The Predictive Factors of Combined Implant Application for Breast Cancer Patients Receiving Immediate Breast Reconstruction with a Pedicled Omental Flap.

BACKGROUND: Whether a laparoscopically harvested omental flap is adequate for total breast reconstruction could not be determined preoperativaly due to lack of reliable assessment methods. This study aimed to establish a statistical model to predict the probability of omental flap insufficiency. METHODS: In this study, 200 female patients with breast cancer receiving immediate breast reconstruction with pure pedicled omental flaps or pedicled omental flaps combined with implants after nipple-areolar complex-sparing mastectomy were divided into two groups depending on whether implants were needed or not. The clinical characteristics of these two groups were compared. Correlation of body mass index (BMI) and omental volume was analyzed. Binary logistic regression was performed to predict the probability of implant requirement based on clinical parameters, showing significant differences between the two groups. RESULTS: The patients who needed implants in adjunct treatment were younger. In addition, they had larger breast specimens and smaller omental volumes than the others whose omental flaps were sufficient for total breast reconstruction. Body mass index and omental volume showed a moderately positive correlation. Age, specimen volume, and BMI all were entered into the logistic regression equation. For the patients with a BMI lower than 24.0 kg/m2, the probability of requiring implants was 5.467 times that of comparable patients with a BMI of 24.0 kg/m2 or higher. At the cutoff of 0.61, the regression equation yielded a sensitivity of 84.2% and a specificity of 72.1% in recognizing subjects with the necessity of implant application. CONCLUSION: The combination of BMI, age, and volume of breast specimen could predict with high accuracy whether implants are required for breast cancer patients receiving pedicled omental flap-based breast reconstruction.

Improved survival after primary tumor resection in distant metastasis medullary thyroid carcinoma: a population-based cohort study with propensity score matching.

Few studies have investigated the impact of primary tumor resection (PTR) on patients with distant metastasis medullary thyroid carcinoma (DMMTC). This population-based study aims to assess the application of PTR in DMMTC patients, ascertain its benefits, and identify optimal surgical indications. DMMTC Patients diagnosed between 2010 and 2020 were included through the Surveillance, Epidemiology, and End Results (SEER) program. Logistic regression analysis identified driving factors of surgical decision-making. Propensity score matching (PSM), Kaplan-Meier method, and Cox regression were utilized to compare overall survival (OS) and disease-specific survival (DSS) between surgical and non-surgical groups. Subgroup analyses were performed to determine optimal surgical indications. Of 238 DMMTC patients included, 122 (51.3%) patients underwent PTR. Extrathyroidal extension and N1 stage emerged as independent factors promoting the surgical decision. PSM-adjusted survival analyses revealed significant advantages in both OS and DSS for the surgical group. Moreover, subgroup analyses indicated that except for patients aged ≥ 65 years, tumors ≤ 20 mm, or with multiple metastasized sites (> 1), the others significantly benefit from PTR. PTR significantly improves prognosis in selected DMMTC patients. The decision to undergo PTR in other patients should be based on a comprehensive assessment of the disease, surgeon's experience, and family discussions for potential survival benefits.

An automatic parathyroid recognition and segmentation model based on deep learning of near-infrared autofluorescence imaging.

INTRODUCTION: Near-infrared autofluorescence imaging (NIFI) can be used to identify parathyroid gland (PG) during surgery. The purpose of the study is to establish a new model, help surgeons better identify, and protect PGs. METHODS: Five hundred and twenty three NIFI images were selected. The PGs were recorded by NIFI and marked with artificial intelligence (AI) model. The recognition rate for PGs was calculated. Analyze the differences between surgeons of different years of experience and AI recognition, and evaluate the diagnostic and therapeutic efficacy of AI model. RESULTS: Our model achieved 83.5% precision and 57.8% recall in the internal validation set. The visual recognition rate of AI model was 85.2% and 82.4% on internal and external sets. The PG recognition rate of AI model is higher than that of junior surgeons (p < 0.05). CONCLUSIONS: This AI model will help surgeons identify PGs, and develop their learning ability and self-confidence.

Subgroup analysis of steadily increased trends in medullary thyroid carcinoma incidence and mortality in the USA, 2000-2020: a population-based retrospective cohort study.

