Shared genetics and causal association between plasma levels of SARS-CoV-2 entry receptor ACE2 and Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the highest risk of COVID-19 infection, hospitalization, and mortality. However, it remains largely unclear about the link between AD and COVID-19 outcomes. ACE2 is an entry receptor for SARS-CoV-2. Circulating ACE2 is a novel biomarker of death and associated with COVID-19 outcomes. METHODS: Here, we explored the shared genetics and causal association between AD and plasma ACE2 levels using large-scale genome-wide association study, gene expression, expression quantitative trait loci, and high-throughput plasma proteomic profiling datasets. RESULTS: We found a significant causal effect of genetically increased circulating ACE2 on increased risk of AD. Cross-trait association analysis identified 19 shared genetic variants, and three variants rs3104412, rs2395166, and rs3135344 at chromosome 6p21.32 were associated with COVID-19 infection, hospitalization, and severity. We mapped 19 variants to 117 genes, which were significantly upregulated in lung, spleen, and small intestine, downregulated in brain tissues, and involved in immune system, immune disease, and infectious disease pathways. The plasma proteins corresponding to LST1, AGER, TNXB, and APOC1 were predominantly associated with COVID-19 infection, ventilation, and death. CONCLUSION: Together, our findings suggest the shared genetics and causal association between AD and plasma ACE2 levels, which may partially explain the link between AD and COVID-19.

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia-reperfusion rats by activating Prkaca-mediated cAMP/PKA-MAPK pathway.

Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co-IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen-glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R-stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R-induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R-stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA-MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca-mediated activation of the cAMP/PKA-MAPK pathway, thereby improving brain injury in cerebral ischaemia-reperfusion.

Interpretation of 10 years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10 years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

rs56405341 Variant Associates with Expression of C4orf33 and C4orf33 Was Downregulated in Alzheimer's Disease and Progressive Supranuclear Palsy.

The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.

Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors.

Serine/threonine protein kinase PLK4 is a master regulator of centriole duplication, which is significant for maintaining genome integrity. Accordingly, due to the detection of PLK4 overexpression in a variety of cancers, PLK4 has been identified as a candidate anticancer target. Thus, it is a very meaningful to find effective and safe PLK4 inhibitors for the treatment of cancer. However, the reported PLK4 inhibitors are scarce and have potential safety issues. In this study, a series of novel and potent PLK4 inhibitors with an aminopyrimidine core was obtained utilizing the scaffold hopping strategy. The in vitro enzyme activity results showed that compound 8h (PLK4 IC50 = 0.0067 µM) displayed high PLK4 inhibitory activity. In addition, compound 8h exhibited a good plasma stability (t1/2 > 289.1 min), liver microsomal stability (t1/2 > 145 min), and low risk of DDIs. At the cellular level, it presented excellent antiproliferative activity against breast cancer cells. Taken together, these results suggest that compound 8h has potential value in the further research of PLK4-targeted anticancer drugs.

Development and validation of a non-invasive model for predicting significant fibrosis based on patients with nonalcoholic fatty liver disease in the United States.

Background: Liver fibrosis is closely related to abnormal liver function and liver cancer. Accurate noninvasive assessment of liver fibrosis is of great significance for preventing disease progression and treatment decisions. The purpose of this study was to develop and validate a non-invasive predictive model for the asses`sment of significant fibrosis in patients with non-alcoholic fatty liver disease. Methods: Information on all participants for 2017-2018 was extracted from the NHANES database. The eligible patients with significant fibrosis (n=123) and non-significant fibrosis (n=898) were selected to form the original dataset. Variable selection was performed using least absolute shrinkage and selection operator (Lasso) regression, and multivariate logistic regression analysis was used to develop a prediction model. The utility of the model is assessed in terms of its discrimination, calibration and clinical usability. Bootstrap-resampling internal validation was used to measure the accuracy of the prediction model. Results: This study established a new model consisting of 9 common clinical indicators and developed an online calculator to show the model. Compared with the previously proposed liver fibrosis scoring system, this model showed the best discrimination and predictive performance in the training cohort (0.812,95%CI 0.769-0.855) and the validation cohort (0.805,95%CI 0.762-0.847), with the highest area under curve. Specificity(0.823), sensitivity(0.699), positive likelihood ratio(3.949) and negative likelihood ratio(0.366) were equally excellent. The calibration plot of the predicted probability and the actual occurrence probability of significant fibrosis shows excellent consistency, indicating that the model calibration is outstanding. Combined with decision curve analysis, this model has a great benefit in the range of 0.1-0.8 threshold probability, and has a good application value for the diagnosis of clinical significant fibrosis. Conclusion: This study proposes a new non-invasive diagnostic model that combines clinical indicators to provide an accurate and convenient individualized diagnosis of significant fibrosis in patients with non-alcoholic fatty liver disease.

Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer.

Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure-activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. SP27 exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia.

Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.

Design, synthesis, and biological evaluation of a potent PLK4 inhibitor WY29 with 1H-pyrazolo[3,4-d]pyrimidine scaffold.

Centriole duplication occurs once per cell cycle and is regulated by Polo-like kinase 4 (PLK4). Overexpression of PLK4 in somatic cells can lead to the excessive formation of centrioles, directly causing chromosome segregation errors and tumorigenesis. In this study, we described our efforts to develop a series of PLK4 inhibitors with 1H-pyrazolo[3,4-d]pyrimidine core, and further structure- and receptor-based design and optimization resulted in a potent inhibitor WY29 (IC50 = 0.027 µM), which exhibited good selectivity to other PLK family members (PLK1-3). At the cellular level, compound WY29 showed excellent antiproliferative activity against three breast cancer cell lines (MCF-7, BT474, and MDA-MB-231) while weak inhibitory activity was found on normal cell line HUVECs. In addition, the in vitro preliminary drug-like properties evaluation of compound WY29 showed outstanding stability in human plasma and liver microsomes, and weak inhibitory activity against the major subtypes of human cytochrome P450. Also, the drug-like properties prediction of compound WY29 displayed remarkable drug-like properties (drug-likeness mode score: 1.06). In conclusion, these results support the further development of compound WY29 as a lead compound for PLK4-targeted anticancer drug discovery.

Edaravone Attenuates Aß 1-42-Induced Inflammatory Damage and Ferroptosis in HT22 Cells.

Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer's disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aß 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aß1-42-induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1ß and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aß 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.

Structure-based discovery of 1-(3-fluoro-5-(5-(3-(methylsulfonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)-3-(pyrimidin-5-yl)urea as a potent and selective nanomolar type-II PLK4 inhibitor.

Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase involved in regulating cell mitosis and centriole duplication, and has emerged as a therapeutic target for treating multiple cancers. At first, the design and in vitro validation of PLK4 inhibitors (12a-12e, 17a-17f, 22a-22e) bearing 1H-pyrazolo[3,4-b]pyridine scaffold was described and lead compound 22a (IC50 = 0.106 µM) was identified. Then, selectivity- and activity-guided development of a series of potent and selective type-II PLK4 inhibitors using a homology model approach was carried out. Further structure-based optimization resulted in a potent type-II PLK4 inhibitor 29u (IC50 = 0.026 µM), which exhibited outstanding selectivity in a panel of 47 kinases at a single concentration of 1.0 µM. Furthermore, compound 29u significantly inhibited the proliferation of breast cancer cell line MCF-7 with an IC50 value of 1.52 µM, while it exhibited no inhibitory effect on normal cell lines (L02 and HUVECs). Meanwhile, the clone formation, senescence and migration abilities of compound 29u were evaluated using MCF-7 cells. The detailed biological evaluation revealed that compound 29u could arrest cell division in S/G2 phase by inhibiting PLK4, and then affect the expression of downstream signalling pathway proteins regulated by PLK4. Moreover, the in vitro preliminary evaluation of the drug-like properties of compound 29u exhibited outstanding plasma stability, moderate liver microsomal stability, and low risk of drug-drug interactions (DDIs). The current discovery will support the further development of compound 29u as a lead compound for PLK4-targeted anticancer drug discovery and as a useful chemical probe for the further biological research of PLK4.

Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer.

Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC50 values of < 10 nM. Among them, compound 24j (PLK4 IC50 = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC50 values of 0.36, 1.35, and 2.88 µM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer.

Identification of novel and potent PROTACs targeting FAK for non-small cell lung cancer: Design, synthesis, and biological study.

