Publications by authors named "J Michael Engle"

343 Publications

Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain.

Radiat Res 2021 Apr 7. Epub 2021 Apr 7.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Brain metastases develop in over 60% of advanced melanoma patients and negatively impact quality of life and prognosis. In a murine melanoma model, we previously showed that an in situ vaccination (ISV) regimen, combining radiation treatment and intratumoral (IT) injection of immunocytokine (IC: anti-GD2 antibody fused to IL2), along with the immune checkpoint inhibitor anti-CTLA-4, robustly eliminates peripheral flank tumors but only has modest effects on co-occurring intracranial tumors. In this study, we investigated the ability of low-dose radiation to the brain to potentiate anti-tumor immunity against a brain tumor when combined with ISV + anti-CTLA-4. B78 (GD2+, immunologically "cold") melanoma tumor cells were implanted into the flank and the right striatum of the brain in C57BL/6 mice. Flank tumors (50-150 mm3) were treated following a previously optimized ISV regimen [radiation (12 Gy × 1, treatment day 1), IT-IC (50 mg daily, treatment days 6-10), and anti-CTLA-4 (100 mg, treatment days 3, 6, 9)]. Mice that additionally received whole-brain radiation treatment (WBRT, 4 Gy × 1) on day 15 demonstrated significantly increased survival compared to animals that received ISV + anti-CTLA-4 alone, WBRT alone or no treatment (control) (P < 0.001, log-rank test). Timing of WBRT was critical, as WBRT administration on day 1 did not significantly enhance survival compared to ISV + anti-CTLA-4, suggesting that the effect of WBRT on survival might be mediated through immune modulation and not just direct tumor cell cytotoxicity. Modest increases in T cells (CD8+ and CD4+) and monocytes/macrophages (F4/80+) but no changes in FOXP3+ regulatory T cells (Tregs), were observed in brain melanoma tumors with addition of WBRT (on day 15) to ISV + anti-CTLA-4. Cytokine multiplex immunoassay revealed distinct changes in both intracranial melanoma and contralateral normal brain with addition of WBRT (day 15) to ISV + anti-CTLA-4, with notable significant changes in pro-inflammatory (e.g., IFNg, TNFa and LIX/CXCL5) and suppressive (e.g., IL10, IL13) cytokines as well as chemokines (e.g., IP-10/CXCL10 and MIG/CXCL9). We tested the ability of the alkylphosphocholine analog, NM600, to deliver immunomodulatory radiation to melanoma brain tumors as a targeted radionuclide therapy (TRT). Yttrium-86 (86Y) chelated to NM600 was delivered intravenously by tail vein to mice harboring flank and brain melanoma tumors, and PET imaging demonstrated specific accumulation up to 72 h at each tumor site (∼12:1 brain tumor/brain and ∼8:1 flank tumor/muscle). When NM600 was chelated to therapeutic b particle-emitting 90Y and administered on treatment day 13, T-cell infiltration and cytokine profiles were altered in melanoma brain tumor, like that observed for WBRT. Overall, our results demonstrate that addition of low-dose radiation, timed appropriately with ISV administration to tumors outside the brain, significantly increases survival in animals co-harboring melanoma brain tumors. This observation has potentially important translational implications as a treatment strategy for increasing the response of tumors in the brain to systemically administered immunotherapies.
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http://dx.doi.org/10.1667/RADE-20-00237.1DOI Listing
April 2021

Characterization of actinide resin for separation of Mn from bulk target material.

Nucl Med Biol 2021 Mar 3;96-97:19-26. Epub 2021 Mar 3.

University of Wisconsin, Department of Medical Physics, 1111 Highland Avenue, Madison, WI 53711, United States of America; University of Wisconsin, Department of Radiology, 600 Highland Avenue, Madison, WI 53792, United States of America. Electronic address:

We report an extraction chromatography-based method via Actinide Resin for the isolation of radio-manganese from both natural chromium and isotopically enriched iron targets for cyclotron production of Mn and Mn. For the separation of Mn from nCr, a decay-corrected radiochemical yield of 83.7 ± 8.4% was achieved. For Mn from Fe, a decay-corrected radiochemical yield of 78 ± 11% was achieved. This automatable method efficiently isolates both radionuclides from accelerator target material.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.02.005DOI Listing
March 2021

Anticipation to Social and Nonsocial Dynamic Cues in Preschool-Age Children.

Child Dev 2021 Mar 9. Epub 2021 Mar 9.

University of California, San Diego.

The ability to learn from expectations is foundational to social and nonsocial learning in children. However, we know little about the brain basis of reward expectation in development. Here, 3- to 4-year-olds (N = 26) were shown a passive associative learning paradigm with dynamic stimuli. Anticipation for reward-related stimuli was measured via the stimulus preceding negativity (SPN). To our knowledge, this is the first study to measure an SPN in children younger than age 6. Our findings reveal distinct anticipatory neural signatures for social versus nonsocial stimuli, consistent with previous research in older children. This study suggests an SPN can be elicited in preschoolers and is larger for social than nonsocial stimuli.
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http://dx.doi.org/10.1111/cdev.13551DOI Listing
March 2021

Status and future perspectives of Meitner-Auger and low energy electron-emitting radionuclides for targeted radionuclide therapy.

Nucl Med Biol 2021 Mar-Apr;94-95:106. Epub 2021 Feb 16.

Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

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http://dx.doi.org/10.1016/j.nucmedbio.2021.02.001DOI Listing
February 2021

ImmunoPET/NIRF/Cerenkov multimodality imaging of ICAM-1 in pancreatic ductal adenocarcinoma.

