An Online Model for Central Lymph Node Metastases in Papillary Thyroid Carcinoma With BRAF V600E Mutation.

BACKGROUND: To construct a predictive model to direct the dissection of the central lymph nodes in papillary thyroid cancer (PTC) with BRAF V600E mutation by identifying the risk variables for central lymph node metastases (CLNM). METHODS: Data from 466 PTC patients with BRAF V600E mutations underwent thyroid surgery was collected and analyzed retrospectively. For these patients, we conducted univariate and multivariate logistic regression analysis to find risk variables for CLNM. To construct a nomogram, the independent predictors were chosen. The calibration, discrimination, and clinical utility of the predictive model were assessed by training and validation data. RESULTS: CLNM was present in 323/466 PTC patients with BRAF V600E mutations. By using univariate and multivariate logistic regression, we discovered that gender, age, tumor size, multifocality, and pathological subtype were all independent predictors of CLNM in PTC patients with BRAF V600E mutations. A predictive nomogram was created by combining these variables. In both training and validation groups, the nomogram demonstrated great calibration capacities. The training and validation groups' areas under the curve (AUC) were 0.772 (specificity 0.694, sensitivity 0.728, 95% CI: 0.7195-0.8247) and 0.731 (specificity 0.778, sensitivity 0.653, 95% CI: 0.6386-0.8232) respectively. According to the nomogram's decision curve analysis (DCA), the nomogram might be beneficial. As well, an online dynamic calculator was developed to make the application of this nomogram easier in the clinic. CONCLUSION: An online nomogram model based on the 5 predictors included gender, age, pathological subtype, multifocality, and tumor size was confirmed to predict CLNM and guide the central lymph nodes dissection in PTC patients with BRAF V600E mutations.

Identification of a four-miRNA signature predicts the prognosis of papillary thyroid cancer.

BACKGROUND: In recently diagnosed patients with thyroid cancer, papillary thyroid cancer (PTC), as the most common histological subtype, accounts for 90% of all cases. Although PTC is known as a relatively adolescent malignant disease, there still is a high possibility of recurrence in PTC patients with a poor prognosis. Therefore, new biomarkers are necessary to guide more effective stratification of PTC patients and personalize therapy to avoid overtreatment or inadequate treatment. Accumulating evidence demonstrates that microRNAs (miRNAs) have broad application prospects as diagnostic biomarkers in cancer. AIM: To explore novel markers consisting of miRNA-associated signatures for PTC prognostication. METHODS: We obtained and analyzed the data of 497 PTC patients from The Cancer Genome Atlas. The patients were randomly assigned to either a training or testing cohort. RESULTS: We discovered 237 differentially expressed miRNAs in tumorous thyroid tissues compared with normal tissues, which contained 172 up-regulated and 65 down-regulated miRNAs. The evaluation of differently expressed miRNAs was conducted using our risk score model. We then successfully generated a four-miRNA potential prognostic signature [risk score = (-0.001 × hsa-miR-181a-2-3p) + (0.003 × hsa-miR-138-5p) + (-0.018 × hsa-miR-424-3p) + (0.284 × hsa-miR-612)], which reliably distinguished patients from high and low risk with a significant difference in the overall survival (P < 0.01) and was effective in predicting the five-year disease survival rate with the area under the receiver operating characteristic curve of 0.937 and 0.812 in the training and testing cohorts, respectively. Additionally, there was a trend indicated that high-risk patients had shorter relapse-free survival, although statistical significance was not reached (P = 0.082) in our sequencing cohort. CONCLUSION: Our results indicated a four-miRNA signature that has a robust predictive effect on the prognosis of PTC. Accordingly, we would recommend more radical therapy and closer follow-ups for high-risk groups.

Serum deprivation response functions as a tumor suppressor gene in papillary thyroid cancer.

The mechanism of papillary thyroid cancer (PTC) has shown numerous recurrently mutated genes, but the discovery of abnormal expression of novel tumor suppressor genes has been slow. The aim of our study is to explore the biological functions of SDPR in thyroid cancer. We reanalyzed the RNA-Seq data of PTC from The Cancer Genome Atlas (TCGA) database and found that serum deprivation response (SDPR) was significantly downregulated in PTC. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was performed to assess the expression of SDPR. Both loss- and gain-of-function experiments, and flow cytometry were performed to investigate the functions. SDPR was significantly downregulated in PTC. Reduced expression of SDPR was associated with larger tumor size, more serious lymph node metastasis, and advanced American Joint Committee on Cancer (AJCC) stage. Patients with lower SDPR expression had a shorter recurrence-free survival. SDPR expression and AJCC stage were independent predictors of poor recurrence-free survival (RFS). Moreover, cell proliferation, colony formation, and migration were inhibited after SDPR overexpression, whereas knockdown of SDPR exerted an oncogenic effect. SDPR induction also initiated the mesenchymal-epithelial transition, alongside suppressing AKT signaling and cyclin family expression. Apart from DNA methylation, LOC105373813, may also co-regulate SDPR expression by forming a stable hybrid with SDPR messenger RNA. Our study indicated that SDPR may function as a potential prognostic marker in PTC.