The intracellular non-receptor tyrosine protein kinase Focal adhesion kinase (FAK) is a key signalling regulator, which mediates tumor survival, invasion, metastasis, and angiogenesis through its kinase catalytic functions and non-kinase scaffolding functions. Previous efforts have clarified that it is crucial to address both FAK kinase and scaffolding functions instead of just inhibiting FAK kinase activity because it may be insufficient to completely block FAK signaling. Proteolysis targeting chimera (PROTAC) technology is a method of targeting a specific protein and inducing its degradation in the cell, which can simultaneously eliminate both kinase-dependent enzymatic functions and scaffolding functions. In current study, we designed and synthesized a series of novel FAK PROTACs and the optimal PROTAC B5 exhibited potent FAK affinity with an IC50 value of 14.9 nM. Furthermore, in A549 cells, PROTAC B5 presented strong FAK degradation activity (86.4% degradation @ 10 nM), powerful antiproliferative activity (IC50 = 0.14 ± 0.01 µM) and inhibited cell migration and invasion in a concentration-dependent manner. Additionally, the in vitro preliminary drug-like properties evaluation of PROTAC B5 showed outstanding plasma stability and moderate membrane permeability. Together, current results provided a promising FAK PROTAC B5 as lead compound for cancer-related drug discovery and FAK-degradation functions exploration in biological systems.

Rare renal metastases from differentiated thyroid carcinoma: early clinical detection and treatment based on radioiodine.

OBJECTIVE: The aim of this study was to explore the clinical characteristics of renal metastatic cancer, the methods for its detection by radioiodine (131)I, and the response to (131)I treatment in fourteen patients with renal metastases from differentiated thyroid carcinoma (DTC). SUBJECTS AND METHODS: DTC patients (n = 2,955) that received treatment with (131)I were retrospectively analyzed. Scans ((131)I-WBS, (31)I-SPECT/CT and/or (18)F-FDG-PET/CT) were performed after an oral therapeutic dose of (131)I. Therapeutic efficacy was evaluated based on changes in Tg and anatomical imaging changes at renal lesions. RESULTS: Among these 14 patients, 11 had avidity for (131)I, but three patients did not accumulate (131)I after (131)I treatment. In the 11 (131)I-positive renal lesions, 10 cases were detected by (131)I-SPECT/CT combined with another imaging modality and one case by (131)I-WBS combined with ultrasonography (US). In the three (131)I-negative renal lesions, two cases were detected by 18F-FDG-PET/CT and one case by computed tomography (CT). In 11 patients with (131)I-avid renal metastases, Serum Tg levels in 81.82% (9/11) patients showed a gradual decline, and 18.18% (2/11) of the patients showed a significant elevation. There was no marked difference in serum Tg before the last (131)I treatment (Z = 0.157; p = 0.875). Only one patient presented partial response, eight patients exhibited stable disease, and renal metastases progressed in two patients showing progressive disease. No patients reached complete response. CONCLUSION: (131)I-SPECT/CT, combined with another imaging modality after (131)I-WBS, can contribute to the early detection of renal metastases of DTC. (131)I therapy is a feasible and effective treatment for most DTC renal metastases with avidity for (131)I.

Rare renal metastases from differentiated thyroid carcinoma: early clinical detection and treatment based on radioiodine / Metástases renais raras de carcinoma diferenciado da tireoide: detecção clínica precoce e tratamento com radioiodoterapia

Objective : The aim of this study was to explore the clinical characteristics of renal metastatic cancer, the methods for its detection by radioiodine (131I), and the response to 131I treatment in fourteen patients with renal metastases from differentiated thyroid carcinoma (DTC).Subjects and methods : DTC patients (n = 2,955) that received treatment with 131I were retrospectively analyzed. Scans (131I-WBS, 31I-SPECT/CT and/or 18F-FDG-PET/CT) were performed after an oral therapeutic dose of 131I. Therapeutic efficacy was evaluated based on changes in Tg and anatomical imaging changes at renal lesions.Results : Among these 14 patients, 11 had avidity for 131I, but three patients did not accumulate 131I after 131I treatment. In the 11 131I-positive renal lesions, 10 cases were detected by 131I-SPECT/CT combined with another imaging modality and one case by 131I-WBS combined with ultrasonography (US). In the three 131I-negative renal lesions, two cases were detected by 18F-FDG-PET/CT and one case by computed tomography (CT). In 11 patients with 131I-avid renal metastases, Serum Tg levels in 81.82% (9/11) patients showed a gradual decline, and 18.18% (2/11) of the patients showed a significant elevation. There was no marked difference in serum Tg before the last 131I treatment (Z = 0.157; p = 0.875). Only one patient presented partial response, eight patients exhibited stable disease, and renal metastases progressed in two patients showing progressive disease. No patients reached complete response.Conclusion : 131I-SPECT/CT, combined with another imaging modality after 131I-WBS, can contribute to the early detection of renal metastases of DTC. 131I therapy is a feasible and effective treatment for most DTC renal metastases with avidity for 131I. Arq Bras Endocrinol Metab. 2014;58(3):260-9.

