Immune-Related RNA-Binding Protein-Based Signature With Predictive and Prognostic Implications in Patients With Lung Adenocarcinoma.

Background: Dysregulation of RNA-binding proteins (RBPs) in cancers is associated with immune and cancer development. Here, we aimed to profile immune-related RBPs in lung adenocarcinoma (LUAD) and construct an immune-related RBP signature (IRBPS) to predict the survival and response to immunotherapy. Methods: A correlation analysis was performed to establish a co-expression network of RBPs and immune-related genes (IRGs) to characterize immune-related RBPs in the TCGA-LUAD cohort (n = 497 cases). Then, a combination of the Random survival forest (RSF) and Cox regression analysis was performed to screen the RBPs and establish IRBPS. This was followed by independent validation of IRBPS in GSE72094 (n = 398 cases), GSE31210, (n = 226 cases), and GSE26939 (n = 114 cases). Differences between the low- and high-risk groups were compared in terms of gene mutations, tumor mutation burden, tumor-infiltrating lymphocytes, and biomarkers responsive to immunotherapy. Results: DDX56, CTSL, ZC3H12D, and PSMC5 were selected and used to construct IRBPS. The high-risk scores of patients had a significantly worse prognosis in both training and testing cohorts (p < 0.0001 and p < 0.05, respectively), and they tended to be older and have an advanced TNM stage. Furthermore, IRBPS was a prognostic factor independent of age, gender, smoking history, TNM stage, and EGFR mutation status (p = 0.002). In addition, high-risk scores of IRBPS were significantly correlated with tumor-infiltrating lymphocytes (p < 0.05). They also had a high level of PD-L1 protein expression (p < 0.01), number of neoantigens (p < 0.001), and TMB (p < 0.001), implying the possible prediction of IRBPS in the immunotherapy of LUAD. Conclusion: The currently established IRBPS encompassing immune-related RBPs might serve as a promising tool to predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among LUAD patients.

Assessment of quantitative dynamic contrast-enhanced MRI in distinguishing different histologic grades of breast phyllode tumor.

OBJECTIVES: To investigate whether quantitative DCE-MRI (qDCE-MRI) could help distinguish breast phyllodes tumor (PT) grades. MATERIALS AND METHODS: This retrospective study included 67 breast PTs (26 benign lesions, 25 borderline lesions, and 16 malignant lesions) from April 2016 to July 2020. MRI was performed with a 1.5-T MR system. Perfusion parameters (Ktrans, kep, ve, iAUC60) derived from qDCE-MRI, tumor size, and the mean ADC value were correlated with histologic grades using Spearman's rank correlation coefficient. Ktrans, kep, ve, and iAUC60 of three histologic grades were also calculated and compared. RESULTS: The Spearman correlation coefficient with histologic grade of the tumor size was 0.578 (p < 0.001); the ADC value was not correlated with histologic grades of breast PT (p = 0.059). The Ktrans, kep, ve, and iAUC60 of benign breast PTs were significantly lower than those of borderline breast PTs (p < 0.001) and lower than those of malignant breast PTs (p < 0.001). In comparison, the Ktrans, ve, and iAUC60 of borderline breast PTs were significantly lower than those of malignant breast PTs (p < 0.001, p < 0.001, p = 0.007, respectively). For ROC analysis, AUCs of Ktrans, ve, and iAUC60 were higher than tumor size and ADC value for differentiating three PT grades. CONCLUSION: Quantitative and semi-quantitative perfusion parameters (Ktrans, ve, and iAUC60, especially Ktrans) derived from qDCE-MRI showed better diagnosis efficiency than tumor size and ADC for grading breast PTs. Therefore, qDCE-MRI may be helpful for preoperative differentiating breast PT grades. KEY POINTS: • Quantitative dynamic contrast-enhanced MRI can be used as a complementary noninvasive method to improve the differential diagnosis of breast PT. • Ktrans, ve, and iAUC60 derived from qDCE-MRI showed better diagnosis efficiency than tumor size and ADC for grading breast PTs.