The incidence rate of medullary thyroid carcinoma (MTC) continues to grow, along with its mortality rate in the USA. However, the subgroup trends in MTC have not yet been established. This population-based retrospective cohort study was based on the Surveillance, Epidemiology, and End Results (SEER) 17/12 registry database. Subgroup analysis was performed through clinicopathological and treatment-related characteristics. Annual average percentage change (AAPC) was calculated using joinpoint regression analysis. A total of 3833 MTC patients and 536 death cases were diagnosed in the SEER database. Between 2000 and 2019, the incidence (AAPC = 1.64) and mortality (AAPC = 3.46) rates of MTC continued to rise. Subgroup analysis showed the proportion of elderly patients (65-84 years) gradually increased in incidence between 2000 and 2020. Patients with early-stage tumors, such as tumors ≤20 mm, showed the same trends. Aspects of treatment, the implementation rate of total thyroidectomy (AAPC = 0.38) and lymph node dissection (AAPC = 1.06) also increased persistently in almost all of the age subgroups. The incidence and mortality of MTC consistently increased from 2000 to 2019. Subgroup analysis indicated a significant increase in elderly patients and early-stage patients, and more attention should be paid to the management of these increased subgroups.

Hypoxic papillary thyroid carcinoma cells-secreted exosomes deliver miR-221-3p to normoxic tumor cells to elicit a pro-tumoral effect by regulating the ZFAND5.

Papillary thyroid cancer (PTC) has seen a worldwide expansion in incidence in the past three decades. Tumor-derived exosomes have been associated with the metastasis of cancer cells and are present within the local hypoxic tumor microenvironment, where they mediate intercellular communication by transferring molecules including microRNAs (miRNAs) between cells. Although miRNAs have been shown to serve as non-invasive biomarkers for cancer diagnosis, the role of hypoxia-induced tumor-derived exosomes in PTC progression remains unclear. Herein, we investigated the differentially expressed miRNA expression profiles from GEO datasets (GSE191117 and GSE151180) by using the DESeq package in R and identified a novel role for miR-221-3p as an oncogene in PTC development. In vivo and in vitro loss and gain assays were used to clarify the mechanism of hypoxic PTC cells derived exosomal-miR-221-3p in PTC. miR-221-3p was upregulated in human PTC plasma exosomes, tissues and cell lines. We found that hypoxic PTC cells derived exosomal-miR-221-3p promoted normoxic PTC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, while inhibition of miR-221-3p limited PTC tumor growth in our PTC xenograft model in nude mice. We finally identified ZFAND5, to be a miR-221-3p target. Mechanistically, hypoxic PTC cell lines-derived exosomes carrying miR-221-3p promoted PTC tumorigenesis by regulating ZFAND5. Our findings further the understanding of the underlying mechanisms associated with PTC progression and identify exosomal-miR-221-3p as a potential biomarker for the diagnosis and prognosis of PTC patients. Our study also suggests that miR-221-3p inhibitors could be a potential treatment strategy for PTC.

Clinical efficacy and inflammatory reaction of submental endoscopic thyroidectomy versus conventional thyroidectomy: A prospective randomized study.

OBJECTIVES: This prospective study aimed to explore the clinical efficacy and inflammatory reaction of submental endoscopic thyroidectomy versus conventional thyroidectomy. METHODS: We prospectively recruited 45 patients (total 90 patients) who met the eligibility criteria to undergo conventional open thyroidectomy or submental endoscopic thyroidectomy from January 2021 to July 2022 in the Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. These patients were evaluated using the following indices: number of lymph nodes dissected, complications, pain severity, inflammatory indicators, cosmetic satisfaction, and economic cost. All data were analyzed by the t-test or chi-squared test. RESULTS: Ninety patients were enrolled. The two groups did not significantly differ regarding baseline characteristics. All patients who underwent thyroidectomy had a similar trauma index and increased level of inflammation. There were no significant differences between the open thyroidectomy and submental endoscopic thyroidectomy groups in the total number of lymph nodes dissected, number of positive lymph nodes, drainage volume, and complications. The Vancouver scar score and cosmetic satisfaction score were significantly better in the submental endoscopic thyroidectomy group than the open thyroidectomy group. The submental endoscopic thyroidectomy group had a significantly lower pain scores on postoperative days 1 and 2, less downtime, and cheaper medical and esthetic costs than the open thyroidectomy group. CONCLUSION: Compared with conventional open thyroidectomy, submental endoscopic thyroidectomy did not increase the degree of trauma, had superior clinical efficacy, caused less pain, required a shorter downtime, achieved a better cosmetic effect, and was associated with lower healthcare costs.