Eur J Nucl Med Mol Imaging 2021 Feb 3. Epub 2021 Feb 3.

Department of Radiology, University of Wisconsin-Madison, Room 7137, 1111 Highland Ave, Madison, WI, 53705, USA.

Purpose: We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI).

Methods: ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer.

Results: ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [Zr]Zr-DFO-ICAM-1-IR800 compared to [Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1-targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology.

Conclusion: We successfully developed a dual-labeled ICAM-1-targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation.
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http://dx.doi.org/10.1007/s00259-021-05216-3DOI Listing
February 2021

ImmunoPET of CD146 in Orthotopic and Metastatic Breast Cancer Models.

Bioconjug Chem 2021 Jan 21. Epub 2021 Jan 21.

Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

The overexpression of CD146 in breast cancer is considered a hallmark of tumor progression and metastasis, particularly in triple negative breast cancer. Aimed at imaging differential CD146 expressions in breast cancer, a noninvasive method for predictive prognosis and diagnosis was investigated using a Cu-labeled CD146-specific monoclonal antibody, YY146. CD146 expression was screened in human breast cancer cell lines using Western blotting. Binding ability was evaluated using flow cytometry and immunofluorescent staining. YY146 was conjugated with 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with Cu following standard procedures. Serial PET or PET/CT imaging was performed in orthotopic and metastatic breast cancer tumor models. Biodistribution was performed after the final time point of imaging. Finally, tissue immunofluorescent staining and hematoxylin and eosin (H&E) staining were performed on tumor tissues. The MDA-MB-435 cell line showed the highest CD146 expression level, whereas MCF-7 had the lowest level at the cellular level. ImmunoPET showed that MDA-MB-435 orthotopic tumors had high and clear radioactive accumulation after the administration of Cu-NOTA-YY146. The tumor uptake of Cu-NOTA-YY146 in MDA-MB-435 was significantly higher than that in MCF-7 and nonspecific IgG control groups ( < 0.01). Biodistribution verified the PET imaging results. For metastatic models, Cu-NOTA-YY146 allowed for the visualization of high radioactivity accumulation in metastatic MDA-MB-435 tumors, which was confirmed by ex vivo biodistribution of lung tissues. H&E staining proved the successful building of metastatic tumor models. Immunofluorescent staining verified the differential expression of CD146 in orthotopic tumors. Therefore, Cu-NOTA-YY146 could be used as an immunoPET probe to visualize CD146 in the breast cancer model and is potentially useful for cancer diagnosis, prognosis prediction, and monitoring therapeutic response.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00649DOI Listing
January 2021

Accelerator Production of Scandium Radioisotopes: Sc-43, Sc-44, and Sc- 47.

Curr Radiopharm 2021 Jan 12. Epub 2021 Jan 12.

Departments of Medical Physics and Radiology, University of Wisconsin Madison. B1303 WIMR Cyclotron Laboratory, 1111 Highland Avenue, Madison WI 53705,. United States.

Scandium radioisotopes are increasingly considered viable radiolabels for targeted molecular imaging (Sc-43, Sc-44) and therapy (Sc-47). Significant technological advances have increased the quantity and quality of available radioscandium in the past decade, motivated in part by the chemical similarity of scandium to therapeutic radionuclides like Lu-177. The production and radiochemical isolation techniques applied to scandium radioisotopes are reviewed, focusing on charged particle and electron linac initiated reactions and using calcium and titanium starting materials.
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http://dx.doi.org/10.2174/1874471014999210112205535DOI Listing
January 2021

Meitner-Auger Electron Emitters for Targeted Radionuclide Therapy: Mercury-197m/g and Antimony-119.

Curr Radiopharm 2021 Jan 11. Epub 2021 Jan 11.

Chemistry, Science, University of British Columbia, BC,. Canada.

Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art in production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony-119 (119Sb) and mercury-197 (197Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin.
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http://dx.doi.org/10.2174/1874471014999210111201630DOI Listing
January 2021

Thinking Counterfactually Supports Children's Evidence Evaluation in Causal Learning.

Child Dev 2021 Jan 9. Epub 2021 Jan 9.

University of California, San Diego.

Often, the evidence we observe is consistent with more than one explanation. How do learners discriminate among candidate causes? The current studies examine whether counterfactuals help 5-year olds (N = 120) select between competing hypotheses and compares the effectiveness of these prompts to a related scaffold. In Experiment 1, counterfactuals support evidence evaluation, leading children to privilege and extend the cause that accounted for more data. In Experiment 2, the hypothesis that accounted for the most evidence was pitted against children's prior beliefs. Children who considered alternative outcomes privileged the hypothesis that accounted for more observations, whereas those who explained relied on prior beliefs. Findings demonstrate that counterfactuals recruit attention to disambiguating evidence and outperform explanation when data contrast with existing beliefs.
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http://dx.doi.org/10.1111/cdev.13518DOI Listing
January 2021

A review of accelerator-produced Ga-68 with solid targets.

Curr Radiopharm 2020 Dec 23. Epub 2020 Dec 23.

Departments of Medical Physics and Radiology, University of Wisconsin Madison. B1303 WIMR Cyclotron Laboratory, 1111 Highland Avenue, Madison WI 53705. United States.

