sentence SummarySWIR imaging under ambient lighting is highly sensitive to pHLIP ICG, a cancer targeting fluorescent agent currently under clinical investigation.

Pancreatic cancer (PC) remains the fourth leading cause of cancer death; therefore, there is a clinically unmet need for novel therapeutics and diagnostic markers to treat this devastating disease. Physicians often rely on biopsy or CT for diagnosis, but more specific protein biomarkers are highly desired to assess the stage and severity of PC in a noninvasive manner. Serum biomarkers such as carbohydrate antigen 19-9 are of particular interest as they are commonly elevated in PC but have exhibited suboptimal performance in the clinic. MUC5AC has emerged as a useful serum biomarker that is specific for PC versus inflammation. We developed RA96, an anti-MUC5AC antibody, to gauge its utility in PC diagnosis through immunohistochemical analysis and whole-body PET in PC. Methods: In this study, extensive biochemical characterization determined MUC5AC as the antigen for RA96. We then determined the utility of RA96 for MUC5AC immunohistochemistry on clinical PC and preclinical PC. Finally, we radiolabeled RA96 with (89)Zr to assess its application as a whole-body PET radiotracer for MUC5AC quantification in PC. Results: Immunohistochemical staining with RA96 distinguished chronic pancreatitis, pancreatic intraepithelial neoplasia, and varying grades of pancreatic ductal adenocarcinoma in clinical samples. (89)Zr-desferrioxamine-RA96 was able to detect MUC5AC with high specificity in mice bearing capan-2 xenografts. Conclusion: Our study demonstrated that RA96 can differentiate between inflammation and PC, improving the fidelity of PC diagnosis. Our immuno-PET tracer (89)Zr-desferrioxamine-RA96 shows specific detection of MUC5AC-positive tumors in vivo, highlighting the utility of MUC5AC targeting for diagnosis of PC.

The important insights yielded by molecular imaging (MI) into relevant biologic signatures at an organ-specific and systemic level are not achievable with conventional imaging methods and thus provide an essential link between preclinical and clinical research. New diagnostic probes and imaging methods revealing comprehensive functional and molecular information are being provided by MI research, several of which have found their way into clinical application. However, there are also reservations about the impact of MI and its added value over conventional, often less expensive, diagnostic imaging methods. This perspective discusses seminal research directions for the MI field that have the potential to result in added value to the patient. Emphasis is placed on MI without probes, MI based on radiotracers and small molecules, MI nano- and microsystems, and MI in context with comprehensive diagnostics. Furthermore, besides technical innovations and probes, emerging clinical indications are highlighted.

Trametinib is an extremely potent allosteric inhibitor of mitogen-activated protein kinase (MAPK)/extracellular-signal–regulated kinase (ERK) (MEK) 1/2, which has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAF(V600E)/K mutations. Though trametinib is highly efficacious, adverse side effects, including skin, gastrointestinal, and hepatic toxicity, are dose-limiting and can lead to treatment termination. Development of a noninvasive tool to visualize and quantify the delivery and distribution of trametinib (either as a single agent or in combination with other therapeutics) to tumors and organs would be helpful in assessing therapeutic index, personalizing individual dose, and potentially predicting resistance to therapy. Methods: To address these issues, we have developed a radiolabeled trametinib and evaluated the in vitro and in vivo properties. (123)I-, (124)I-, and (131)I-trametinib, pure tracer analogs to trametinib, were synthesized in more than 95% purity, with an average yield of 69.7% and more than 100 GBq/μmol specific activity. Results: Overall, (124)I-trametinib uptake in a panel of cancer cell lines can be blocked with cold trametinib, confirming specificity of the radiotracer in vitro and in vivo. (124)I-trametinib was taken up at higher rates in KRAS and BRAF mutant cell lines than in wild-type KRAS cancer cell lines. In vivo, biodistribution revealed high uptake in the liver 2 h after injection, followed by clearance through the gastrointestinal tract over 4 d. Importantly, uptake higher than expected was observed in the lung and heart for up to 24 h. Peak uptake in the skin and gastrointestinal tract was observed between 6 and 24 h, whereas in B16F10 melanoma–bearing mice peak tumor concentrations were achieved between 24 and 48 h. Tumor uptake relative to muscle and skin was relatively low, peaking at 3.4- to 8.1-fold by 72 h, respectively. The biodistribution of (124)I-trametinib was significantly reduced in mice on trametinib therapy, providing a quantitative method to observe MEK inhibition in vivo. Conclusion: (124)I-trametinib serves as an in vivo tool to personalize the dose instead of using the current single-fixed-dose scheme and, when combined with radiomic data, to monitor the emergence of therapy resistance. In addition, the production of iodinated trametinib affords researchers the ability to measure drug distribution for improved drug delivery studies.