Single-Cell Transcriptomic Atlas of Parathyroid Adenoma and Parathyroid Carcinoma.

Primary hyperparathyroidism is typically characterized by monoclonal parathyroid tumors that secrete an excessive amount of parathyroid hormone (PTH). However, the underlying pathogenesis of tumorigenesis remains unclear. We performed single-cell transcriptomic analysis on five parathyroid adenoma (PA) and two parathyroid carcinoma (PC) samples. A total of 63,909 cells were divided into 11 different cell categories; endocrine cells accounted for the largest proportion of cells in both PA and PC, and patients with PC had larger populations of endocrine cells. Our results revealed significant heterogeneity in PA and PC. We identified cell cycle regulators that may play a critical role in the tumorigenesis of PC. Furthermore, we found that the tumor microenvironment in PC was immunosuppressive, and endothelial cells had the highest interactions with other cell types, such as fibroblast-musculature cells and endocrine cells. PC development may be stimulated by fibroblast-endothelial cell interactions. Our study clarifies the transcriptional signatures that underlie parathyroid tumors and offer a potential significant contribution in the study of pathogenesis of PC. © 2023 American Society for Bone and Mineral Research (ASBMR).

Clinical characteristics and long-term outcomes for parapharyngeal metastases of well-differentiated thyroid cancer during 131 I therapy and follow-up.

OBJECTIVE: Parapharyngeal metastases (PPM) are rarely observed in patients with well-differentiated thyroid cancer (WDTC). Radioiodine (131 I) therapy has been the main treatment for metastatic and recurrent DTC after thyroidectomy. This study was performed to evaluate the clinicopathological features and long-term outcomes associated with survival of patients with PPM at the end of follow-up. DESIGN: In total, 14,984 consecutive patients with DTC who underwent 131 I therapy after total or near-total thyroidectomy from 2004 to 2021 were retrospectively reviewed. Therapeutic efficacy was evaluated using the Response Evaluation Criteria in Solid Tumours v1.1 and logistic regression analysis. The disease status was determined using dynamic risk stratification. Disease-specific survival (DSS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. PATIENTS: Seventy-five patients with PPM from WDTC were enroled in this study. Their median age at the initial diagnosis of PPM was 40.2 ± 14.1 years, and the patients comprised 32 men and 43 women (male:female ratio, 1.00:1.34). Of the 75 patients, 43 (57.33%) presented with combined distant metastases. Fifty-seven (76.00%) patients had 131 I avidity and 18 had non-131 I avidity. At the end of follow-up, 22 (29.33%) patients showed progressive disease. Sixteen of the 75 patients died; of the remaining 59 patients, 6 (8.00%) had an excellent response, 6 (8.00%) had an indeterminate response, 10 (13.33%) had an biochemical incomplete response, and 37 (49.33%) had a structural incomplete response. Multivariate analysis confirmed that age at initial PPM diagnosis, the maximal size of PPM, and 131 I avidity had significant effects on progressive disease of PPM lesions (p = .03, p= .02, and p < .01, respectively). The 5- and 10-year DSS rates were 98.49% and 62.10%, respectively. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with a poor prognosis (p = .03 and p = .04, respectively). CONCLUSION: The therapeutic effect for PPM was closely associated with 131 I avidity, age at initial PPM diagnosis, and maximal size of PPM at the end of follow-up. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with poor survival.

Genetic analysis and clinicopathologic features of locally advanced papillary thyroid cancers: a prospective observational study.