Ga-68 is a positron-emitting nuclide that has recently achieved clinical acceptance as the diagnostic radionuclide in PET tracers used for theranostic studies of Lu-177 labeled therapeutic drugs due to the ease of access provided by Ge-68/Ga-68 generators. An alternative method of production currently being explored uses accelerators to form Ga-68 directly. This review of Ga-68 production strategies discusses available accelerator targetry at a range of beam energies and intensities, the many radiochemical separation techniques available to isolate Ga-68 from irradiated targets, isotopically enriched target material recovery, and the implications of these techniques for downstream radiolabeling applications.
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http://dx.doi.org/10.2174/1874471013666201224113651DOI Listing
December 2020

Developing the Ce and La pair as companion positron emission tomography diagnostic isotopes for Ac and Th radiotherapeutics.

Nat Chem 2021 03 14;13(3):284-289. Epub 2020 Dec 14.

Department of Nuclear Engineering, University of California, Berkeley, CA, USA.

Developing targeted α-therapies has the potential to transform how diseases are treated. In these interventions, targeting vectors are labelled with α-emitting radioisotopes that deliver destructive radiation discretely to diseased cells while simultaneously sparing the surrounding healthy tissue. Widespread implementation requires advances in non-invasive imaging technologies that rapidly assay therapeutics. Towards this end, positron emission tomography (PET) imaging has emerged as one of the most informative diagnostic techniques. Unfortunately, many promising α-emitting isotopes such as Ac and Th are incompatible with PET imaging. Here we overcame this obstacle by developing large-scale (Ci-scale) production and purification methods for Ce. Subsequent radiolabelling and in vivo PET imaging experiments in a small animal model demonstrated that Ce (and its La daughter) could be used as a PET imaging candidate for Ac (with reduced Ce) or Th (with oxidized Ce). Evaluating these data alongside X-ray absorption spectroscopy results demonstrated how success relied on rigorously controlling the Ce/Ce redox couple.
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http://dx.doi.org/10.1038/s41557-020-00598-7DOI Listing
March 2021

Automated, cassette-based isolation and formulation of high-purity [Cu]CuCl from solid Ni targets.

EJNMMI Radiopharm Chem 2020 Nov 5;5(1):21. Epub 2020 Nov 5.

Cyclotrons and TRACERcenter, GE Healthcare, GEMS PET Systems AB, Uppsala, Sweden.

Background: A need for improved, cassette-based automation of Cu separation from irradiated Ni targets was identified given the growing interest in theranostics, and generally lengthy separation chemistries for Cu/Ni, upon which Cu chemistry is often based.

Methods: A method for separating Cu from irradiated Ni targets was therefore developed, with provision for target recycling. Following deuteron irradiation, electroplated Ni targets were remotely transferred from the cyclotron and dissolved in acid. The dissolved target solution was then transferred to an automated FASTlab chemistry module, where sequential TBP and TK201 (Triskem) resins isolated the [Cu]CuCl, removed Ni, Co, and Fe, and concentrated the product into a formulation suitable for anticipated radiolabelling reactions.

Results: Cu saturation yields of 190 ± 33 MBq/μA from energetically thick Ni targets were measured. The average, decay-corrected, activity-based dissolution efficiency was 97.5 ± 1.4% with an average radiochemical yield of 90.4 ± 3.2% (N = 5). The isolated activity was collected approximately 65 min post end of bombardment in ~ 2 mL of 0.06 M HCl (HCl concentration was verified by titration). Quality control of the isolated [Cu]CuCl (N = 5) measured Co content of (8.3 ± 0.6) × 10% vs. Cu by activity, Ni separation factors ≥ (2.2 ± 1.8) × 10, EoB molar activities 85 ± 23 GBq/μmol and NOTA-based EoB apparent molar activities of 31 ± 8 MBq/nmol and 201 MBq/nmol for the 30 min and 3.3 h (N = 1) irradiations, respectively.

Conclusion: High purity Cu was produced with the developed automated method using a single-use, cassette-based approach. It was also applicable for Cu, as demonstrated with a single proof-of-concept Ni target production run.
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http://dx.doi.org/10.1186/s41181-020-00108-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644601PMC
November 2020

Comparison of continuous versus intermittent infusion cyclosporine and impact on transplant related outcomes in allogeneic transplant recipients.

J Oncol Pharm Pract 2020 Nov 2:1078155220970608. Epub 2020 Nov 2.

Hematology, Oncology, and Transplant, University of Minnesota, Minneapolis, MN, USA.

Introduction: Continuous infusion (CIVI) cyclosporine (CsA) is an alternative for allograft recipients intolerant of twice daily infusions (TDI). The importance of achieving therapeutic levels of CsA early after allogeneic HCT has been demonstrated in previous studies. Our study evaluated the incidence of acute graft versus host disease (GVHD) and survival among patients receiving CIVI vs. TDI CsA during their first allogeneic HCT.

Methods: A retrospective study of adult patients undergoing first allogeneic HCT at the University of Minnesota Medical Center between 2011 and 2017. Patients were grouped according to the administration method. The primary outcome was the occurrence of acute grade II-IV GVHD by day +180. Secondary outcomes included the 1-year incidence of chronic GVHD, relapse, and overall survival.

Results: 42 patients intolerant of TDI CsA received CsA via CIVI for >48 hours for a median of 9 days (range, 3-32 days). CsA concentrations were similar between groups. We found no difference between the rates of grade II-IV acute (45% vs 53%, p = 0.59) or chronic (17% vs 30%, p = 0.20) GVHD or overall survival (57% vs 67%, p = 0.10). Subgroup analysis of patients that received myeloablative conditioning or umbilical cord blood did not reveal significant differences in GVHD or overall survival. Cumulative incidence of relapse was higher among the continuous infusion group (39% vs. 23%, p < 0.01).