MiR-1246 regulates the PI3K/AKT signaling pathway by targeting PIK3AP1 and inhibits thyroid cancer cell proliferation and tumor growth.

One of the most prevalent forms of endocrine malignancies is thyroid cancer. Herein, we explored the mechanisms whereby miR-1246 is involved in thyroid cancer. Phosphoinositide 3-kinase adapter protein 1 (PIK3AP1) was identified as a potential miR-1246 target, with the online Gene Expression Omnibus (GEO) database. The binding between miR-1246 and PIK3AP1 and the dynamic role of these two molecules in downstream PI3K/AKT signaling were evaluated. Analysis of GEO data demonstrated significant miR-1246 downregulation in thyroid cancer, and we confirmed that overexpression of miR-1246 can inhibit migratory, invasive, and proliferative activity in vitro and tumor growth in vivo. Subsequent studies indicated that miR-1246 overexpression decreased the protein level of PIK3AP1 and the phosphorylation of PI3K and AKT, which were reversed by PIK3AP1 overexpression. At the same time, overexpression of PIK3AP1 also reversed the miR-1246 mimics-induced inhibition proliferative, migratory, and invasive activity, while promoting increases in apoptotic death, confirming that miR-1246 function was negatively correlated with that of PIK3AP1. Subsequently, we found that the miR-1246 mimics-induced inhibition of PI3K/AKT phosphorylation was reversed by the PI3K/AKT activator IGF-1. miR-1246 mimics inhibited proliferative, migratory, and invasive activity while promoting increases in apoptotic death, which were reversed by IGF-1. Furthermore, miR-1246 agomir can inhibit tumor growth in vivo. We confirmed that miR-1246 affects the signaling pathway of PI3K/AKT via targeting PIK3AP1 and inhibits the development of thyroid cancer. Thus, miR-1246 is a new therapeutic target for thyroid cancer.

Machine learning-based prediction of invisible intraprostatic prostate cancer lesions on 68 Ga-PSMA-11 PET/CT in patients with primary prostate cancer.

PURPOSE: 68 Ga-PSMA PET/CT has high specificity and sensitivity for the detection of both intraprostatic tumor focal lesions and metastasis. However, approximately 10% of primary prostate cancer are invisible on PSMA-PET (exhibit no or minimal uptake). In this work, we investigated whether machine learning-based radiomics models derived from PSMA-PET images could predict invisible intraprostatic lesions on 68 Ga-PSMA-11 PET in patients with primary prostate cancer. METHODS: In this retrospective study, patients with or without prostate cancer who underwent 68 Ga-PSMA PET/CT and presented negative on PSMA-PET image at either of two different institutions were included: institution 1 (between 2017 and 2020) for the training set and institution 2 (between 2019 and 2020) for the external test set. Three random forest (RF) models were built using selected features extracted from standard PET images, delayed PET images, and both standard and delayed PET images. Then, subsequent tenfold cross-validation was performed. In the test phase, the three RF models and PSA density (PSAD, cut-off value: 0.15 ng/ml/ml) were tested with the external test set. The area under the receiver operating characteristic curve (AUC) was calculated for the models and PSAD. The AUCs of the radiomics model and PSAD were compared. RESULTS: A total of 64 patients (39 with prostate cancer and 25 with benign prostate disease) were in the training set, and 36 (21 with prostate cancer and 15 with benign prostate disease) were in the test set. The average AUCs of the three RF models from tenfold cross-validation were 0.87 (95% CI: 0.72, 1.00), 0.86 (95% CI: 0.63, 1.00), and 0.91 (95% CI: 0.69, 1.00), respectively. In the test set, the AUCs of the three trained RF models and PSAD were 0.903 (95% CI: 0.830, 0.975), 0.856 (95% CI: 0.748, 0.964), 0.925 (95% CI:0.838, 1.00), and 0.662 (95% CI: 0.510, 0.813). The AUCs of the three radiomics models were higher than that of PSAD (0.903, 0.856, and 0.925 vs. 0.662, respectively; P = .007, P = .045, and P = .005, respectively). CONCLUSION: Random forest models developed by 68 Ga-PSMA-11 PET-based radiomics features were proven useful for accurate prediction of invisible intraprostatic lesion on 68 Ga-PSMA-11 PET in patients with primary prostate cancer and showed better diagnostic performance compared with PSAD.