PURPOSE: Locally advanced papillary thyroid cancer (LAPTC) has poor prognosis. Large-scale genomic testing has revealed multiple oncogenic drivers which may be essential for understanding tumor progression. However, the accurate identification of high recurrence risk and poor prognosis in thyroid carcinoma remains unclear. The objective of this study was to analyze genetic profile and clinicopathologic features of locally advanced papillary thyroid cancers. METHODS: An observational cohort study was performed to identify molecular characteristics of LAPTC and a prognosis comparison of LAPTC with different genetic mutations. ThyroSeq v2 next-generation sequencing (57-gene panel) was performed on fresh tumor tissue. Then, the clinicopathological features between tumors with different genetic mutations were compared. Additionally, correlations of tumor recurrence and disease free survival with different genetic alterations were analyzed. RESULTS: This study showed that the main mutation is common BRAFV600E (66.2%, 43/65) in LAPTC, followed by the TERT promoter mutations (38.5%, 25/65). Synergetic mutations of BRAFV600E and TERT promoters (B&T) were identified in 26.2% LAPTC (17/65), which is associated with tall-cell variant, extrathyroidal invasion and advanced tumor stage (III/IV). The synergetic mutations of B&T are also significantly associated with higher risk of recurrence (hazard ratio [HR], 6.0; 95% confidence interval, CI 1.26-28.55, P = 0.02) and mortality (17.6%, 3/17). CONCLUSIONS: Synergetic mutations of B&T are common in LAPTC, which is associated with the aggressive clinicopathologic features and an increased risk of recurrence and mortality. This finding may help to predict aggressive behavior of LAPTC and to assist in clinical decision-making.

Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population.

OBJECTIVE: To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. METHODS: Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed. RESULTS: Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch. CONCLUSION: Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.

Preoperative neoadjuvant targeted therapy with apatinib for inoperable differentiated thyroid cancer: A case report.

RATIONALE: Though the majority of differentiated thyroid cancer (DTC) patients have a good prognosis after careful and standardized therapy, approximately 13% to 15% of DTC cases show surprisingly aggressive behavior and invasion of the surrounding structures, and a few progress to unresectable diseases. In this study, we report a case of an inoperable locally advanced DTC patient who underwent a curative operation after treatment of preoperative monotherapy of apatinib in a short time. PATIENT CONCERNS: A 64-year-old woman complained of dysphagia due to large cervical mass, which severely invaded the left esophagus at the junction of the neck and thorax. DIAGNOSES: The female patient was diagnosed with locally advanced papillary thyroid cancer (PTC) by cytopathology and it was difficult to perform a safe and complete removal. INTERVENTIONS: Apatinib (500 mg orally once a day) was initially used to treat this patient as a neoadjuvant therapy. OUTCOMES: Six weeks later, the tumor dramatically shrunk from 56 × 37 mm to 29 × 26 mm with well-controlled mild hypertension. After a 10-day interval of apatinib withdrawal, complete tumor excision was accomplished through cervical incision without esophageal fistula. Postoperative thyroid stimulating hormone suppression and radioiodine 131I ablation therapy were performed. At the 1-year follow-up evaluation, no tumor recurrence or metastasis was observed. LESSONS: Preoperative short term targeted treatment with apatinib for locally advanced inoperable DTC may become a promising neoadjuvant therapy that, can reduce the tumor size and decrease stage, thus making the complete and safe removal of the lesion feasible.

MiR-153-3p Suppresses Cell Proliferation, Invasion and Glycolysis of Thyroid Cancer Through Inhibiting E3F3 Expression.

PURPOSE: The aim was to research the role of miR-153-3p and E2F3 in the development of thyroid tumors. METHODS: A total of 91 thyroid cancer patients were involved. The role of miR-153-3p in THCA cell lines and Nthy-ori3-1 cell line was researched. qPCR was used to detect miR-153-3p and E2F3 expression. MiR-153-3p mimic, inhibitor, siE2F3 or corresponding controls were transfected in cells. CCK8 was used to verify the proliferation. Cell cycle and apoptosis was detected by flow cytometry. Transwell assay was applied for migration and invasion, and glycolysis was monitored. The binding of miR-153-3p and E2F3 was predicted by targetscan database, and verified by luciferase reporter and RNA-pull down assay. Western blot was used to detect E2F3 expression. Rescue assay was undertaken to verify the effect of siE2F3 on miR-153-3p inhibitor. Moreover, the effect of miR-153-3p mimic on tumor volume and weight was measured. IHC assay was processed to E2F3 and Ki67 expression, and TUNEL assay was used for apoptosis. RESULTS: MiR-153-3p expressed lower in thyroid tumors and cells. The level of miR-153-3p was negatively related with TNM stage. MiR-153-3p inhibited cell proliferation, invasion migration, and induced cycle arrest and apoptosis. Moreover, it negatively regulated E2F3. siE2F3 rescued effects of miR-153-3p inhibitor in all above biological processes in thyroid cancer cells. MiR-153-3p inhibited tumor growth. Moreover, it inhibited E2F3 and Ki67 expression, and also increased apoptosis in vivo. CONCLUSION: MiR-153-3p suppresses cell proliferation, invasion and glycolysis of thyroid cancer through inhibiting E3F3 expression, which may be a biomarker for thyroid cancer diagnose.