Conclusion: Due to the finding of increased risk of relapse, cyclosporine should be administered as traditional twice daily infusion unless necessary. A prospective clinical trial is needed to confirm these results.
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http://dx.doi.org/10.1177/1078155220970608DOI Listing
November 2020

Cyclotron produced La as a PET imaging surrogate of therapeutic Ac.

J Nucl Med 2020 Oct 30. Epub 2020 Oct 30.

Departments of Medical Physics, University of Wisconsin Madison, United States.

The aim of this work is to explore La as a PET imaging surrogate of Ac using a DOTA-based, tumor-targeting alkylphosphocholine (NM600).

Methods: La was produced on a biomedical cyclotron. For in vivo experiments, mice bearing 4T1 tumors were administered [La]-NM600, and PET/CT scans were acquired up to 24h post-injection (p.i.). Following the last timepoint, ex vivo tissue distribution was measured to corroborate in vivo PET data. Ex vivo tissue distribution was performed at 4h and 24h p.i. in mice injected with [Ac]-NM600.

Results: PET/CT images showed elevated, persistent [La]-NM600 uptake in the tumor. Low bone accumulation confirmed the in vivo stability of the conjugate. Ex vivo biodistribution validated the image-derived quantitative data, and the comparison of the [La]-NM600 and [Ac]-NM600 tissue distribution revealed similar biodistribution of the two radiotracers.

Conclusions: These findings suggest that La is a suitable imaging surrogate to probe the in vivo biodistribution of Ac radiotherapeutics.
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http://dx.doi.org/10.2967/jnumed.120.255794DOI Listing
October 2020

Auditory and Visual System White Matter Is Differentially Impacted by Normative Aging in Macaques.

J Neurosci 2020 11 13;40(46):8913-8923. Epub 2020 Oct 13.

Division of Neural System, Memory and Aging, University of Arizona, Tucson, Arizona 85724

Deficits in auditory and visual processing are commonly encountered by older individuals. In addition to the relatively well described age-associated pathologies that reduce sensory processing at the level of the cochlea and eye, multiple changes occur along the ascending auditory and visual pathways that further reduce sensory function in each domain. One fundamental question that remains to be directly addressed is whether the structure and function of the central auditory and visual systems follow similar trajectories across the lifespan or sustain the impacts of brain aging independently. The present study used diffusion magnetic resonance imaging and electrophysiological assessments of auditory and visual system function in adult and aged macaques to better understand how age-related changes in white matter connectivity at multiple levels of each sensory system might impact auditory and visual function. In particular, the fractional anisotropy (FA) of auditory and visual system thalamocortical and interhemispheric corticocortical connections was estimated using probabilistic tractography analyses. Sensory processing and sensory system FA were both reduced in older animals compared with younger adults. Corticocortical FA was significantly reduced only in white matter of the auditory system of aged monkeys, while thalamocortical FA was lower only in visual system white matter of the same animals. Importantly, these structural alterations were significantly associated with sensory function within each domain. Together, these results indicate that age-associated deficits in auditory and visual processing emerge in part from microstructural alterations to specific sensory white matter tracts, and not from general differences in white matter condition across the aging brain. Age-associated deficits in sensory processing arise from structural and functional alterations to both peripheral sensory organs and central brain regions. It remains unclear whether different sensory systems undergo similar or distinct trajectories in function across the lifespan. To provide novel insights into this question, this study combines electrophysiological assessments of auditory and visual function with diffusion MRI in aged macaques. The results suggest that age-related sensory processing deficits in part result from factors that impact the condition of specific white matter tracts, and not from general decreases in connectivity between sensory brain regions. Such anatomic specificity argues for a framework aimed at understanding vulnerabilities with relatively local influence and brain region specificity.
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http://dx.doi.org/10.1523/JNEUROSCI.1163-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659446PMC
November 2020

Chelation with a twist: a bifunctional chelator to enable room temperature radiolabeling and targeted PET imaging with scandium-44.

Chem Sci 2020 Jan 20;11(2):333-342. Epub 2019 Nov 20.

Department of Chemistry , Stony Brook University , 100 Nicolls Road , Stony Brook , 11790 , New York , USA . Email:

Scandium-44 has emerged as an attractive, novel PET radioisotope with ideal emission properties and half-life ( = 3.97 h, β = 632 keV) well matched to the pharmacokinetics of small molecules, peptides and small biologics. Conjugates of the current gold-standard chelator for Sc, 1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid (DOTA), require heating to achieve radiochemical complexation, limiting application of this isotope in conjunction with temperature-sensitive biologics. To establish Sc(iii) isotopes as broadly applicable tools for nuclear medicine, development of alternative bifunctional chelators is required. To address this need, we characterized the Sc(iii)-chelation properties of the small-cavity triaza-macrocycle-based, picolinate-functionalized chelator Hmpatcn. Spectroscopic and radiochemical studies establish the [Sc(mpatcn)] complex as kinetically inert and appropriate for biological applications. A proof-of-concept bifunctional conjugate targeting the prostate-specific membrane antigen (PSMA), picaga-DUPA, chelates Sc to form Sc(picaga)-DUPA at room temperature with an apparent molar activity of 60 MBq μmol and formation of inert -Λ and -Δ-twist isomers. Sc(picaga)-DUPA exhibits a of 1.6 nM for PSMA, comparable to the F-based imaging probe DCFPyL ( = 1.1 nM) currently in phase 3 clinical trials for imaging prostate cancer. Finally, we successfully employed Sc(picaga)-DUPA to image PSMA-expressing tumors in a preclinical mouse model, establishing the picaga bifunctional chelator as an optimal choice for the Sc PET nuclide.
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http://dx.doi.org/10.1039/c9sc04655kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472660PMC
January 2020

Noninvasive Evaluation of CD20 Expression Using Cu-Labeled F(ab') Fragments of Obinutuzumab in Lymphoma.