Extracellular vesicles (EV) are comprised of vesicles budding from cell membranes and smaller intracellular vesicles shed by cells. EV play a role in remodeling the tumor microenvironment (TME) and support tumor progression. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with a carboxypeptidase function, frequently associated with poor clinical prognosis in prostate cancer (PCa). We previously identified an oncogenic PSMA signaling function in prostate cancer. Others demonstrated that EV isolated from the plasma of patients with high-grade PCa carry PSMA, but so far no pathophysiological effect has been associated with PSMA-bearing EV. Here we demonstrate that EV from PCa cells are able to transfer PSMA and its functionality to cells in the TME. The consequence of that EV-mediated PSMA transfer is an acute to long-term increased secretion of vascular endothelial growth factor-A (VEGF-A), angiogenin, pro-angiogenic and pro-lymphangiogenic mediators and increased 4E binding protein 1 (4EBP-1) phosphorylation in tumors. We compare EV from PCa cells with or without PSMA expression to address the role of PSMA-bearing EV in promoting pro-tumoral changes in the TME using classical molecular biology and novel molecular imaging approaches.

Cerenkov luminescence (CL) is produced by medical radioisotopes when charged (commonly beta (β+/-)) particles travel faster than light in a dielectric medium (tissue). This blue-weighted luminescence is both continuous and proportional to the reciprocal wavelength. CL imaging (CLI) promises an economical alternative to PET but is limited by the optical properties of tissue and special setup requirements. CL has been detected in the shortwave infrared (SWIR) spectrum (900 – 1700 nm) from linear accelerators operating in the MeV range but so far not from medical radioisotopes. This work is the first to show that the order of magnitude weaker SWIR CL from medical radioisotopes predicted by the Frank-Tamm equation can also be detected, using commercially available SWIR components. SWIR CL was detected from five clincial radioisotopes: 90Y, 68Ga, 18F, 89Zr, 131I and from 32P, used in biomedical research. The advantage of radioisotope SWIR CLI over conventional CLI is shown in terms of significantly increased light penetration and reduced scattering at tissue depth, in line with the known advantages of SWIR imaging. We report the radioisotope SWIR spectrum, the current detection sensitivity limit (0.23 µCi/µl of 68Ga) and determine the feasibility of SWIR CLI with ex vivo and in vivo preclinical examples. Further improvements in SWIR optics and technology are required to enable widespread adoption.

