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Cell May 2019Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in...
Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.
Topics: Animals; Apolipoproteins E; Astrocytes; Brain; Fatty Acids; Homeostasis; Lipid Droplets; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neurons; Oxidation-Reduction; Rats; Rats, Sprague-Dawley
PubMed: 31130380
DOI: 10.1016/j.cell.2019.04.001 -
Molecules (Basel, Switzerland) Apr 2021Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and... (Review)
Review
Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.
Topics: Animals; Fluorodeoxyglucose F18; Humans; Neoplasms; Positron Emission Tomography Computed Tomography; Radioisotopes; Therapeutics
PubMed: 33924345
DOI: 10.3390/molecules26082232 -
Journal of Nuclear Medicine : Official... May 2021Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen...
Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using Ac-PSMA imaging and therapy (I&T). Fourteen patients receiving Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Thirty-four cycles of Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Our first clinical data for TAT using Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on Ac-PSMA-617 TAT.
Topics: Actinium; Antigens, Surface; Beta Particles; Glutamate Carboxypeptidase II; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 33008928
DOI: 10.2967/jnumed.120.251017 -
Journal of Nuclear Medicine : Official... Sep 2022Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of...
Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of neuroendocrine tumors (NETs) with the β-particle emitter Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the success of Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted α-emitter therapy with isotopes such as Pb has the potential to improve both. Here, we present the preliminary results of the phase 1 first-in-humans dose-escalation trial evaluating Pb-DOTAMTATE (a bifunctional metal chelator [DOTAM] and the SSTR-targeting peptide [TATE]) in patients with somatostatin receptor-positive NETs. Twenty subjects with histologically confirmed NETs, prior positive somatostatin analog scans, and no prior history of Lu/Y/In peptide receptor radiotherapy, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 μCi/kg) of Pb-DOTAMTATE administered at 8-wk intervals, intravenously. Ten subjects received the highest dose, 2.50 MBq/kg/cycle (67.6 μCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiologic response of 80% was observed for the first 10 subjects treated at the recommended phase 2 dose. Targeted α-therapy with Pb-DOTAMTATE has been shown to be well tolerated. Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, Pb-DOTAMTATE would provide a substantial benefit over currently Food and Drug Administration-approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.
Topics: Chelating Agents; Humans; Lead; Lead Radioisotopes; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Positron-Emission Tomography; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 34992153
DOI: 10.2967/jnumed.121.263230 -
ELife Aug 2020Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd...
Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a 'surrogate agonist' that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.
Topics: Cryoelectron Microscopy; Frizzled Receptors; Humans; Wnt Signaling Pathway
PubMed: 32762848
DOI: 10.7554/eLife.58464 -
Frontiers in Immunology 2020Phagocytic integrins are endowed with the ability to engulf and dispose of particles of different natures. Evolutionarily conserved from worms to humans, they are... (Review)
Review
Phagocytic integrins are endowed with the ability to engulf and dispose of particles of different natures. Evolutionarily conserved from worms to humans, they are involved in pathogen elimination and apoptotic and tumoral cell clearance. Research in the field of integrin-mediated phagocytosis has shed light on the molecular events controlling integrin activation and their effector functions. However, there are still some aspects of the regulation of the phagocytic process that need to be clarified. Here, we have revised the molecular events controlling phagocytic integrin activation and the downstream signaling driving particle engulfment, and we have focused particularly on αβ/CR3, αβ/CR4, and a brief mention of αβ/αβintegrins.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Humans; Integrin alphaXbeta2; Integrins; Macrophage-1 Antigen; Membrane Proteins; Phagocytosis; Protein-Tyrosine Kinases; Signal Transduction; Talin; rap1 GTP-Binding Proteins
PubMed: 32425937
DOI: 10.3389/fimmu.2020.00738 -
Seminars in Interventional Radiology Oct 2021Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that... (Review)
Review
Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that dates back to the 1960s. As β particles are created during Y decay, bremsstrahlung radiation is created as the particles interact with tissues, allowing for imaging with a gamma camera. Inherent qualities of bremsstrahlung radiation make its imaging difficult. SPECT and SPECT/CT can be used but suffer from limitations related to low signal-to-noise bremsstrahlung radiation. However, with optimized imaging protocols, clinically adequate images can still be obtained. A finite but detectable number of positrons are also emitted during Y decay, and many studies have demonstrated the ability of commercial PET/CT and PET/MR scanners to image these positrons to understand Y distribution and help quantify dose. PET imaging has been proven to be superior to SPECT for quantitative imaging, and therefore will play an important role going forward as we try and better understand dose/response and dose/toxicity relationships to optimize personalized dosimetry. The availability of PET imaging will likely remain the biggest barrier to its use in routine post- Y imaging; thus, SPECT/CT imaging with optimized protocols should be sufficient for most posttherapy subjective imaging.
PubMed: 34629714
DOI: 10.1055/s-0041-1735569 -
Seminars in Radiation Oncology Jan 2021In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed... (Review)
Review
In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed therapy and norepinephrine transporter targeted I-MIBG therapies by the FDA and the rapid progress of highly promising beta and alpha emitter tagged PSMA directed therapy of prostate cancer have stimulated clinically impactful changes in practice. Many novel strategies are being explored and novel radiopharmaceutical therapeutic agents including peptide based ligands as well as antibodies or antibody fragments are being developed preclinically or are in early phase clinical trials. While beta particle emitters have most commonly been used for targeted radiotherapy and radioimmunotargeting, there is an emerging interest in alpha emitters that cause greater density of ionization events leading to increased double-strand DNA damage and cluster breaks because of the high-energy particles within a shorter tissue range of penetration and thereby lower toxicity to adjacent normal tissues.
Topics: Humans; Male; Precision Medicine; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 33246639
DOI: 10.1016/j.semradonc.2020.07.010