147 research outputs found

    Imaging PARP with [18F]rucaparib in pancreatic cancer models

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    PURPOSE: Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. METHOD: We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. RESULTS: Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. CONCLUSION: Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers

    [123I]CC1:A PARP-Targeting, Auger Electron-Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

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    Poly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron-emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Auger electrons to kill cancer cells through the creation of complex DNA damage, with minimal damage to surrounding normal tissue. Here, we report on [ 123I]CC1, an 123I-labeled PARP inhibitor for radioligand therapy of cancer.Methods: Copper-mediated 123I iododeboronation of a boronic pinacol ester precursor afforded [ 123I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [ 123I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [ 123I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG).Results: In vitro and in vivo studies showed selective uptake of [ 123I]CC1 in all models. Significantly reduced clonogenicity, a proxy for tumor growth inhibition by ionizing radiation in vivo, was observed in vitro after treatment with as little as 10 Bq [ 123I]CC1. Biodistribution at 1 h after intravenous administration showed PSN1 tumor xenograft uptake of 0.9 ± 0.06 percentage injected dose per gram of tissue. Intravenous administration of a relatively low amount of [ 123I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [ 123I]CC1 did not cause significant toxicity to normal tissues.Conclusion: Taken together, these results show the potential of [ 123I]CC1 as a radioligand therapy for PARP-expressing cancers. </p

    [123I]CC1:A PARP-Targeting, Auger Electron-Emitting Radiopharmaceutical for Radionuclide Therapy of Cancer

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    Poly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron-emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Auger electrons to kill cancer cells through the creation of complex DNA damage, with minimal damage to surrounding normal tissue. Here, we report on [ 123I]CC1, an 123I-labeled PARP inhibitor for radioligand therapy of cancer.Methods: Copper-mediated 123I iododeboronation of a boronic pinacol ester precursor afforded [ 123I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [ 123I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [ 123I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG).Results: In vitro and in vivo studies showed selective uptake of [ 123I]CC1 in all models. Significantly reduced clonogenicity, a proxy for tumor growth inhibition by ionizing radiation in vivo, was observed in vitro after treatment with as little as 10 Bq [ 123I]CC1. Biodistribution at 1 h after intravenous administration showed PSN1 tumor xenograft uptake of 0.9 ± 0.06 percentage injected dose per gram of tissue. Intravenous administration of a relatively low amount of [ 123I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [ 123I]CC1 did not cause significant toxicity to normal tissues.Conclusion: Taken together, these results show the potential of [ 123I]CC1 as a radioligand therapy for PARP-expressing cancers. </p

    Growth and properties of GaSbBi alloys

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    Molecular-beam epitaxy has been used to grow GaSb 1− x Bi x alloys with x up to 0.05. The Bi content, lattice expansion, and film thickness were determined by Rutherford backscattering and x-ray diffraction, which also indicate high crystallinity and that >98% of the Bi atoms are substitutional. The observed Bi-induced lattice dilation is consistent with density functional theory calculations. Optical absorption measurements and valence band anticrossing modeling indicate that the room temperature band gap varies from 720 meV for GaSb to 540 meV for GaSb 0.95Bi0.05, corresponding to a reduction of 36 meV/%Bi or 210 meV per 0.01 Å change in lattice constant

    High Bi content GaSbBi alloys

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    The epitaxial growth, structural, and optical properties of GaSb 1– x Bi x alloys have been investigated. The Bi incorporation into GaSb is varied in the range 0 < x ≤ 9.6% by varying the growth rate (0.31–1.33 μm h−1) at two growth temperatures (250 and 275 °C). The Bi content is inversely proportional to the growth rate, but with higher Bi contents achieved at 250 than at 275 °C. A maximum Bi content of x = 9.6% is achieved with the Bi greater than 99% substitutional. Extrapolating the linear variation of lattice parameter with Bi content in the GaSbBi films enabled a zinc blende GaBi lattice parameter to be estimated of 6.272 Å. The band gap at 300 K of the GaSbBi epitaxial layers decreases linearly with increasing Bi content down to 410 ± 40 meV (3 μm) for x = 9.6%, corresponding to a reduction of ∼35 meV/%Bi. Photoluminescence indicates a band gap of 490 ± 5 meV at 15 K for x = 9.6%

    Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

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    Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability

    Beacon v2 and Beacon networks: A "lingua franca" for federated data discovery in biomedical genomics, and beyond

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    Beacon is a basic data discovery protocol issued by the Global Alliance for Genomics and Health (GA4GH). The main goal addressed by version 1 of the Beacon protocol was to test the feasibility of broadly sharing human genomic data, through providing simple "yes" or "no" responses to queries about the presence of a given variant in datasets hosted by Beacon providers. The popularity of this concept has fostered the design of a version 2, that better serves real-world requirements and addresses the needs of clinical genomics research and healthcare, as assessed by several contributing projects and organizations. Particularly, rare disease genetics and cancer research will benefit from new case level and genomic variant level requests and the enabling of richer phenotype and clinical queries as well as support for fuzzy searches. Beacon is designed as a "lingua franca" to bridge data collections hosted in software solutions with different and rich interfaces. Beacon version 2 works alongside popular standards like Phenopackets, OMOP, or FHIR, allowing implementing consortia to return matches in beacon responses and provide a handover to their preferred data exchange format. The protocol is being explored by other research domains and is being tested in several international projects
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