J Nucl Med 2021 Mar 21;62(3):372-378. Epub 2020 Aug 21.

Departments of Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin

CD20-overexpressed non-Hodgkin lymphoma typically indicates progressive malignancy. Obinutuzumab is a next-generation Food and Drug Administration-approved humanized monoclonal antibody that targets CD20. Previous studies with Zr-labeled obinutuzumab have successfully imaged CD20 in vivo. However, delayed tumor uptake and increased radioactive exposure caused by long blood circulation limit its clinical translation. This study aimed to develop Cu-labeled F(ab') fragments of obinutuzumab for imaging CD20 in lymphoma xenograft tumor models. F(ab') fragments were produced from obinutuzumab using an IgG-degrading enzyme of (IdeS) enzyme and purified with protein A beads. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography were performed to evaluate the products and their stability. F(ab') products were conjugated with p-SCN-Bn-NOTA (NOTA) for Cu radiolabeling. Western blotting was performed to screen the CD20 expression levels of lymphoma cells. Enzyme-linked immunosorbent assay, flow cytometry, and confocal imaging were used to test the binding affinity in vitro. Serial PET imaging and biodistribution studies in subcutaneous lymphoma-bearing mice were performed using Cu-NOTA-F(ab')-obinutuzumab or Cu-NOTA-F(ab')-IgG. F(ab')-obinutuzumab and F(ab')-IgG produced by the IdeS digestion system were confirmed with sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography. The radiochemical purity of Cu-labeled F(ab') fragments was no less than 98%, and the specific activity was 56.3 ± 7.9 MBq/mg ( = 6). Among the 5 lymphoma cell lines, Ramos showed the strongest expression of CD20, and CLL-155 showed the lowest, as confirmed by enzyme-linked immunosorbent assay, flow cytometry, and confocal imaging. PET imaging revealed rapid and sustained tumor uptake of Cu-NOTA-F(ab')-obinutuzumab in Ramos tumor-bearing mice. The peak tumor uptake (9.08 ± 1.67 percentage injected dose per gram of tissue [%ID/g]) in the Ramos model was significantly higher than that in the CCL-155 model (2.78 ± 0.62 %ID/g) or the Cu-NOTA-F(ab')-IgG control (1.93 ± 0.26 %ID/g, = 4, < 0.001). The tumor-to-blood and tumor-to-muscle ratios were 7.3 ± 1.6 and 21.9 ± 9.0, respectively, at 48 h after injection in the Cu-NOTA-F(ab')-obinutuzumab group. Of the measured off-target organs, the kidneys showed the highest uptake. Ex vivo immunofluorescent staining verified the differential CD20 expression in the Ramos and CCL-155 tumor models. This study demonstrated that Cu-NOTA-F(ab')-obinutuzumab had a rapid and sustained tumor uptake in CD20-positive lymphoma with high contrast, which could enable noninvasive evaluation of CD20 levels in the clinic.
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http://dx.doi.org/10.2967/jnumed.120.246595DOI Listing
March 2021

Prevention of Hepatic Ischemia-Reperfusion Injury by Carbohydrate-Derived Nanoantioxidants.

Nano Lett 2020 09 14;20(9):6510-6519. Epub 2020 Aug 14.

Department of Material Science and Engineering, University of Wisconsin - Madison, Madison, Wisconsin 53706, United States.

Hepatic ischemia-reperfusion injury (IRI), which mainly results from excessive reactive oxygen species (ROS) generated by a reperfusion burst of oxygen, has long been a major cause of liver dysfunction and failure after surgical procedures. Here, a monodispersed hydrophilic carbohydrate-derived nanoparticle (C-NP) was synthesized as a nanoantioxidant that could effectively prevent hepatic IRI. The spherical C-NPs had a size of ∼78 ± 11.3 nm covered with polar surface groups. They were well dispersible in water with good colloidal stability, nontoxicity, and good ROS scavenging capability. The C-NPs also exhibited good circulation lifetime, effective delivery to liver, and gradual degradability with an ability to assist the IRI group maintaining a normal and healthy liver status. The pathology mechanism of C-NPs in hepatic IRI was confirmed to be scavenging of excessive ROS by C-NPs. The effective therapeutic treatment of C-NPs in living animals revealed a great potential in clinical prevention for hepatic IRI.
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http://dx.doi.org/10.1021/acs.nanolett.0c02248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484346PMC
September 2020

Sulfoxide-Containing Polymer-Coated Nanoparticles Demonstrate Minimal Protein Fouling and Improved Blood Circulation.

Adv Sci (Weinh) 2020 Jul 17;7(13):2000406. Epub 2020 May 17.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane QLD 4072 Australia.

Minimizing the interaction of nanomedicines with the mononuclear phagocytic system (MPS) is a critical challenge for their clinical translation. Conjugating polyethylene glycol (PEG) to nanomedicines is regarded as an effective approach to reducing the sequestration of nanomedicines by the MPS. However, recent concerns about the immunogenicity of PEG highlight the demand of alternative low-fouling polymers as innovative coating materials for nanoparticles. Herein, a highly hydrophilic sulfoxide-containing polymer-poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA)-is used for the surface coating of iron oxide nanoparticles (IONPs). It is found that the PMSEA polymer coated IONPs have a more hydrophilic surface than their PEGylated counterparts, and demonstrate remarkably reduced macrophage cellular uptake and much less association with human plasma proteins. In vivo study of biodistribution and pharmacokinetics further reveals a much-extended blood circulation (≈2.5 times longer in terms of elimination half-life ) and reduced accumulation (approximately two times less) in the organs such as the liver and spleen for IONPs coated by PMSEA than those by PEG. It is envisaged that the highly hydrophilic sulfoxide-containing polymers have huge potential to be employed as an advantageous alternative to PEG for the surface functionalization of a variety of nanoparticles for long circulation and improved delivery.
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http://dx.doi.org/10.1002/advs.202000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341081PMC
July 2020

Tissue Factor-Targeted ImmunoPET Imaging and Radioimmunotherapy of Anaplastic Thyroid Cancer.