Underexpression of INPPL1 is associated with aggressive clinicopathologic characteristics in papillary thyroid carcinoma.

PURPOSE: To study the relationship between INPPL1 gene and clinicopathologic characteristics of papillary thyroid carcinoma (PTC). PATIENTS AND METHODS: INPPL1 expression in PTCs was tested by quantitative real-time reverse transcription PCR. The Cancer Genome Atlas (TCGA) RNA-seq data and our mRNA data were used to analyze and reveal the relationship between INPPL1 and aggressive clinicopathologic characteristics of PTC. RESULTS: When compared to normal thyroid tissues, INPPL1 was significantly downregulated in PTC tissues, as revealed by our data and TCGA data. INPPL1 underexpression was remarkably related to aggressive clinicopathologic characteristics such as lymph node metastasis (LNM), histological type, tumor size, mulitifocality, and disease stage in TCGA data. Meanwhile, LNM was confirmed to be associated with underexpression of INPPL1 in our data. In addition, logistic analysis clearly showed that underexpression of INPPL1 was an independent factor for LNM in PTC. CONCLUSION: INPPL1 may be a novel tumor suppressor gene in PTC, which was significantly correlated with aggressive clinicopathologic characteristics, especially LNM.

Next-generation sequence detects ARAP3 as a novel oncogene in papillary thyroid carcinoma.

PURPOSE: Thyroid cancer is the most frequent malignancies of the endocrine system, and it has became the fastest growing type of cancer worldwide. Much still remains unknown about the molecular mechanisms of thyroid cancer. Studies have found that some certain relationship between ARAP3 and human cancer. However, the role of ARAP3 in thyroid cancer has not been well explained. This study aimed to investigate the role of ARAP3 gene in papillary thyroid carcinoma. METHODS: Whole exon sequence and whole genome sequence of primary papillary thyroid carcinoma (PTC) samples and matched adjacent normal thyroid tissue samples were performed and then bioinformatics analysis was carried out. PTC cell lines (TPC1, BCPAP, and KTC-1) with transfection of small interfering RNA were used to investigate the functions of ARAP3 gene, including cell proliferation assay, colony formation assay, migration assay, and invasion assay. RESULTS: Using next-generation sequence and bioinformatics analysis, we found ARAP3 genes may play an important role in thyroid cancer. Downregulation of ARAP3 significantly suppressed PTC cell lines (TPC1, BCPAP, and KTC-1), cell proliferation, colony formation, migration, and invasion. CONCLUSION: This study indicated that ARAP3 genes have important biological implications and may act as a potentially drugable target in PTC.

[Fracture resistance of endodontically treated mandibular premolars restored with e.max press all-ceramic onlays and metal crowns].

PURPOSE: To compare the fracture resistance of endodontically treated mandibular premolars restored with e.max press all-ceramic onlays and metal crowns. METHODS: Forty-five endodontically treated mandibular premolars were randomly divided into 3 groups. Group A were filled with resin as control. Specimens of group B and C were instrumented and prepared for two-wall cavities and restored with metal crowns and ceramic onlays respectively. The specimens were thermocycled, exposed to cyclic loading, and submitted to the static fracture resistance test. Fracture loads and mode of failure were evaluated. The data was analyzed with SPSS13.0 software package. RESULTS: Samples in 2 experimental groups exhibited higher fracture load values than that of the control group (P<0.05). Group C showed higher fracture load values and more favourable fracture patterns compared with group B (P<0.05). CONCLUSIONS: Endodontically treated mandibular molars restored with indirect onlays provide significantly increased fracture resistance and favourable fracture patterns.

[Effect of surface roughness and composition of titanium on proliferation and differentiation of osteoblasts].