A Novel Multimodal Therapy for Anaplastic Thyroid Carcinoma: 125 I Seed Implantation Plus Apatinib After Surgery.

Anaplastic thyroid cancer is known to be the most lethal malignancy among endocrine tumors for its extremely limited survival rate after diagnosis. As a result of this poor survival prognosis, multimodal therapy is currently under investigation to address this global concern. In this reported case, the 125I seed implantation and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor apatinib were co-applied to treat a 49-year-old woman with anaplastic thyroid cancer. After the patient began apatinib administration and underwent 125I seed implantation twice, the tumor size shrank successfully. After a follow-up of 13 months since the initial diagnosis of anaplastic thyroid cancer, the patient survived with a stable disease pathology. In conclusion, this study supports 125I seed implantation and apatinib as effective therapeutic alternatives for inoperable anaplastic thyroid cancer patients.

Network meta-analysis of surgical treatment for secondary hyperparathyroidism.

BACKGROUND: Main surgical treatments for secondary hyperparathyroidism (SHPT) include subtotal parathyroidectomy (sPTX), total parathyroidectomy with autotransplantation (tPTX+AT), and total parathyroidectomy (tPTX); however, determining the best treatment is debatable. We conducted a network meta-analysis (NMA) comparing three treatments in terms of postoperative hypocalcemia (or hypoparathyroidism), postoperative recurrence, and reoperation. METHODS: We searched PubMed, Medline, the Cochrane Library, and Embase for relevant research from inception to July 30, 2019. We performed our Bayesian NMA using R 3.51 software to assess odds ratios (OR) and 95% confidence intervals (CI). Network and forest plots displayed study outputs. Potential publication bias was assessed with funnel plots using software Stata/MP 13.0. RESULTS: Twenty-six articles comprising 5063 patients were included in our NMA, which showed that postoperative hypocalcemia (or hypoparathyroidism) occurred more frequently in tPTX than in sPTX (OR = 3.50, 95% CI 1.10-11.0) or tPTX+AT patients (OR = 1.80, 95% CI 0.66-5.20). Regarding postoperative hypocalcemia (or hypoparathyroidism), there was no significant difference between sPTX and tPTX+AT (OR = 0.53, 95% CI 0.24-1.10). As for recurrence rates, statistically significant differences were observed between sPTX and tPTX (OR = 25.0, 95% CI 5.1-260), tPTX+AT and tPTX (OR = 20.0, 95% CI 4.2-200), and sPTX and tPTX+AT (OR = 1.30, 95% CI 0.65-2.50). Regarding reoperation rates, sPTX experienced higher incidence compared with tPTX+AT (OR = 1.20, 95% CI 0.53-2.70) or tPTX patients (OR = 2.70, 95% CI 1.20-14.00). CONCLUSIONS: TPTX+AT is recommended as the most efficient and safe surgical SHPT treatment with minimal adverse effects. Large-scale randomized controlled trials are recommended to confirm the NMA results.

Transoral endoscopic selective lateral neck dissection for papillary thyroid carcinoma: a pilot study.

BACKGROUND: Transoral endoscopic thyroid surgery via the vestibular approach (TOETVA) has been gradually accepted worldwide due to its scar-free effect on the neck. Even central cervical lymphadenectomy has been performed in some cases of papillary thyroid carcinoma (PTC). However, there are few reports involving lateral neck dissection with TOETVA. In this study, we attempted to perform selective lateral neck dissection (SLND) for PTC via a transoral vestibular approach. METHODS: This prospective study was conducted from January 2016 to December 2018 in twenty PTC patients with unilateral T1 tumors without capsular invasion and patients with abnormal level III and IV lymph nodes who underwent SLND via a transoral vestibular approach. RESULTS: Endoscopic surgery was successfully accomplished in all 20 PTC patients. The mean age was 29.2 ± 5.5 (20-41) years. The mean operation time was 146.0 ± 18.7 (114-193) min. The average postoperative hospital stay was 6.8 ± 1.3 (5-10) days. The mean number of removed nodes was 7.4 ± 2.5 (4-12) in the central neck and 10.9 ± 2.8 (6-16) in the lateral neck, and the positive yield amounts were 2.0 ± 1.2 (0-4) and 2.7 ± 1.9 (0-6), respectively. No major complications occurred except for 1 case of transient unilateral recurrent laryngeal nerve palsy and two cases of effusion in the operative area. No evidence of persistent or recurrent disease was observed in these patients during a mean follow-up of 24.3 ± 9.1 (6-36) months. The cosmetic results and protection of personal privacy of this procedure were excellent. CONCLUSION: Endoscopic SLND via the transoral vestibular approach is feasible, safe, and effective for selected PTCs. A multicenter large comparative study is necessary.