Altered Topological Patterns of Gray Matter Networks in Tinnitus: A Graph-Theoretical-Based Study.

OBJECTIVE: Tinnitus is a prevalent hearing disorder, which could have a devastating impact on a patient's life. Functional studies have revealed connectivity pattern changes in the tinnitus brains that suggested a change of network dynamics as well as topological organization. However, no studies have yet provided evidence for the topological network changes in the gray matter. In this research, we aim to use the graph-theoretical approach to investigate the changes of topology in the tinnitus brain using structural MRI data, which could provide insights into the underlying anatomical basis for the neural mechanism in generating phantom sounds. METHODS: We collected 3D MRI images on 46 bilateral tinnitus patients and 46 age and gender-matched healthy controls. Brain networks were constructed with correlation matrices of the cortical thickness and subcortical volumes of 80 cortical/subcortical regions of interests. Global network properties were analyzed using local and global efficiency, clustering coefficient, and small-world coefficient, and regional network properties were evaluated using the betweenness coefficient for hub connectivity, and interregional correlations for edge properties. Between-group differences in cortical thickness and subcortical volumes were assessed using independent sample t-tests, and local efficiency, global efficiency, clustering coefficient, sigma, and interregional correlation were compared using non-parametric permutation tests. RESULTS: Tinnitus was found to have increased global efficiency, local efficiency, and cluster coefficient, indicating generally heightened connectivity of the network. The small-world coefficient remained normal for tinnitus, indicating intact small-worldness. Betweenness centrality analysis showed that hubs in the amygdala and parahippocampus were only found for tinnitus but not controls. In contrast, hubs in the auditory cortex, insula, and thalamus were only found for controls but not tinnitus. Interregional correlation analysis further found in tinnitus enhanced connectivity between the auditory cortex and prefrontal lobe, and decreased connectivity of the insula with anterior cingulate gyrus and parahippocampus. CONCLUSION: These findings provided the first morphological evidence of altered topological organization of the brain networks in tinnitus. These alterations suggest that heightened efficiency of the brain network and altered auditory-limbic connection for tinnitus, which could be developed in compensation for the auditory deafferentation, leading to overcompensation and, ultimately, an emotional and cognitive burden.

Nonstoichiometric Cu0.6Ni0.4Co2O4 Nanowires as an Anode Material for High Performance Lithium Storage.

Transition metal oxide is one of the most promising anode materials for lithium-ion batteries. Generally, the electrochemical property of transition metal oxides can be improved by optimizing their element components and controlling their nano-architecture. Herein, we designed nonstoichiometric Cu0.6Ni0.4Co2O4 nanowires for high performance lithium-ion storage. It is found that the specific capacity of Cu0.6Ni0.4Co2O4 nanowires remain 880 mAh g-1 after 50 cycles, exhibiting much better electrochemical performance than CuCo2O4 and NiCo2O4. After experiencing a large current charge and discharge state, the discharge capacity of Cu0.6Ni0.4Co2O4 nanowires recovers to 780 mAh g-1 at 50 mA g-1, which is ca. 88% of the initial capacity. The high electrochemical performance of Cu0.6Ni0.4Co2O4 nanowires is related to their better electronic conductivity and synergistic effect of metals. This work may provide a new strategy for the design of multicomponent transition metal oxides as anode materials for lithium-ion batteries.

Systematic evaluation of lithium-excess polyanionic compounds as multi-electron reaction cathodes.