PURPOSE: To study the effects of surface roughness and composition of titanium on proliferation and differentiation of osteoblasts. METHODS: Osteoblasts were cultured on 5 commercially pure titanium (cp Ti) substrates of ground (S0), blasted with 108-130 µm(S1), 216-301 µm(S2), 356-411 µm (S3) TiO2 particles and titanium-sprayed plasma(TPS) surfaces. Surfaces prepared by hand grinding with SiC paper of 600 grits served as control (S0). Electron microprobe was used to evaluate the TiO2 film structure of the 5 titanium surfaces. For proliferation and differentiation measurement, osteoblasts were cultured for 1, 3, 5 and 7 days, evaluated by MTT Assay, ALP activity and OC level. SPSS12.0 software package was used for one-way ANOVA. RESULTS: The number of cells was the highest on S3 and TPS surfaces after 1 day culture. The same results were observed after 5 days. On day 3 and 7, S3 surface was the highest(P<0.05). The number of cells on all experimental groups were higher than S0 surfaces at each time point(P<0.05). Increase of ALP activity were detected on S0, S1 and S2 surfaces after 1, 3, 5 days. However, there was no difference between S3 and TPS surfaces(P>0.05). After 7 days, ALP activity increased significantly on TPS surface than on S1 or S2 surfaces. ALP activity on S3 surfaces was the highest(P<0.05). The ALP activity on all experimental groups were higher than S0 surfaces at each time point(P<0.05). An increase in OC production was detected on S0, S1, S2 and S3 surfaces after 1, 3, 5 days. The highest OC production was on S3 surface was on day 7(P<0.05). CONCLUSIONS: It was concluded that for TiO2 blasted surfaces, Ra ranging from 1.260 µm to 3.530 µm would optimize proliferation and differentiation of osteoblasts. Blasting was an effective treatment method for osteointegration in vitro.

Hashimoto's thyroiditis, microcalcification and raised thyrotropin levels within normal range are associated with thyroid cancer.

BACKGROUND: To confirm whether clinical and biochemical parameters or Hashimoto's thyroiditis (HT) could predict the risks of malignancy among subjects who underwent thyroidectomy, as well as to determine the influence of HT on the biological behavior of papillary thyroid cancer (PTC). METHODS: A total of 2,052 patients who underwent initial thyroidectomy were enrolled between June 2006 and August 2008. Serum free T4, free T3, thyrotropin (TSH), thyroglobulin, thyroglobulin antibody, antimicrosomal antibody, tumor-associated status, and thyroid disorders were documented. RESULTS: Binary logistic regression analysis was performed to define the risk predictors for thyroid cancer. Finally, calcification, HT, TSH, and age, were entered into the multivariate model. Multivariate logistic regression analysis revealed the risk of thyroid cancer increases in parallel with TSH concentration within normal range, and the risk for malignancy significantly increased with serum TSH 1.97-4.94 mIU/L, compared with TSH less than 0.35 mIU/L (OR = 1.951, 95% CI = 1.201-3.171, P = 0.007). Increased risks of thyroid cancer were also detected among the patients with HT (OR = 3.732, 95% CI = 2.563-5.435), and microcalcification (OR = 14.486, 95% CI = 11.374-18.449). The effects of HT on the aggressiveness of PTC were not observed in extrathyroidal invasion (P = 0.347), capsular infiltration (P = 0.345), angioinvasion (P = 0.512), and lymph node metastases (P = 0.634). CONCLUSIONS: The risk of malignancy increases in patients with higher level TSH within normal range, as well as the presence of HT and microcalcification. No evidence suggests that coexistent HT alleviates the aggressiveness of PTC.

Different distribution of breast ductal carcinoma in situ, ductal carcinoma in situ with microinvasion, and invasion breast cancer.

BACKGROUND: Breast ductal cancer in situ (DCIS) can recur or progress to invasive ductal cancer (IDC), and the interim stage include DCIS with microinvasion (DCIS-Mi). In this article, we attempt to study the study the differences of clinicopathological features, imaging data, and immunohistochemical-based subtypes among DCIS, DCIS-Mi, and IDC. METHODS: In this retrospective study, we attempt to compare the clinicopathological features, immunohistochemical results and imaging data of 866 patients (included 73 DCIS, 72 DCIS-Mi, and 721 IDC). RESULTS: Patients with DCIS and DCIS-Mi were younger than those with IDC (P = 0.007). DCIS and DCIS-Mi often happened in premenopausal women while IDC was opposite (P <0.001). The incidence of IDC with node-positive was significantly higher than it in DCIS and DCIS-Mi (P <0.001). We also observed that the Her2-positive was more often found in patients with pure DCIS compared to those with DCIS-Mi and DCIS-I (P <0.001). There was a significant difference between the four subgroups (Luminal-A, Luminal-B, ERBB2+, Basal-like) from DCIS, DCIS-Mi, and IDC (P <0.001). Basal-like patients were fewer than other subgroups in DCIS, DCIS-Mi, and IDC. The incidence of the first performance of ultrasound (catheter winded and nodular mass) and mammography (nodular mass) had significantly difference among patients with DCIS, DCIS-Mi, and IDC (P <0.001). CONCLUSIONS: Different clinicopathological, immunohistochemical, and imaging features among DCIS, DCIS-Mi, and IDC indicate that they are distinct entities. A larger sample size is needed for further study.