MicroRNA 483-3p targets Pard3 to potentiate TGF-ß1-induced cell migration, invasion, and epithelial-mesenchymal transition in anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is associated with poor prognosis and is often untreatable. MicroRNA 483-3p (miR-483) and partitioning-defective 3 (Pard3), a member of the Pard family, have functions and regulatory mechanisms in ATC. The abnormal regulation of miR-483 may play an important role in tumorigenesis, and Par3 is known to regulate cell polarity, cell migration, and cell division. Tumor proliferation promoted by the regulation of miRNA expression can be regulated in thyroid cancer by upregulating transforming growth factor-ß1 (TGF-ß1), which is thought to interact with Pard3. When compared with adjacent non-tumor tissues, we found that miR-483 was upregulated and Pard3 was downregulated in 80 thyroid tumor samples. Disease-free survival was decreased when expression of miR-483 was upregulated and Pard3 expression was downregulated. Cell growth, migration, and invasion were induced by overexpression of miR-483. However, knockdown of miR-483 resulted in a loss of cell invasion and viability, both in vitro and in vivo. The expression of Pard3 was increased by the inhibition of miR-483, but TGF-ß1-induced cell migration and invasion were decreased by miR-483 inhibition. A dual-luciferase reporter assay determined that Pard3 expression was downregulated when targeted with miR-483. The epithelial-mesenchymal transition (EMT), as well as Tiam1-Rac signaling, was induced by TGF-ß1, which was decreased by the overexpression of Pard3. Pard3 decreased the inhibition of EMT and Tiam-Rac1 signaling, which resulted from transfection of ATC cells with miR-483. Overall, the results showed that downregulation of Pard3 resulted in increased cell invasion and EMT in ATC, which was promoted by treatment with miR-483. These findings suggest novel therapeutic targets and treatment strategies for this disease.

A somatic mutation of RasGRP3 decreases Na+/I- symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway.

Mutation profiles of advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer have revealed the pathogenic roles of the established oncogenic mutations of BRAF and PI3KCA, but the involvement of other genes is presently unknown. In the present study, we performed whole-exome sequencing on 10 tissue samples of metastases of RAI-refractory differentiated thyroid cancers and identified a recurrent hot-spot mutation (c.1924G>T) in the RasGRP3 gene, which codes for Ras guanine nucleotide-releasing protein 3. This mutation was found to occur at a high frequency (20%) in samples of metastases of RAI-refractory differentiated thyroid cancers compared with other types of thyroid cancer. Overexpression of mutant RasGRP3 significantly promoted cell proliferation, migration, and invasiveness of 8505C and BHT101 cells compared with cells transfected with wild-type RasGRP3 or an empty vector. In addition, mutant RasGRP3 decreased the expression of sodium iodide symporter (NIS) and thyroid-stimulating hormone receptor (TSHR), reduced the iodine uptake ability, and increased Akt phosphorylation in thyroid cancer cells. Finally, we showed that LY294002, an inhibitor of PI3K/Akt signaling, attenuated the effects of mutant RasGRP3 on thyroid cancer cells. Thus, our study revealed that the c.1924G>T hot-spot mutation in RasGRP3 is a more frequent genetic alteration in metastases of RAI-refractory differentiated thyroid cancer. This mutant RasGRP3 activated the Akt pathway, promoted thyroid cancer cell proliferation and invasion, and reduced NIS expression and the iodine uptake ability.

Case report: incidental parathyroid adenoma in a Chinese diabetic patient with hypercalcemia and normal parathyroid hormone levels.