Polyanion cathodes with multi-electron redox always facilitate wider application in a metal ion-based battery system because of their high capacity and safety. However, the irreversible phase transformation and interfacial deterioration remain major impediments. Herein, using monoclinic Li3V2(PO4)3 as a model, the impact of excess lithium on its electrochemical properties are demonstrated. It was determined that a maximum of 5% excess lithium could be incorporated into the monoclinic structure, and a further overdose of lithium led to the formation of secondary phase Li3PO4. The excess Li+ ions are located at both octahedral and interstitial sites, which enable enhanced redox kinetics that are mainly attributed to accelerated ionic movement induced by alternate diffusion behavior of Li+ ions in a three-dimensional permeation path. Moreover, Li-excess local configurations can stabilize the lattice oxygen and provide a favorable cathode-electrolyte interface, which synergistically relieves the structural degradation during electrochemical cycling, thus guaranteeing exceptional cycling stability (e.g., 82.5% after 1000 cycles at 1000 mA g-1). These findings provide a comprehensive understanding of defect/electronic structure/ion transport and the intrinsic properties of polyanionic Li3V2(PO4)3 and may help to pave the way for other highly stable electrodes for rechargeable batteries.

Rational Design of an Ionic Liquid-Based Electrolyte with High Ionic Conductivity Towards Safe Lithium/Lithium-Ion Batteries.

It is a very urgent and important task to improve the safety and high-temperature performance of lithium/lithium-ion batteries (LIBs). Here, a novel ionic liquid, 1-(2-ethoxyethyl)-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (PYR1(2o2) TFSI), was designed and synthesized, and then mixed with dimethyl carbonate (DMC) as appropriate solvent and LiTFSI lithium salt to produce an electrolyte with high ionic conductivity for safe LIBs. Various characterizations and tests show that the highly flexible ether group could markedly reduce the viscosity and provide coordination sites for Li-ion, and the DMC could reduce the viscosity and effectively enhance the Li-ion transport rate and transference number. The electrolyte exhibits excellent electrochemical performance in Li/LiFeO4 cells at room temperature as well as at a high temperature of 60 °C. More importantly, with the addition of DMC, the IL-based electrolyte remains nonflammable and appropriate DMC can effectively inhibit the growth of lithium dendrites. Our present work may provide an attractive and promising strategy for high performance and safety of both lithium and lithium-ion batteries.

Factors suggesting relapse of Grave's disease after first radioiodine therapy. Analysis of 607 cases.

OBJECTIVE: Despite the effectiveness of radioiodine therapy (RIT), a few patients are refractory and show relapse, warranting repeated RIT (RRIT). The purpose of this study is to explore the risk factors for RRIT. SUBJECTS AND METHODS: We retrospectively analyzed 607 cases treated with iodine-131 (131I) between January 2013 and June 2016. Patients were categorized into two groups: RRIT (n=76) or non-RRIT (n=531). Univariate analysis and a final multivariate model were used to determine the risk factors for RRIT. P<0.05 indicated significance. After a mean 314.5MBq dose of 131I, 76 patients underwent secondary therapy. RESULTS: In the univariate analysis, the differences in terms of age, gender, family history of hyperthyroidism, course of disease, 24-hour 131I uptake, curve shape of 131I uptake, dose of 131I, thyroid peroxidase antibody, and thyrotrophin receptor antibody were not statistically significant (P>0.05). Anti-thyroid drug (ATD) treatment history, thyroid mass and dose of 131I were statistically significant (P values: 0.001, <0.001 and <0.001, respectively). Binary logistic analysis of factors that lead to repeated RIT showed a higher probability of ATD treatment history [OR=2.919, 95%CI (1.424, 5.982), P=0.003] and thyroid mass [OR=1.042, 95%CI(1.031, 1.052), P<0.001] associated with RRIT. CONCLUSION: Patients treated with ATD before radioiodine treatment and with larger thyroid mass are at a higher risk for repeated radioiodine treatment.

Multifactor Analysis of Thyroid Stiffness in Graves Disease: A Preliminary Study.