Overexpression of miR-221 is associated with aggressive clinicopathologic characteristics and the BRAF mutation in papillary thyroid carcinomas.

Correlation between clinicopathogenetic features and the expression of specific miRNAs is unclear in papillary thyroid carcinoma (PTC). We therefore sought to assess whether miR-221 was associated with aggressive clinicopathologic characteristics and the BRAF mutation. We studied the expression levels of miR-221 using northern blot quantitated by scion image in 51 cases of PTCs. The status of BRAF of PTCs was analyzed through direct DNA sequencing. Mann-Whitney U test was used to analyze different expression of miR-221 in PTCs with distinct clinicopathogenetic characteristics including gender, age, tumor size, multifocality, extrathyroidal invasion, disease stages, node metastasis, and BRAF status. Compared with the normal thyroid tissues, the relative expression of miR-221 in tumor tissues was significantly upregulated (p < 0.001). Overexpression of miR-221 was significantly associated with extrathyroidal invasion (p = 0.001), lymph node metastasis (p = 0.046), advanced disease stages III-IV (p = 0.001), and the BRAF mutation (p = 0.014). While among BRAF wild tumors, miR-221 was only associated with extarthyroidal invasion, it showed strong association with all above aggressive features among BRAF mutation tumors. MiR-221 may be of potential importance in determining the aggressive properties of PTCs including the BRAF mutation, and it may further refine the risk stratification by BRAF mutation in PTCs.

Preoperative BRAF mutation is predictive of occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma.

BACKGROUND AND OBJECTIVE: The optimal resection extent for clinically unilateral papillary thyroid microcarcinoma (PTMC) remains controversial. The objective was to investigate risk factors associated with occult contralateral carcinoma, and put emphasis on the predictive value of preoperative BRAF mutation. MATERIALS AND METHODS: 100 clinically unilateral PTMC patients all newly diagnosed, previously untreated were analyzed in a prospective cohort study. We assessed the T1799A BRAF mutation status in FNAB specimens obtained from all PTMC patients before undergoing total thyroidectomy (TT) and central lymph node dissection (CLND) for PTMC. Univariate and multivariate analyses were used to reveal the incidence of contralateral occult cancer, difference of risk factors and predictive value, with respect to the following variables: preoperative BRAF mutation status, age, gender, tumor size, multifocality of primary tumor, capsular invasion, presence of Hashimoto thyroiditis and central lymph node metastasis. RESULTS: 20 of 100 patients (20%) had occult contralateral lobe carcinoma. On multi-variate analysis, preoperative BRAF mutation (p = 0.030, OR = 3.439) and multifocality of the primary tumor (p = 0.004, OR = 9.570) were independent predictive factors for occult contralateral PTMC presence. However, there were no significant differences between the presence of occult contralateral carcinomas and age, gender, tumor size, capsular invasion, Hashimoto thyroiditis and central lymph node metastasis. CONCLUSIONS: Total thyroidectomy, including the contralateral lobe, should be considered for the treatment of unilateral PTMC if preoperative BRAF mutation is positive and/or if the observed lesion presents as a multifocal tumor in the unilateral lobe.

Factors predictive of papillary thyroid micro-carcinoma with bilateral involvement and central lymph node metastasis: a retrospective study.

BACKGROUND: The optimal resection extent for papillary thyroid microcarcinoma (PTMC) remains controversial. The objective of the study was to investigate risk factors of bilateral PTMC and central lymph node metastasis (CLNM) to guide surgical strategies for PTMC patients. METHODS: We retrospectively reviewed 211 PTMC patients who underwent total thyroidectomy (TT) and 122 clinical lymph node-negative (cN0) cases that underwent prophylactic central lymph node dissection (CLND) between 2010 and 2011. The frequency, pattern, and predictive factors for bilateral PTMC and CLNM in these patients were studied using univariate and multivariate analysis with respect to the following variables: age, gender, extrathyroidal extension (ETE), T stage, with Hashimoto thyroiditis (HT), tumor size and multifocality based on final pathology, and preoperative evaluation using ultrasonography (US). RESULTS: Fifty-four of 211 (25.6%) patients had bilateral PTMC. In multivariate analysis, multifocality (P < 0.001, OR = 23.900) and tumor size ≥7 mm (P = 0.014, OR = 2.398) based on US were independent predictive factors for bilateral PTMC which was also independently associated with multifocality (P < 0.001, OR = 29.657) and tumor size ≥7 mm (P = 0.005, OR = 2.863) based on final pathology. Among 122 cN0 patients who underwent prophylactic CLND, we found 49.2% of patients had CLNM. CLNM was independently associated with men, age <50 years and tumor size ≥7 mm based on final pathology or preoperative US. CONCLUSIONS: TT should be considered for PTMC patients who are found multifocality and tumor size ≥7 mm based on preoperative US. CLND need be considered in cN0 patients who are men, aged <50 years or tumor size ≥7 mm based on preoperative US.