RATIONALE: Parathyroid hormone PTH) levels are the main parameters to differentiate primary hyperparathyroidism (PHPT) from non-PTH-dependent hypercalcemia. We report a case of hypercalcemia with normal PTH levels due to a parathyroid adenoma. PATIENT CONCERNS: A 52-year-old female patient presented with 2-year history of documented sustained high-normal serum calcium and hypercalcemia (2.51-3.03 mmol/L) with normal serum intact PTH levels (21.95-40.15 pg/ mL). DIAGNOSES: A parathyroid tumor was localized by ultrasonography and 99mTc-sestamibi dual-phase fusion imaging with single-photon emission computed tomography/computed tomography. INTERVENTIONS: Parathyroidectomy was performed to excise the tumor completely. OUTCOMES: A 1.2-cm-sized parathyroid adenoma was removed surgically. The serum calcium was declined to normal level immediately after resection, as well as in 4- month follow-ups. The immunohistological diagnosis proved to be a PTH positive parathyroid adenoma. LESSONS: In case of hypercalcemia, serum intact PTH and parathyroid imaging should be monitored to evaluate the presence of parathyroid adenoma with care because PHPT could present with inappropriate normal PTH.

Knockdown of GATAD2A suppresses cell proliferation in thyroid cancer in vitro.

GATAD2A (GATA zinc finger domain containing 2A), is a subunit of NuRP (nucleosome remodeling and histone deacetylation) which plays key roles in tumor growth inhibition and embryonic development. However, its role in thyroid cancer remains unclear. In our study, we established two thyroid cancer cell lines by lentivirus-delivered short hairpin (shRNA) to knockdown the expression of GATAD2A. Then loss-of-function assays indicated that knockdown of GATAD2A decreased the ability of cell proliferation and colony formation in thyroid cancer cells by MTT and colony formation assay, respectively. Moreover, cell cycle assay by flow cytometry revealed that the percentage of cells in G0/G1 phase was significantly decreased in GATAD2A knockdown cells accompanied by increase of cells in G2/M phase. Furthermore, inhibition of GATAD2A promoted cell apoptosis via elevating the expression of caspase-3 and PARP cleavage using Annexin V/7-AAD double staining and western blotting. In conclusion, GATAD2A is an essential factor in thyroid cancer cell growth and apoptosis, and may be a potential therapeutic biomarker in thyroid cancer.

Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-ß-induced tumor formation.

Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor ß (TGF-ß)/Smad signaling and is implicated in a wide range of cellular responses. However, the exact mechanism whereby Smurf2 controls TGF-ß-induced signaling pathways remains unknown. Here, we identified the relationship between the alternate TGF-ß signaling pathways: TGF-ß/PI3K/Akt/ß-catenin and TGF-ß/Smad2/3/FoxO1/PUMA and Smurf2. The results showed that TGF-ß promoted proliferation, invasion, and migration of human pancreatic carcinoma (PANC-1) cells through the PI3K/Akt/ß-catenin pathway. Inhibiting the PI3K/Akt signal transformed the TGF-ß-induced cell response from promoting proliferation to Smad2/3/FoxO1/PUMA-mediated apoptosis. The activation of Akt inhibited the phosphorylation/activation of Smad3 and promoted the phosphorylation/inactivation of FoxO1, inhibiting the nuclear translocation of both Smad3 and FoxO1 and inhibiting the expression of PUMA, a key apoptotic mediator. However, downregulation of Smurf2 in PANC-1 cells removed Akt-mediated suppression of Smad3 and FoxO1, allowing TGF-ß-induced phosphorylation/activation of Smad2/3, dephosphorylation/activation of FoxO1, nuclear translocation of both factors, and activation of PUMA-mediated apoptosis. Downregulation of Smurf2 also decreased invasion and migration in TGF-ß-induced PANC-1 cells. The in vivo experiments also revealed that downregulation of Smurf2 delayed the growth of xenograft tumors originating from PANC-1 cells especially when treated with TGF-ß. Taken together, these results indicate that expression of Smurf2 plays a central role in the determination and activation/inhibition of particular cellular pathways and the ultimate fate of cells induced by TGF-ß. An increased understanding of the intricacies of the TGF-ß signaling pathway may provide a new anti-cancer therapeutic target.