Objetivo : O objetivo deste estudo foi analisar as características clínicas de metástases renais, os métodos para sua detecção por radioiodo (131I) e a resposta ao tratamento com 131I em 14 pacientes com metástases renais de carcinoma diferenciado da tireoide (DTC).Sujeitos e métodos Pacientes com DTC (n = 2.955) que receberam tratamento com 131I foram analisados retrospectivamente. 131I-PCI, 31I-SPECT/CT e/ou 18F-FDG-PET/CT foram feitos após uma dose terapêutica oral de 131I. A eficácia terapêutica foi baseada nas alterações da Tg e nas imagens anatômicas das lesões renais.Resultados : Dos 14 pacientes, 11 apresentaram lesões ávidas por 131I, mas três pacientes não acumularam 131I depois do tratamento com 131I. Nas 11 lesões renais positivas para 131I, 10 casos foram detectados por 131I-SPECT/CT combinado com outra modalidade de exame de imagem e um caso por 131I-WBS combinado com US. Nas três lesões renais negativas para 131I, dois casos foram detectados por 18F-FDG-PET/CT e um caso por tomografia computadorizada (TC). Em 11 pacientes com metástases renais ávidas por 131I, os níveis séricos de Tg em 81,82% (9/11) dos pacientes mostraram um declínio gradual e 18,18% (2/11) apresentaram uma elevação significativa. Não houve diferenças marcadas na Tg sérica antes do último tratamento com 131I (Z = 0,157; p = 0,875). Apenas um paciente apresentou resposta parcial, oito pacientes apresentaram doença estável e as metástases renais progrediram em dois pacientes que apresentaram doença progressiva. Nenhum dos pacientes apresentou resposta completa.Conclusão : 131I-SPECT/CT, combinada com outra modalidade de diagnóstico por imagem após 131I-PCI, pode contribuir para a detecção precoce de metástases renais de DTC. O tratamento ...

Large thigh and buttock muscle metastases as the initial manifestation of follicular thyroid cancer.

Follicular thyroid carcinoma (FTC) is the second most common thyroid malignancy after papillary thyroid carcinoma (PTC). It has a greater tendency than PTC to metastasize to distant organs such as the lung and bone. FTC metastasis to skeletal muscle is extremely rare. Here, we report a 65-year-old woman with large thigh and buttock muscle metastases as the first manifestation of FTC.

Iodine-131 SPET/CT and 18F-FDG PET/CT for the identification and localization of mediastinal lymph node metastases from differentiated thyroid carcinoma.

Mediastinal lymph node metastases (MLNM) from differentiated thyroid carcinoma (DTC) are considered difficult to diagnose. The aim of this study was to assess the value of iodine-131 (131I) single photon emission tomography/computed tomography (SPET/CT) and of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for the diagnosis of MLNM from DTC. Five hundred and eleven consecutive patients operated for DTC and treated with 131I for ablation of the remnant thyroid and/or for treatment of metastases were enrolled in the study and underwent an 131I whole body scan (131I-WBS). Thirty seven sites of increased 131I uptake, on the 131I-WBS that could be an indication for MLNM were re-evaluated by a 131I-SPET/CT scan. Thirty four other patients with negative 131I-WBS but having elevated serum thyroglobulin (Tg), were examined by 18F-FDG PET/CT to possibly diagnose MLNM. A total of 44 DTC patients with MLNM were identified, among the above 37 and 34 cases: 25/37 (67.6%) cases were examined and identified by 131I-SPET/CT and 19/34 (55.9%) cases by 18F-FDG PET/CT. A total of 25 and 19 cases were identified. The male-to-female ratio and the average age in patients with 18F-FDG-avid MLNM were significantly higher than in patients with 131I-avid MLNM. Among the above 44 patients, 40 patients had superior mediastinal nodal metastases, 9 had aortic nodal metastases and only 1 inferior mediastinal nodal metastases. A patient could have metastases in more than one site. In conclusion, our study suggests that in 511 operated DTC patients, treated for remnant ablation and/or for metastases and examined by 131I-WBS, there were 37 cases doubtful of having MLNM in the 131I-WBS and 34 cases doubtful, because of negative 131I-WBS and elevated Tg. The 131I-SPET/CT scan was sensitive for detecting MLNM in 25 of the 37 cases and the 18F-FDG PET/CT in 19 of the 34 cases. These hybrid imaging modalities, when applied as above, were suitable for detecting more MLNM and thus, better supporting treatment planning in these DTC patients.