Significance Glutamate-ureido-lysine (GUL) probes are specific for prostate-specific membrane antigen (PSMA), overexpressed by most prostate cancers. This antigen can be lost as the cancer progresses. Recent reports have indicated that GUL probes can still identify these PSMA-negative tumors, indicating that the expression of alternative PSMA-like proteins may change during disease progression. In this study we identified two such candidate protein targets, NAALADaseL and mGluR8, by using a combined computational chemistry, data mining, molecular biology, radiochemistry, and synthetic chemistry approach. This work consequently prepares the groundwork for developing specific probes that can identify this progression, indicates directions for neuroendocrine prostate cancer research, and highlights the utility of a multidisciplinary approach for the rapid identification of unidentified proteins interacting with diagnostic probes., Prostate-specific membrane antigen (PSMA) is highly overexpressed in most prostate cancers and is clinically visualized using PSMA-specific probes incorporating glutamate-ureido-lysine (GUL). PSMA is effectively absent from certain high-mortality, treatment-resistant subsets of prostate cancers, such as neuroendocrine prostate cancer (NEPC); however, GUL-based PSMA tracers are still reported to have the potential to identify NEPC metastatic tumors. These probes may bind unknown proteins associated with PSMA-suppressed cancers. We have identified the up-regulation of PSMA-like aminopeptidase NAALADaseL and the metabotropic glutamate receptors (mGluRs) in PSMA-suppressed prostate cancers and find that their expression levels inversely correlate with PSMA expression and are associated with GUL-based radiotracer uptake. Furthermore, we identify that NAALADaseL and mGluR expression correlates with a unique cell cycle signature. This provides an opportunity for the future study of the biology of NEPC and potential therapeutic directions. Computationally predicting that GUL-based probes bind well to these targets, we designed and synthesized a fluorescent PSMA tracer to investigate these proteins in vitro, where it shows excellent affinity for PSMA, NAALADaseL, and specific mGluRs associated with poor prognosis.

The presence of metastasis in local lymph nodes (LNs) is a key factor influencing choice of therapy and prognosis in cervical and endometrial cancers; therefore, the exploration of sentinel LNs (SLNs) is highly important. Currently, however, SLN mapping requires LN biopsy for pathologic evaluation, since there are no clinical imaging approaches that can identify tumor-positive LNs in early stages. Staging lymphadenectomy poses risks, such as leg lymphedema or lymphocyst formation. Furthermore, in 80%-90% of patients, the explored LNs are ultimately tumor-free, meaning most patients are unnecessarily subjected to lymphadenectomy. Methods: Current lymphoscintigraphy methods identify only the anatomic location of the SLNs and do not provide information on their tumor status. There are no noninvasive methods to reliably identify metastases in LNs before surgery. We have developed positron lymphography (PLG), a method to detect tumor-positive LNs, in which 18F-FDG is injected interstitially into the uterine cervix on the day of surgery, and its rapid transport through the lymphatic vessels to the SLN is then visualized with dynamic PET/CT. We previously showed that PLG was able to identify metastatic LNs in animal models. Here, we present the first results from our pilot clinical trial (clinical trials identifier NCT02285192) in 23 patients with uterine or cervical cancer. On the morning of surgery, 18F-FDG was injected into the cervix, followed by an immediate dynamic PET/CT scan of the pelvis and a delayed 1-h whole-body scan. Results: There were 3 (15%) node-positive cases on final pathologic analysis, and all of these LNs (including 1 with a focus of only 80 tumor cells) were identified by PLG. There were 2 (10%) false-positive cases with PLG, in which the final pathology of the corresponding SLNs was negative for tumor. Conclusion: This first-in-humans study of PLG in women with uterine and cervical cancer demonstrates its feasibility and its ability to identify patients with nodal metastases and warrants further evaluation in additional studies.

Acute myeloid leukaemia (AML) is a fatal disease for most patients. We have found that ferumoxytol (Feraheme®), a FDA approved iron oxide nanoparticle for iron deficiency treatment, demonstrates an anti-leukaemia effect in vitro and in vivo. Using leukaemia cell lines and primary AML patient samples, we show that low expression of the iron exporter ferroportin (FPN) results in a susceptibility of these cells by an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron leads to increased oxidative stress and cell death. Ferumoxytol treatment results in a significant reduction of disease burden in a murine leukaemia model and patient-derived xenotransplants (PDX) bearing leukaemia cells with low FPN expression. Our findings show how a clinical nanoparticle considered previously largely biologically inert could be rapidly incorporated into clinical trials for patients with leukaemia with low FPN levels., One Sentence Summary: Administration of the clinically approved iron oxide nanoparticle drug ferumoxytol in vitro results in an anti-leukaemia effect and in vivo extended overall survival in part due to the low expression of the iron export protein ferroportin.