OBJECTIVE. The aim of this study was to evaluate the value of shear wave elastography (SWE) in Graves disease (GD) and to identify the potential factors influencing thyroid stiffness. MATERIALS AND METHODS. A total of 207 subjects were enrolled and underwent SWE examination in the study, including 162 patients with GD and 45 healthy volunteers with normal thyroids, matched for age and sex. For all subjects, five measurements of elastic modulus values (SWE mean, SWE minimum, and SWE maximum of a 9-mm ROI) were performed on each thyroid lobe, and a mean value was calculated. The indicators including free three-triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroid size, isthmus thickness, anti-thyroid peroxidase (TPO) antibodies (Abs), and antithyroglobulin (TG) Abs were detected in the 162 patients with GD, among whom 88 patients underwent initial TSH receptor (TR) Ab examination. RESULTS. The elastic modulus values for patient with GD were significantly higher than those for healthy control subjects. The ROC AUC values for GD by SWE mean was 0.656, and the cutoff value was 15.45 kPa. The sensitivity and specificity were 56.8% and 71.1%, respectively. The duration of disease, thyroid size, isthmus thickness, and levels of TPO Ab, TG Ab, and TR Ab were positively correlated with SWE mean in GD. However, there was no correlation between age, FT3, FT4, TSH, and SWE mean. CONCLUSION. Quantitative SWE helps in the diagnosis of GD. The duration of disease, thyroid size, isthmus thickness, and levels of thyroid autoantibodies (TPO Ab, TG Ab, and TR Ab) could influence thyroid stiffness of GD.

LncRNA BISPR promotes the progression of thyroid papillary carcinoma by regulating miR-21-5p.

Our study attempted to verify the effect of lncRNA BST2 interferon-stimulated positive regulator (BISPR) on cell viability, propagation and invasiveness of thyroid papillary carcinoma (TPC) and the interactive relationship between BISPR and miR-21-5p. Microarray analyzed the aberrant expression lncRNA BISPR in TPC. BISPR and miR-21-5p as well as B-cell lymphoma-2 (Bcl-2) expressions in TPC cells were determined by quantitative polymerase chain reaction (qRT-PCR) and Western blot. Cell counting kit-8 (CCK-8) assay, dual luciferase reporter assay, and transwell assay were conducted to manifest cell viability, propagation, and invasiveness of TPC cells. Flow cytometry was performed to determine the apoptosis and cell cycle of TPC cells. Mouse xenograft model was built to testify the effect of BISPR on tumor growth. BISPR in TPC tissues was over-expressed. BISPR knockdown restrained the propagation and invasiveness and enhanced the iodine uptake of TPC cells. The tumor-forming rate reduced after BISPR knockdown. In addition, miR-21-5p was lowly expressed in cancer tissues. BISPR promoted the development of TPC cells by inhibiting miR-21-5p expression. Bcl-2 was suppressed by miR-21-5p and sh-BISPR. BISPR, which was over-expressed in TPC, improved TPC cell viability, propagation, and invasiveness. MiR-21-5p was lowly expressed in TPC which inhibited Bcl-2 expression. BISPR stimulated propagation and invasiveness of TPC cells by depressing miR-21-5p.

Long noncoding RNA NEAT1 regulate papillary thyroid cancer progression by modulating miR-129-5p/KLK7 expression.

Considering the dilemma in papillary thyroid cancer treatment, this study intended to find solution in molecular respect. By probing into lncRNA-NEAT1/miR-129-5p/KLK7 interaction, this study would provide new targets for future treatment. Microarray analysis and R language package were applied to select possible lncRNA and miRNA. Luciferase reporter assay and RNA pull-down test were employed in the detection of target relationship between lncRNA and miRNA. Clone formation assay, flow cytometry analysis, wound healing assay, and transwell assay were, respectively, used to observe effects of lncRNA NEAT1/miR-129-5p/KLK7 to papillary thyroid cancer cells. Western blot and qRT-PCR were used to validate protein expressions and mRNA expressions in PTC tissues and cells. LncRNA NEAT1 was highly expressed in PTC tissues and cell lines and could deteriorate PTC by promoting proliferation, invasion, and migration accompanied by less apoptosis. Besides, miR-129-5p/lncRNA NEAT1 were found to negatively correlate with each other by direct target relationship and their combination suppressed the progression of PTC. KLK7, a highly expressed downstream protein in PTC tissues, could be directly regulated by miR-129-5p in a negative way. KLK7 accelerated the deterioration of PTC in vitro experiments which could be reversed by sh-lnc RNA NEAT1 and miR-129-5p mimics. In vivo experiments, silence of lncRNA NEAT1 restrain tumor growth in weight and volume. In conclusion, lncRNA NEAT1 suppression could inhibit PTC progression by upregulating miR-129-5p, which suppressed KLK7 expression either in vitro or vivo experiments.

Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells.

Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

Postoperative radioactive iodine-131 ablation is not necessary among patients with intermediate-risk differentiated thyroid carcinoma: a population-based study.

OBJECTIVE: To assess the effectiveness of radioactive iodine (RAI) ablation among patients with intermediate-risk differentiated thyroid cancer (DTC) following surgery. SUBJECTS AND METHODS: This population based study obtained information from the Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2013). National Cancer Institute, DCCPS, Surveillance Research Programme, Surveillance Systems Branch, released April 2016, based on the November 2015 submission. A total of 93,530 patients with primary thyroid cancer were identified in the SEER database during the period of 2004-2013 and focused on patients with DTC post-operatively treated or not treated with radioactive iodine (RAI). From these 9,127 patients were selected who had intermediate-risk DTC. A total of 8,601 patients were included in this study. For the overall population, the mean age of the population was 47.3 years and the majority were female (70.5%). RESULTS: Kaplan-Meier analysis found the mean overall survival time (os) for subjects with no radiation therapy which was 112.9 months and 114.9 months for those who received RAI ablation treatment (P<0.001). However, thyroid cancer-specific survival was not significantly different between treatment groups (117.7 vs. 118.0 months, log-rank test P=0.164). Overall survival and thyroid cancer-specific 1 year, 5 years, and 10-years survival rates were ≥89.8% and were similar between both treated groups. Multivariate analysis found age, gender, histologic type, and degree of lymph node metastases to be associated with OS, and age, gender, degree of lymph node metastasis and extra-thyroid tumor spread were independent factors for cancer-specific survival. In DTC patients with intermediate cancer risk multivariate analysis found that RAI was associated with a reduced risk of mortality compared with no radiation therapy (HR=0.710, 95% CI: 0.562-0.897, P=0.004) but no significant difference was seen in cancer-specific survival, either based on whole study population or on tumor size category. CONCLUSION: In DTC patients with intermediate cancer risk although postoperative RAI ablation following surgery showed a benefit in overall survival, no significant difference was seen in cancer-specific survival, either based on whole study population or on tumor size category.

Follow-up and evaluation of the pregnancy outcome in women of reproductive age with Graves' disease after 131Iodine treatment.

The aims of the present study were to analyze the outcomes of pregnancy, after 131I treatment, in patients of reproductive age with Graves' hyperthyroidism and to investigate the effects, if any, of the 131I treatment on the mothers and newborns. From 2009 to 2014, 257 pregnant female patients with Graves' hyperthyroidism in the outpatients at the Department of Nuclear Medicine and 166 healthy pregnant women from the Department of Obstetrics at Sun Yat-Sen Memorial Hospital were included in our study. They were divided into a 131I therapy group (n = 130) and an anti-thyroid drug (ATD) group (n = 127) according to their therapy before conception. The neonatal gender, rate of preterm birth, body weight ratio and occurrence of low birth weight [except for higher rates of abortion (odds ratio; OR = 2.023) and cesarean delivery (OR = 1.552) in patients with Graves' hyperthyroidism] showed no statistically significant differences from those of the healthy group (P > 0.05). The level of intrauterine growth restriction did not differ between the Graves' hyperthyroidism group and the healthy group (8 vs 2, 3.0% vs 1.2%). The outcomes of pregnancy among the 131I therapy group, ATD group and healthy group also showed no significant differences. Of the patients treated with 131I, no significant differences were observed in the outcomes of their pregnancies, whether they received propylthiouracil (PTU), levothyroxine or no additional drug treatment during pregnancy. Women with hyperthyroidism who were treated with 131I therapy could have normal delivery if they ceased 131I treatment for at least six months prior to conception and if their thyroid function was reasonably controlled and maintained using the medication: anti-thyroid drug and levothyroxine before and during pregnancy.