Adv Sci (Weinh) 2020 Jul 17;7(13):1903595. Epub 2020 May 17.

Departments of Radiology and Medical Physics University of Wisconsin-Madison Madison WI 53705 USA.

Anaplastic thyroid cancer (ATC) is the most aggressive subtype of thyroid cancers with a dismal prognosis. It is aimed to explore a new biomarker and devise a marker-dependent theranostic pair for ATC. Flow cytometry is used to determine tissue factor (TF) expression in thyroid cancer cell lines. ALT-836, a TF-specific monoclonal antibody, is radiolabeled with Cu to develop Cu-NOTA-ALT-836. The diagnostic utility is assessed by immuno-positron emission tomography (immunoPET) imaging in ATC models. To facilitate total surgical removal of orthotopic ATCs, a near-infrared fluorescent imaging probe IRDye 800CW-ALT-836 is designed. As the therapeutic component, I-ALT-836 is further developed and the radioimmunotherapy (RIT) efficacy of this agent is interrogated in orthotopic ATC models. The results demonstrate that TF is highly expressed on the ATC cell line THJ-16T. Cu-NOTA-ALT-836 immunoPET imaging clearly delineates both subcutaneous and orthotopic ATCs, with a peak tumor uptake of 19.93 ± 2.17% ID per g ( = 3) and 37.20 ± 1.71% ID per g ( = 3), respectively. Fluorescent imaging with IRDye 800CW-ALT-836 facilitates the total resection of orthotopic ATCs. Moreover, I-ALT-836 RIT prolongs the survival of ATC-bearing mice. Taken together, TF is a promising marker for ATC and successive use of Cu-NOTA-ALT-836 and I-ALT-836 can realize precise management of ATC.
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http://dx.doi.org/10.1002/advs.201903595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341097PMC
July 2020

Assuring Quality in Pharmacy Education During a Time of Crisis.

Authors:
Janet P Engle

Am J Pharm Educ 2020 06;84(6):ajpe8135

Accreditation Council for Pharmacy Education, Chicago, Illinois.

The COVID-19 pandemic has disrupted all facets of pharmacy education, including accreditation and certification activities. In a very short period of time, Doctor of Pharmacy (PharmD) programs and pharmacy technician programs had to convert to teaching classes online, experiential education sites had to figure out how to train student pharmacists and pharmacy technicians while ensuring their safety, continuing pharmacy education providers had to move their in-person courses online, and the Accreditation Council for Pharmacy Education (ACPE) had to postpone accreditation site visits. Given the challenges faced by our constituencies, the ACPE implemented processes and suggested solutions that stayed within the boundaries of the standards while at the same time allowing flexibility so that organizations could achieve their educational outcomes even given the constraints produced by the pandemic.
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http://dx.doi.org/10.5688/ajpe8135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334348PMC
June 2020

Fifty Years of Radiopharmaceuticals.

J Nucl Med Technol 2020 06;48(Suppl 1):34S-39S

Molecular Imaging Core, Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee; and.

To celebrate the 50th anniversary of the founding of the SNMMI Technologist Section in 1970, the Radiopharmaceutical Sciences Council board of directors is pleased to contribute to this celebratory supplement of the with a perspective highlighting major developments in the radiopharmaceutical sciences that have occurred in the last 50 years.
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June 2020

Selenium-Doped Carbon Quantum Dots Act as Broad-Spectrum Antioxidants for Acute Kidney Injury Management.

Adv Sci (Weinh) 2020 Jun 29;7(12):2000420. Epub 2020 Apr 29.

Department of Pharmaceutical Sciences University of Wisconsin-Madison Madison WI 53705 USA.

The manifestation of acute kidney injury (AKI) is associated with poor patient outcomes, with treatment options limited to hydration or renal replacement therapies. The onset of AKI is often associated with a surfeit of reactive oxygen species. Here, it is shown that selenium-doped carbon quantum dots (SeCQDs) have broad-spectrum antioxidant properties and prominent renal accumulation in both healthy and AKI mice. Due to these properties, SeCQDs treat or prevent two clinically relevant cases of AKI induced in murine models by either rhabdomyolysis or cisplatin using only 1 or 50 µg per mouse, respectively. The attenuation of AKI in both models is confirmed by blood serum measurements, kidney tissue staining, and relevant biomarkers. The therapeutic efficacy of SeCQDs exceeds amifostine, a drug approved by the Food and Drug Administration that also acts by scavenging free radicals. The findings indicate that SeCQDs show great potential as a treatment option for AKI and possibly other ROS-related diseases.
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http://dx.doi.org/10.1002/advs.202000420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312409PMC
June 2020

In vivo characterization of PD-L1 expression in breast cancer by immuno-PET with Zr-labeled avelumab.

Am J Transl Res 2020 15;12(5):1862-1872. Epub 2020 May 15.

Departments of Radiology and Medical Physics, University of Wisconsin-Madison 1111 Highland Avenue, Madison 53705, Wisconsin, United States.

