Brain disease is one of the greatest threats to public health. Brain theranostics is recently taking shape, indicating the treatments of stroke, inflammatory brain disorders, psychiatric diseases, neurodevelopmental disease, and neurodegenerative disease. However, several factors, such as lack of endophenotype classification, blood-brain barrier (BBB), target determination, ignorance of biodistribution after administration, and complex intercellular communication between brain cells, make brain theranostics application difficult, especially when it comes to clinical application. So, a more thorough understanding of each aspect is needed. In this review, we focus on recent studies regarding the role of exosomes in intercellular communication of brain cells, therapeutic effect of graphene quantum dots, transcriptomics/epitranscriptomics approach for target selection, and in vitro/in vivo considerations.
Blood-Brain Barrier ; Brain Diseases ; Brain ; Classification ; Endophenotypes ; Exosomes ; Graphite ; Neurodegenerative Diseases ; Public Health ; Quantum Dots ; Stroke ; Theranostic Nanomedicine

Prostate-specific membrane antigen (PSMA) is highly expressed in PCa, which gradually increases in high-grade tumors, metastatic tumors, and tumors nonresponsive to androgen deprivation therapy. PSMA has been a topic of interest during the past decade for both diagnostic and therapeutic targets. Radioligand therapy (RLT) utilizes the delivery of radioactive nuclides to tumors and tumor-associated targets, and it has shown better efficacy with minimal toxicity compared to other systemic cancer therapies. Nuclear medicine has faced a new turning point claiming theranosis as the core of academic identity, since new RLTs have been introduced to clinics through the official new drug development processes for approval from the Food and Drug Administration (FDA) or European Medical Agency. Recently, PSMA targeting RLT was approved by the US FDA in March 2022. This review introduces PSMA RLT focusing on ongoing clinical trials to enhance our understanding of nuclear medicine theranosis and strive for the development of new radiopharmaceuticals.

Brain disease is one of the greatest threats to public health. Brain theranostics is recently taking shape, indicating the treatments of stroke, inflammatory brain disorders, psychiatric diseases, neurodevelopmental disease, and neurodegenerative disease. However, several factors, such as lack of endophenotype classification, blood-brain barrier (BBB), target determination, ignorance of biodistribution after administration, and complex intercellular communication between brain cells, make brain theranostics application difficult, especially when it comes to clinical application. So, a more thorough understanding of each aspect is needed. In this review, we focus on recent studies regarding the role of exosomes in intercellular communication of brain cells, therapeutic effect of graphene quantum dots, transcriptomics/epitranscriptomics approach for target selection, and in vitro/in vivo considerations.

Objective: Burr hole trephination is a common treatment for chronic subdural hematoma, intracranial hematoma, and intraventricular hematoma due to its effective drainage of hematoma, minimal invasiveness and short operation time. However, cosmetic complications such as scalp depression can occur. The aim of this study was to evaluate the usefulness of an allogenic acellular dermal matrix (ADM) to prevent scalp depression at the burr hole site. Methods: A retrospective analysis was performed with 75 cases in 66 patients who were treated with burr hole trephination from January 2018 to December 2019. These cases divided into 2 groups; based on the method used to cover the burr hole site: Gelfoam packing only (GPO) and ADM. The degree of the scalp depression was measured from the more recent follow-up brain computed tomography scan. Results: There was a significant difference in the degree of scalp depression between GPO and ADM groups (p=0.003). No significant correlation between patient's age and the degree of scalp depression (GPO: p=0.419, ADM: p=0.790). There were no wound infection complication in either group. Conclusion ADM is a suitable material to prevent scalp depression after burr hole trephination.