Vitamin K3 increased BMD at 1 and 2 months post-surgery and the maximum stress of the middle femur in the rat.

The therapeutic effects of vitamin K3 (VK3) on osteoporosis are still unknown. In this study, we hypothesized that VK3 possesses therapeutic effects on osteoporosis; to verify this hypothesis, the ovariectomized rat was used as an osteoporosis model. Fifty-six Sprague-Dawley female rats aged 8 to 9 months were randomly assigned to 4 groups: sham surgery, ovariectomy with saline, ovariectomy with low-dose VK3, and ovariectomy with high-dose VK3. Intramuscular injection of VK3 was performed every other day beginning 1 month postoperatively. The therapeutic effects of VK3 on osteoporosis were evaluated by measurement of bone mineral density (BMD), bone biochemical markers, biomechanical properties, and bone morphometric parameters. The overall average BMD in VK3-treated groups increased to a level between those of the ovariectomy group and the sham surgery group. The procollagen I N-terminal peptide level peaked at 2 months after surgery in all groups except in the group that had undergone ovariectomy with low-dose VK3. The tartrate-resistant acid phosphatase 5b level increased more slowly at 4 months after surgery than at 2 months after surgery in the VK3-treated groups. The ovariectomy with high-dose VK3 group had the highest maximum stress of the middle femur of all groups. With VK3 treatment, the trabecular bone area percentage increased. All morphometric indicators for the middle tibia in the VK3-treated groups reached the levels found in the sham surgery group. In summary, VK3 therapy increased BMD at 1 and 2 months postsurgery and the maximum stress of the middle femur. In addition, VK3 therapy slowed the increase in bone turnover in ovariectomized rats. Furthermore, VK3 can improve morphometric indicators for the middle tibia. Our preliminary study indicates that VK3 has a potential therapeutic effect on osteoporosis and is worthy of further investigation.

Expression of miR-100 and RBSP3 in FTC-133 cells after exposure to 131I.

BACKGROUND: Sodium iodide ((131)I) therapy for the management of differentiated thyroid cancer is based on the deposition of certain doses of ionizing radiation, which can modulate microRNA (miRNA, miR) expression. Recent studies have suggested that miR-100 is significantly differentially expressed between benign and malignant thyroid tissue samples and modulates retinoblastoma 1 serine phosphates from human chromosome 3 (RBSP3), which is involved in the regulation of cell growth and differentiation. Therefore, the authors tested the hypothesis that a potential mechanism of (131)I treatment affects miR-100, which in turn regulates RBSP3 to modulate cell proliferation in thyroid cancer in vitro. MATERIALS AND METHODS: A follicular thyroid carcinoma cell line (FTC-133) was treated with (131)I or transfected with an oligonucleotide (miR-100 mimics, inhibitor, or negative control). Real-time quantitative PCR was used to confirm the expression levels of the miR-100 and RBSP3 mRNAs. Western blot analysis was performed to detect the levels of the RBSP3 protein. The cell cycle was analyzed on a cytofluorimeter by fluorescence-activated cell sorting analysis. RESULTS: RBSP3 protein expression was detected in FTC-133 cells. (131)I treatment inhibited the expression of miR-100 in FTC cells, as assessed by real-time quantitative PCR analysis, whereas it upregulated the RBSP3 mRNA and protein. Overexpression and knockdown experiments indicated that miR-100 repressed the expression of the RBSP3 mRNA by blocking its translation. Overexpression of miR-100 led to the downregulation of the RBSP3 protein and promoted the transition of FTC cells from the G1 to the S phase, as assessed using FACS analysis. CONCLUSION: (131)I treatment inhibited the expression of miR-100, which modulated RBSP3 in FTC cells. The new mechanism of suppression of the proliferation of FTC cells by I described here might occur through the downregulation of miR-100.

Differentiation of E14 mouse embryonic stem cells into thyrocytes in vitro.