Programmed death protein 1 and programmed death-ligand 1 (PD-1/PD-L1) have been widely studied as one of the most critical immune check-point pairs in the cancer microenvironment. In breast cancer (BrCa), the expression of PD-L1 is regarded as a determinant biomarker for patient stratification and prediction of inhibition response. Quantitative positron emission tomography (PET) imaging of PD-L1 expression in tumors using a therapeutic antibody in the clinic seems to be a promising approach that can complement conventional histopathological methods and overcome several issues, such as the tumor heterogeneities, sampling representativeness and clear differentiation of positive and negative results. In this study, we synthesized and evaluated Zr-labeled avelumab (Ave) for the in vivo characterization of PD-L1 expression in BrCa. Confocal imaging of BrCa cells and flow cytometry were employed to evaluate PD-L1 expression in MDA-MB-231 cells. The intact human monoclonal antibody targeting PD-L1, i.e., Ave, was conjugated to p-SCN-Deferoxamine (Df) and labeled with Zr. After intravenous injection of Zr-Df-avelumab (Zr-Df-Ave), PET imaging of MDA-MB-231 tumor-bearing mice, with or without blocking, was performed. High PD-L1 expression of MDA-MB-231 cells was confirmed by in vitro immuno-fluorescent staining and flow cytometry. PET imaging indicated the peak uptake of Zr-Df-Ave in the tumor (6.4±1.0 %ID/g), spleen (10.2±0.7 %ID/g) and lymph nodes (6.9±1.0 %ID/g) at 48 h after injection (n=4). Blocking study using unlabeled Ave could reduce the tracer uptake in these tissues (5.2±1.0 %ID/g in the tumor, 4.9±0.5 %ID/g in the spleen and 5.8±1.1 %ID/g in lymph nodes at 48 h, n=4), which demonstrated the specificity of Zr-Df-Ave. Biodistribution study and immuno-fluorescent staining were consistent with the quantitative data from PET imaging. Herein, we offer the evidence supporting the value of immuno-PET imaging using Zr-Df-Ave for non-invasive characterization of PD-L1 expression in BrCa and the applicability of this tracer in BrCa for treatment evaluation after immunotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270013PMC
May 2020

Motives for Smoking in Those With PTSD, Depression, and No Psychiatric Disorder.

J Dual Diagn 2020 Jul-Sep;16(3):285-291. Epub 2020 May 12.

Center for Tobacco Research and Intervention and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Approaches for effectively treating smoking in those with posttraumatic stress disorder (PTSD) and with major depressive disorder (MDD) could be improved by identifying motivational processes underlying their tobacco dependence. The goal of this study was to identify the motivational processes influencing smoking dependence among smokers with PTSD and with MDD relative to non-diagnosed controls. Participants were United States (US) veterans who smoked daily ( = 162) and met DSM-IV criteria for either PTSD ( = 52), MDD ( = 52), or no current psychiatric disorder (controls;  = 58). Smoking dependence motives were assessed via the Brief Wisconsin Inventory for Smoking Dependence Motives (Brief WISDM). The 11 Brief WISDM subscales are categorized into two major factors: Primary Dependence Motives and Secondary Dependence Motives. Smokers with PTSD scored higher than non-diagnosed controls on the following Primary Dependence Motives subscales: Automaticity, Craving, and Tolerance (all -values <.05). Smokers with PTSD, relative to controls, also scored higher on the overall Secondary Dependence Motives subscale, and on five of the seven Secondary Dependence Motives subscales: Cue Exposure/Associative Processes, Affective Enhancement, Affiliative Attachment, Cognitive Enhancement, and Weight Control (all -values < .05). Smokers with MDD scored significantly higher than controls on one Primary Dependence Motives subscale: Craving and on four of seven Secondary Dependence Motives subscales: Affective Enhancement, Affiliative Attachment, Cognitive Enhancement, and Weight Control (all -values <.05). Finally, exploratory analyses directly contrasting the PTSD group with the MDD group showed that smokers with PTSD were higher than those with MDD in the overall Secondary Dependence Motives subscale and one of the seven Secondary Dependence Motives subscales: Cue Exposure/Associative Processes (all -values < .05). Results suggest that both Primary Dependence Motives and Secondary Dependence Motives play a meaningful role in motivation to use tobacco in smokers with PTSD; smoking dependence in those with MDD may be primarily influenced by Secondary Dependence Motives.
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http://dx.doi.org/10.1080/15504263.2020.1759846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491602PMC
May 2020

Development and characterization of CD54-targeted immunoPET imaging in solid tumors.

Eur J Nucl Med Mol Imaging 2020 11 11;47(12):2765-2775. Epub 2020 Apr 11.

Departments of Radiology and Medical Physics, University of Wisconsin - Madison, Room 7137, 1111 Highland Avenue, Madison, WI, 53705-2275, USA.

Purpose: Intercellular adhesion molecule-1 (ICAM-1, CD54) is an emerging therapeutic target for a variety of solid tumors including melanoma and anaplastic thyroid cancer (ATC). This study aims to develop an ICAM-1-targeted immuno-positron emission tomography (immunoPET) imaging strategy and assess its diagnostic value in melanoma and ATC models.

Methods: Flow cytometry was used to screen ICAM-1-positive melanoma and ATC cell lines. Melanoma and ATC models were established using A375 cell line and THJ-16T cell line, respectively. An ICAM-1-specific monoclonal antibody (R6-5-D6) and a nonspecific human IgG were radiolabeled with Cu and the diagnostic efficacies were interrogated in tumor-bearing mouse models. Biodistribution and fluorescent imaging studies were performed to confirm the specificity of the ICAM-1-targeted imaging probes.