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a novel human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggered clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling molecules to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS–ED–photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS–ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS–ED–photodoxaz releases doxaz under near-UV irradiation to inhibit cell growth with low nanomolar IC50 values. The MARCKS–ED–photodoxaz system targeting exosomes and utilizing photochemistry will potentially provide a new appro...

Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad spectrum and high absorbance near infrared optoacoustic contrast agent, E4x12-Cy7. Our near infrared tracer (E4x12-Cy7) is based on the amino acid sequence of exendin-4 and targets the glucagon-like peptide-1 receptor (GLP-1R). Cell assays confirmed that E4x12-Cy7 has a high binding affinity (IC50= 4.6 ± 0.8 nM). Using the multi-spectral optoacoustic tomography (MSOT), we imaged E4x12-Cy7 and optoacoustically visualized ß-cell insulinoma xenograftsin vivofor the first time. In the future, similar optoacoustic tracers that are specific for ß-cells and combines optoacoustic and fluorescence imaging modalities could prove to be important tools for monitoring the pancreas for the progression of diabetes.

Cerenkov luminescence (CL) is blue glow light produced by charged subatomic particles travelling faster than the phase velocity of light in a dielectric medium such as water or tissue. CL was first discovered in 1934, but for biomedical research it was recognized only in 2009 after advances in optical camera sensors brought the required high sensitivity. Recently, applications of CL from clinical radionuclides have been rapidly expanding to include not only preclinical and clinical biomedical imaging but also an approach to therapy. Cerenkov Luminescence Imaging (CLI) utilizes CL generated from clinically relevant radionuclides alongside optical imaging instrumentation. CLI is advantageous over traditional nuclear imaging methods in terms of infrastructure cost, resolution, and imaging time. Furthermore, CLI is a truly multimodal imaging method where the same agent can be detected by two independent modalities, with optical (CL) imaging and with positron emission tomography (PET) imaging. CL has been combined with small molecules, biomolecules and nanoparticles to improve diagnosis and therapy in cancer research. Here, we cover the fundamental breakthroughs and recent advances in reagents and instrumentation methods for CLI as well as therapeutic application of CL.

Recent interest in detecting visible photons that emanate from interactions of ionizing radiation (IR) with matter has spurred the development of multifunctional materials that amplify the optical signal from radiotracers. Tailored stimuli-responsive systems may be paired with diagnostic radionuclides to improve surgical guidance and aid in detecting therapeutic radionuclides otherwise difficult to image with conventional nuclear medicine approaches. Because light emanating from these interactions is typically low in intensity and blue-weighted (i.e., greatly scattered and absorbed in vivo), it is imperative to increase or shift the photon flux for improved detection. To address this challenge, a gel that is both scintillating and fluorescent is used to enhance the optical photon output in image mapping for cancer imaging. Tailoring biobased materials to synthesize thixotropic thermoreversible hydrogels (a minimum gelation concentration of 0.12 wt %) offers image-aiding systems which are not only functional but also potentially economical, safe, and environmentally friendly. These robust gels (0.66 wt %, ∼900 Pa) respond predictably to different types of IRs including β- and γ-emitters, resulting in a doubling of the detectable photon flux from these emitters. The synthesis and formulation of such a gel are explored with a focus on its physicochemical and mechanical properties, before being utilized to enhance the visible photon flux from a panel of radionuclides as detected. The possibility of developing a topical cream of this gel makes this system an attractive potential alternative to current techniques, and the multifunctionality of the gelator may serve to inspire future next-generation materials.

Novel translational approaches based on clinical modular nanoplatforms are needed, in order to treat solid cancers according to their discrete molecular features. In the present study, we show that the clinical nanopharmaceutical Ferumoxytol, which consists of a glucose-based coat surrounding an iron oxide core, could identify molecular characteristics of prostate cancer, corresponding to unique phases of the disease continuum. By affixing a targeting probe for the prostate-specific membrane antigen on its surface, the nanopharmaceutical was able to assess the functional state of the androgen receptor pathway via MRI, guiding therapy and delivering it with the same clinical nanoparticle. In order to simultaneously inhibit oncogenic signaling from key oncogenic pathways of more advanced forms of prostate cancer, a single-agent therapy for early-stage disease to inhibit DNA replication, as well as combination therapy with two drugs co-retained within the nanopharmaceutical’s polymeric coating, were tested, and resulted complete tumor ablation. Recalcitrant and terminal forms of the disease were effectively treated with a nanoparmaceutical delivering a combination that upregulates endoplasmic reticulum stress and inhibits metastasis, thereby showing that this multifunctional nanoplatfom can be used in the clinic for patient stratification, as well as precision treatment based on the individual’s unique disease features.