BACKGROUND: If methods of differentiating stem cells into thyrocytes can be perfected, they may provide a ready source of normal thyrocytes for basic research and clinical application. We developed a novel culture method capable of differentiating mouse embryonic stem (ES) cells into thyroid follicular cells. METHODS: E14 mouse ES cells were allowed to differentiate into embryoid bodies and then stimulated with thyroid-stimulating hormone, insulin, and potassium iodide. The resulting differentiated cells were observed for expression of thyrocyte-specific mRNA transcripts with reverse transcriptase (RT)-polymerase chain reaction. To definitively identify thyrocytes, we simultaneously observed the thyrocyte-specific proteins, thyroid transcription factor-1 and PAX-8, with dual-color immunofluorescent labeling. The cells were further characterized by electron microscopy. RESULTS: The ES cells were successfully differentiated into thyrocytes. Differentiated cells expressed PAX-8, thyroid-stimulating hormone receptor, sodium/iodide symporter, thyroperoxidase, and thyroglobulin mRNAs, and coexpressed thyroid transcription factor-1 and PAX-8 proteins. The extent of differentiation was further explored by electron microscopy, which showed that differentiated cells had ultrastructural features similar to adult human thyrocytes, whereas the cells from unstimulated cultures were mostly disintegrated and lacked developed organelle structures. CONCLUSIONS: These data show that E14 mouse ES cells can be differentiated into thyrocytes by culturing with thyroid-stimulating hormone, insulin, and potassium iodide. The development of reliable methods to produce thyroid cells from ES cells is important to future research in thyroid biology and medical applications.

Experimental studies on imaging of infected site with (99m)Tc-labeled ciprofloxacin in mice.

BACKGROUND: Bacterial infection can pose a substantial diagnostic dilemma. (99m)Tc-labeled ciprofloxacin (CPF) was developed as a biologically active radiopharmaceutical to diagnose infection. In the present research, we studied the biodistribution and imaging properties of infection tracer (99m)Tc-CPF in a mouse model of infection. METHODS: CPF was labeled with (99m)Tc and the radiochemical purity and labeling rate were measured. A mouse model of infection was established. We then determined the biodistribution of (99m)Tc-CPF and conducted the whole body scintigraphy of the animal model. RESULTS: (99m)Tc-Ciprotech was stable for at least 6 hours at room temperature. The labeling rate of CPF by (99m)Tc was over 90%. Clearance of radioactivity mainly occurred in the liver and kidney, and the clearance from blood was rapid. Both biodistribution and imaging results showed higher uptake of (99m)Tc-CPF at sites of infection. The infectious tissue/normal tissue ratio peak was 4.30 at 4 hours after injection. CONCLUSIONS: (99m)Tc-CPF is a sensitive radiopharmaceutical for scintigraphy of infectious lesions and it is easy to prepare.

Preparation and identification of monoclonal antibody against human hepatocellular carcinoma with a novel immunization.

The purpose of this study was to prepare and identify a novel monoclonal antibody (MAb) against human primary hepatocellular carcinoma (PHC) with high specificity and activity. The hepatocellular carcinoma cell line HepG2 was used to immunize BALB/c mice for preparing MAb with the classic hybridoma production technique. Tail vein injection immunization combined with intrasplenic injection was applied for improvement. Immunoperoxidase staining studies showed that the MAb was reactive to HepG2 and another hepatocellular carcinoma cell line, SMMC7721, 98.5% (67/68) specimens of hepatocellular carcinoma, but not to normal human liver tissues and tissues derived from the other malignant tumors, except one of the five specimens of cholangiocarcinoma with dubious staining. Laser confocal scanning microscope (LCSM) analysis indicated that the MAb reacted with the whole cell, including the membrane fractions and the cytoplasm. The hybridoma cell contained 103 +/- 5 chromosomes, and the MAb was identified as IgM subclass by ELISA. It was concluded that this combined immunization can effectively produce highly specific MAb against PHC, and this MAb may be of potential use as a targeting agent for radionuclide therapy and chemotherapy for hepatocellular carcinoma.