Purpose: To provide a wider choice of treatment opportunities for patients with neuroendocrine tumor (NET) in Korea, we have conducted a phase 1, open-label, single-arm, dose-escalation study of SNU-KB-01, a no-carrier added (NCA) 177Lu-labeled DOTATATE. Materials and Methods: Seven patients with inoperable, progressive, metastatic, or locally advanced, somatostatin receptor-positive NET with Ki67 index ≤ 20% were enrolled according to the rolling six design. The study consisted of two cohorts to receive 4 cycles of SNU-KB-01 every 8 weeks for the first dose of 5.55 GBq (n=3) and 7.40 GBq (n=4). We assessed the incidence of dose-limiting toxicity (DLT) and adverse event, absorbed dose of kidneys and bone marrow, and objective tumor response. Results: Seven patients completed 4 cycles (21.3-30.1 GBq total dose) of SNU-KB-01. The mean absorbed doses to kidneys and bone marrow were 0.500 mGy/MBq and 0.053 mGy/MBq, respectively, and the total body effective dose was 0.115 mSv/MBq. No DLT was observed and the maximum tolerated dose was 7.40 GBq/cycle. Grade 3 thrombocytopenia occurred in one patient, but no other grade 3 or 4 major hematologic or renal toxicity was observed. The best objective response to SNU-KB-01 was partial response. Overall response rate was 42.9% and disease control rate was 85.7%. Conclusion Treatment with 4 cycles of SNU-KB-01 was well tolerated and resulted in control of disease in most of the patients. Our results indicate SNU-KB-01, an NCA 177Lu-labeled DOTATATE, as a potentially safe and efficacious treatment option for NET patients in Korea.

Since glymphatic was proposed and meningeal lymphatic was discovered, MRI and even PET were introduced to investigate brain parenchymal interstitial fluid (ISF), cerebrospinal fluid (CSF), and lymphatic outflow in rodents and humans. Previous findings by ex vivo fluorescent microscopic, and in vivo two-photon imaging in rodents were reproduced using intrathecal contrast (gadobutrol and the similar)-enhanced MRI in rodents and further in humans. On dynamic MRI of meningeal lymphatics, in contrast to rodents, humans use mainly dorsal meningeal lymphatic pathways of ISF-CSF-lymphatic efflux. In mice, ISF-CSF exchange was examined thoroughly using an intra-cistern injection of fluorescent tracers during sleep, aging, and neurodegeneration yielding many details. CSF to lymphatic efflux is across arachnoid barrier cells over the dorsal dura in rodents and in humans. Meningeal lymphatic efflux to cervical lymph nodes and systemic circulation is also well-delineated especially in humans onintrathecal contrast MRI. Sleep- or anesthesia-related changes of glymphatic-lymphatic flow and the coupling of ISFCSF-lymphatic drainage are major confounders ininterpreting brain glymphatic/lymphatic outflow in rodents. PET imaging in humans should be interpreted based on human anatomy and physiology, different in some aspects, using MRI recently. Based on the summary in this review, we propose non-invasive and longer-term intrathecal SPECT/PET or MRI studies to unravel the roles of brain glymphatic/lymphatic in diseases.

Phospholipase C-gamma1, containing two SH2 and one SH3 domains which participate in the interaction between signaling molecules, plays a significant role in the growth factor-induced signal transduction. However, the role of the SH domains in the growth factor-induced PLC-gamma1 regulation is unclear. By peptide-mass fingerprinting analysis, we have identified SHIP1 as the binding protein for the SH3 domain of PLC-gamma1. SHIP1 was co-immunoprecipitated with PLC-gamma1 and potentiated EGF-induced PLC-gamma1 activation. However, inositol 5'-phosphatase activity of SHIP1 was not required for the potentiation of EGF-induced PLC-gamma1 activation. Taken together, these results suggest that SHIP1 may function as an adaptor protein which can potentiate EGF-induced PLC-gamma1 activation without regards to its inositol 5'-phosphatase activity.
Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Animals ; COS Cells/enzymology ; Cercopithecus aethiops ; Enzyme Activation ; Epidermal Growth Factor/*pharmacology ; Immunoprecipitation ; Inositol 1,4,5-Trisphosphate/metabolism ; Molecular Sequence Data ; Phospholipase C/chemistry/*metabolism ; Phosphoric Monoester Hydrolases/chemistry/*metabolism ; Protein Binding ; Signal Transduction ; src Homology Domains/*physiology