Results: ICAM-1 was strongly expressed on melanoma and advanced thyroid cancer cell lines. Cu-NOTA-ICAM-1 immunoPET imaging efficiently delineated A375 melanomas with a peak tumor uptake of 21.28 ± 6.56 %ID/g (n = 5), significantly higher than that of Cu-NOTA-IgG (10.63 ± 2.58 %ID/g, n = 3). Moreover, immunoPET imaging with Cu-NOTA-ICAM-1 efficiently visualized subcutaneous and orthotopic ATCs with high clarity and contrast. Fluorescent imaging with IRDye 800CW-ICAM-1 also visualized orthotopic ATCs and the tumor uptake could be blocked by the ICAM-1 parental antibody R6-5-D6, indicating the high specificity of the developed probe. Finally, blocking with the human IgG prolonged the circulation of the Cu-NOTA-ICAM-1 in R2G2 mice without compromising the tumor uptake.

Conclusion: ICAM-1-targeted immunoPET imaging could characterize ICAM-1 expression in melanoma and ATC, which holds promise for optimizing ICAM-1-targeted therapies in the future.
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http://dx.doi.org/10.1007/s00259-020-04784-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554090PMC
November 2020

Coordination chemistry of [Y(pypa)] and comparison immuno-PET imaging of [Sc]Sc- and [Y]Y-pypa-phenyl-TRC105.

Dalton Trans 2020 May 9;49(17):5547-5562. Epub 2020 Apr 9.

Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.

Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional Hpypa ligand, Hpypa-phenyl-NCS, is synthesized, conjugated to a monoclonal antibody, TRC105, and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n = 3) even upon prolonged interactions with blood serum proteins, the progressive bone uptake of the Y-counterpart indicated in vivo demetallation, obviating Hpypa as a suitable chelator for Y ion in vivo. The solution chemistry of [Y(pypa)] was studied in detail and the complex found to be thermodynamically stable in solution with a pM value 22.0, ≥3 units higher than those of the analogous DOTA- and CHX-A''-DTPA-complexes; the Y-result in vivo was therefore most unexpected. To explore further this in vivo lability, Density Functional Theory (DFT) calculation was performed to predict the geometry of [Y(pypa)] and the results were compared with those for the analogous Sc- and Lu-complexes; all three adopted the same coordination geometry (i.e. distorted capped square antiprism), but the metal-ligand bonds were much longer in [Y(pypa)] than in [Lu(pypa)] and [Sc(pypa)], which could indicate that the size of the binding cavity is too small for the Y ion, but suitable for both the Lu and Sc ions. Considered along with results from [Y][Y(pypa-phenyl-TRC105)], it is noted that when matching chelators with radionuclides, chemical data such as the thermodynamic stability and in vitro inertness, albeit useful and necessary, do not always translate to in vivo inertness, especially with the prolonged blood circulation of the radiotracer bound to a monoclonal antibody. Although Hpypa is a nonadentate chelator, which theoretically matches the coordination number of the Y ion, we show herein that its binding cavity, in fact, favors smaller metal ions such as Sc and Lu and further exploitation of the Sc-pypa combination is desired.
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http://dx.doi.org/10.1039/d0dt00437eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222037PMC
May 2020

Amyloid duration is associated with preclinical cognitive decline and tau PET.

Alzheimers Dement (Amst) 2020 13;12(1):e12007. Epub 2020 Feb 13.

Wisconsin Alzheimer's Institute University of Wisconsin School of Medicine and Public Health Madison Wisconsin.

Introduction: This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden.

Methods: Cognitively unimpaired participants ( = 257) underwent one to four amyloid PET scans (Pittsburgh Compound B, PiB). Group-based trajectory modeling was applied to participants with longitudinal scans ( = 171) to identify and model amyloid trajectory groups, which were combined with Bayes theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression, and tau PET (MK-6240) were investigated using regression models.

Results: Chronicity explained more heterogeneity in amyloid burden than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau.

Discussion: Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical Alzheimer's disease.
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http://dx.doi.org/10.1002/dad2.12007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085284PMC
February 2020

Y-Labeled Monoclonal Antibody Targeting Tissue Factor for Pancreatic Cancer Theranostics.

Mol Pharm 2020 05 31;17(5):1697-1705. Epub 2020 Mar 31.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Pancreatic cancer is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 7%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis and the lack of efficient therapeutic options. Thus, the development of an efficient, multifunctional PaCa theranostic system is urgently needed. Overexpression of tissue factor (TF) has been associated with increased tumor growth, angiogenesis, and metastasis in many malignancies, including pancreatic cancer. Herein, we propose the use of a TF-targeted monoclonal antibody (ALT836) conjugated with the pair Y as a theranostic agent against pancreatic cancer. For methods, serial PET imaging with Y-DTPA-ALT836 was conducted to map the biodistribution the tracer in BXPC-3 tumor-bearing mice. Y-DTPA-ALT836 was employed as a therapeutic agent that also allowed tumor burden monitoring through Cherenkov luminescence imaging. The results were that the uptake of Y-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time up to 48 h postinjection (p.i.), corroborated through biodistribution studies and further confirmed by Cherenkov luminescence Imaging. In therapeutic studies, Y-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller ( < 0.05) tumor volumes 1 day p.i. Histological analysis of tissues revealed significant damage to the treated tumors. The conclusion is that the use of the Y theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors with promising therapeutic outcomes.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265990PMC
May 2020