[Effect of surface roughness and titanium dioxide layers on commercially pure titanium on attachment of osteoblasts].

OBJECTIVE: To study the effects of surface roughness and titanium dioxide (TiO2) layers on commercially pure titanium (cp-Ti) substrates on attachment of osteoblasts in vitro. METHODS: 250 pure titanium slices were divided into five groups. Osteoblasts were cultured on five cp-Ti substrates of ground, which blasted with 108-130 microm (S1), 216-301 microm (S2), 356-411 microm (S3) TiO2 particles and titanium-sprayed plasma (TPS) surfaces, surfaces prepared by hand grinding with SiC paper to 600 grits served as control (S0). Surface average roughness and the TiO2 film structure was evaluated. For morphology and attachment measurement, osteoblasts were cultured for 1, 4, 12 and 24 h, evaluated by scanning electronic microscope (SEM) observation and MTr assay. RESULTS: Osteoblasts spread well on the titanium surfaces. Further more, osteoblasts spread more well on S3 surfaces. After 1 and 4 h culture, the number of cells on S3 surfaces was the highest (P < 0.05). The number of cells on S3 surfaces was the same (P > 0.05) as TPS surfaces and higher than other groups (P < 0.05) after 12 and 24 h. The number of cells of all experimental groups were higher than S0 surfaces after 4, 12 and 24 h (P < 0.05). CONCLUSION: It was concluded that the coarse TiO2 particles blasted surface would optimize initial osteoblast responses.

[Clinical study of complete dentures supported by two endosteal magnetic-attachment implants].

OBJECTIVE: To evaluate treatment outcomes of mandibular complete denture supported by two endosteal magnetic-attachment implants in edentulous patients with severe mandibular alveolar ridge absorption. METHODS: Eight edentulous patients with severe mandibular alveolar ridge absorption were chosen. Each of them was treated with a complete denture supported by two CDIC implants. The implants were inserted at the areas of two the first premolars respectively. After five months, two magnets were adhered to the inside of the complete dentures. Retention, masticatory efficiency and maximal masticatory force were measured before and after the magnets were adhered and six months later. RESULTS: Statistical analysis revealed that retention, masticatory efficiency and maximal masticatory force were all increased after the magnets were adhered (P < 0.01) and six months later (P < 0.01). CONCLUSION: Retention, maximal masticatory force and masticatory efficiency were significantly increased after the endosteal magnetic attachment implants were applied. It is concluded that mandibular complete denture supported by two endosteal magnetic attachment implants is an effective method for severe alveolar ridge absorption cases.

Poly[[mu2-aqua-bis[(1,10-phenanthroline)nickel(II)]]-di-mu2,mu4-5-nitro-1,3-benzenedicarboxylato].

The reaction of Ni(CH(3)COO)(2).4H(2)O, 5-nitro-1,3-benzenedicarboxylic acid (H(2)nmbdc), 1,10-phenanthroline and water under hydrothermal conditions yields the first reported two-dimensional nickel coordination polymer with water- and carboxylate-bridged dimeric units, viz. [Ni(2)(C(8)H(3)NO(6))(2)(C(12)H(8)N(2))(2)(H(2)O)](n). The coordination polyhedron of the Ni(II) ion in the title structure is an octahedron defined by an N(2)O(4) donor set. The water molecule is positioned on a mirror plane and the 5-nitro-1,3-benzenedicarboxylate group is located on a twofold axis. Two types of nmbdc(2-) coordination mode are observed: one is a bis-monodentate mode, mu(2)-nmbdc(2-), and the other is a bis-bridging mode, mu(4)-nmbdc(2-). The dimeric unit in the title compound is similar to the structural moiety in urease. In the two-dimensional framework in the title compound, strong stacking interactions between benzene rings (mu(2)-nmbdc(2-) and mu(4)-nmbdc(2-)) and 1,10-phenanthroline ligands are observed.