A big challenge in the clinical use of Cerenkov luminescence (CL) imaging is its low signal intensity, which is several orders of magnitude below ambient light. Consequently, highly sensitive cameras, sufficient shielding from background light, and long acquisition times are required. To alleviate this problem, we hypothesized a strategy to convert the weak CL signal into a stronger fluorescence signal by using CL-activated formation of nitrenes from azides to locally fix a fluorescent probe in tissue by the formation of a covalent bond. CL-activated drug delivery was also evaluated using the same azide chemistry. The specific delivery of the CL-activated drug to cancer cells could reduce systemic toxicity, which is a limitation in chemotherapy. Methods: A cyanine-class near-infrared fluorescent dye, Cy7, and doxorubicin were synthetically attached to polyfluorinated aryl azide to form Cy7 azide and DOX azide, respectively. Fibrosarcoma cells were incubated with 18F-FDG and exposed to Cy7 azide with subsequent fluorescence imaging. For CL-activated tagging in vivo, tumor-bearing mice were injected first with 90Y-DOTA-RGD, targeting αvβ3 integrins, and then with the Cy7 azide. Fluorescence signal was imaged over time. Breast cancer cells were incubated with DOX azide and 68Ga, after which cell viability was quantified using an assay. Results: CL photoactivation of Cy7 azide in vitro showed significantly higher fluorescence signal from 18F-FDG–treated than untreated cells. In vivo, CL photoactivation could be shown by using the tumor-specific, integrin-targeting 90Y-DOTA-RGD and the localized activation of Cy7 azide. Here, localized CL-induced fluorescence was detected in the tumors and remained significantly higher over several days than in tumors without CL. We also established as a next step CL-activated drug delivery of DOX azide by showing significantly decreasing cell viability of breast cancer cells in a CL dose–dependent manner in vitro using CL photoactivation of DOX azide. Conclusion: We were able to develop a CL-activated “sticky tag” that converts the low CL signal into a stable and long-lasting, highly intense fluorescence signal. This fluorescent footprint of the radioactive signal might be clinically used for intraoperative surgery. The CL-targeted drug delivery strategy may potentially be used for dual-step targeted therapy.

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA(1) interacts with TRIM21 and α-GA(1) treatment reduced GA levels, increased GA turnover, decreased RAN toxicity and decreased co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA(1) reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA(1) is important for cell entry and efficacy. These data demonstrate RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

Vehicle-to-Everything (V2X) communication allows infrastructure elements, e.g., traffic lights, to directly communicate with vehicles, thereby allowing services like Green Light Optimized Speed Advisory (GLOSA), Probe Vehicle Data (PVD), and Traffic Signal Priority Request (TSP). The idea behind GLOSA is to assist vehicles approaching an intersection with speed advices in order to fulfill a given objective, e.g., minimizing fuel usage, emissions and/or delay. In a prior work (Kloeppel et al., 2019), several GLOSA algorithms were examined and their fitness (in the form of CO2 emissions, fuel usage and delay) were evaluated under largely realistic conditions. This paper is an extension of the prior work and presents further examinations, which include a more detailed study on the behaviour of Diesel-powered vehicles when using the GLOSA algorithm of Stebbins et al. (2017) as well as a study considering fixed-time control coupled with intelligent vehicles.

Wolfgang A. Weber and Johannes Czernin Scientific discoveries published in The Journal of Nuclear Medicine over the past 60 years have shaped the practice of medicine and form the foundation for the future of nuclear medicine, molecular imaging, and theranostics. Nuclear medicine now provides