Cyclooxygenase (COX) is a key enzyme in the conversion of arachidonic acid into prostanoids which participate in various cellular functions including apoptosis, mitogenesis, inflammation, immune modulation and differentiation. Moreover, the synthetic glucocorticoid, dexamethasone has immune modulating and anti-inflammatory effects in vivo. Recently, dexamethasone was found to enhance retinoic acid-induced neuronal differentiation. In this study, we investigated the mechanisms of dexamethasone-mediated neuronal differentiation. Immunoblotting and morphological analysis demonstrated that dexamethasone induced neuronal differentiation through COX 1 induction. This phenomenon was inhibited by indomethacin, a COX inhibitor. In addition, the addition of exogenous prostaglandin E2 (PGE2), a substance produced by the COX-mediated pathway, triggered neurite outgrowth of cells treated with COX inhibitor. Taken together, COX 1 appears to play an important role in dexamethasone-mediated neuronal differentiation.
Animals ; Anti-Inflammatory Agents/pharmacology ; Cell Differentiation/*drug effects ; Cyclooxygenase Inhibitors/pharmacology ; Dexamethasone/*pharmacology ; Dinoprostone/metabolism ; Enzyme Induction ; Hybrid Cells ; Indomethacin/pharmacology ; Isoenzymes/*biosynthesis ; Mice ; Prostaglandin-Endoperoxide Synthase/*biosynthesis ; Rats ; Tumor Cells, Cultured

Renal metastasis of thyroid cancer is extremely rare. We report the case of a 62-year-old woman with Hürthle cell thyroid cancer (HCTC) with lungs, bones, and bilateral kidneys metastases. The renal metastatic lesions were clearly demonstrated by ¹³¹I whole body scan (WBS) with SPECT/CT. However, they exhibited false-negative results in ¹⁸F-FDG PET/CT, kidney ultrasonography, and contrast-enhanced CT scan. The findings imply that tumors have low glucose metabolism and are able to accumulate radioiodine, which is not commonly found in the relatively aggressive nature of HCTC. The patient received two sessions of 200 mCi ¹³¹I therapy within 6 months duration. There was complete treatment response as evaluated by the second post-therapeutic ¹³¹I SPECT/CT and serum thyroglobulin. To our knowledge, renal metastasis from HCTC with positive ¹³¹I but negative ¹⁸F-FDGuptake has not been reported in the literature. This case suggests that ¹³¹I SPECT/CTis useful for lesion localization and prediction of ¹³¹I therapy response.
Female ; Glucose ; Humans ; Kidney ; Lung ; Metabolism ; Middle Aged ; Neoplasm Metastasis ; Positron-Emission Tomography and Computed Tomography ; Sodium Iodide ; Sodium ; Thyroglobulin ; Thyroid Gland ; Thyroid Neoplasms ; Tomography, X-Ray Computed ; Ultrasonography ; Whole Body Imaging

Objective: 68 Ga-NGUL is a novel prostate-specific membrane antigen (PSMA)-targeting tracer based on Glu-Urea-Lys derivatives conjugated to a 1,4,7-triazacyclononane-N,N’,N’’-triacetic acid (NOTA) chelator via a thiourea-type short linker. This phase I clinical trial of 68 Ga-NGUL was conducted to evaluate the safety and radiation dosimetry of 68 Ga-NGUL in healthy volunteers and the lesion detection rate of 68 Ga-NGUL in patients with prostate cancer. Materials and Methods: We designed a prospective, open-label, single-arm clinical trial with two cohorts comprising six healthy adult men and six patients with metastatic prostate cancer. Safety and blood test-based toxicities were monitored throughout the study. PET/CT scans were acquired at multiple time points after administering 68 Ga-NGUL (2 MBq/kg; 96–165 MBq). In healthy adults, absorbed organ doses and effective doses were calculated using the OLINDA/EXM software. In patients with prostate cancer, the rates of detecting suspicious lesions by 68 Ga-NGUL PET/CT and conventional imaging (CT and bone scintigraphy) during the screening period, within one month after recruitment, were compared. Results: All 12 participants (six healthy adults aged 31–32 years and six prostate cancer patients aged 57–81 years) completed the clinical trial. No drug-related adverse events were observed. In the healthy adult group, 68 Ga-NGUL was rapidly distributed, with the highest uptake in the kidneys. The median effective dose coefficient was calculated as 0.025 mSv/MBq, and cumulative activity in the bladder had the highest contribution. In patients with metastatic prostate cancer, 229 suspicious lesions were detected using either 68 Ga-NGUL PET/CT or conventional imaging. Among them, 68 Ga-NGUL PET/CT detected 199 (86.9%) lesions and CT or bone scintigraphy detected 114 (49.8%) lesions. Conclusion 68 Ga-NGUL can be safely applied clinically and has shown a higher detection rate for the localization of metastatic lesions in prostate cancer than conventional imaging. Therefore, 68 Ga-NGUL is a valuable option for prostate cancer imaging.