Gestational cholestasis induced intrauterine growth restriction through triggering IRE1α-mediated apoptosis of placental trophoblast cells.

Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17α-Ethynylestradiol (E2) on gestational day 13 (GD13)-GD17. Some pregnant mice were intraperitoneally injected with 4µ8C on GD13-GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)-treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase-3 and Bax were increased, while placental Bcl2 level was decreased in mice with gestational cholestasis and in DCA-treated trophoblast cells. Further analysis found that placental IRE1α pathway was activated in mice with gestational cholestasis and in DCA-treated trophoblast cells. Interestingly, 4µ8C, an IRE1α RNase inhibitor, significantly inhibited caspase-3 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4µ8C rescued gestational cholestasis-induced placental insufficiency and IUGR. Furthermore, a case-control study demonstrated that placental IRE1α and caspase-3 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1α-mediated apoptosis of placental trophoblast cells.

Identification of calcium metabolism related score associated with the poor outcome in papillary thyroid carcinoma.

Introduction: Papillary thyroid carcinoma is a type of thyroid cancer that exhibits significant variability in prognosis. Extensive research indicates that the impaired signaling of 1,25(OH)2D3-VDR may be a crucial factor in the development and progression of PTC. Methods: To investigate this further, Integrated analysis mRNA expression information from The Cancer Genome Atlas and GEO, we compared gene expression in cancer and normal tissues and identified differentially expressed genes (DEGs). Through this analysis, we identified DEGs and calculated risk estimates for seven genetic markers. Results: Subsequently, we constructed predictive models using LASSO-Cox regression to test the predictive value of these markers. Our results revealed that 64 calcium metabolism-related genes showed significant differences between tumor and normal tissues. Ten of the identified DEGs were significantly associated with overall survival, indicating their potential role in disease progression. Using the average risk score for the seven genetic markers, we divided patients into high- and low-risk groups. We found that patients in the low-risk group had significantly better overall survival than those in the high-risk group, highlighting the importance of these genetic markers in predicting prognosis. Further analysis using Cox regression demonstrated that the risk levels had independent predictive power. Additionally, we conducted functional analysis of the identified genetic markers, which showed significant differences in immune status between the two patient groups. We also investigated the effect of these calcium metabolism-related genes on thyroid cancer biological functions, immune microenvironment, and drug resistance. Discussion: Our findings provide evidence of a novel genetic signature associated with calcium metabolism, which can predict prognosis in patients with PTC. These results may have significant implications for the development of new diagnostic and therapeutic approaches to improve outcomes for PTC patients.

PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause.

Thyroid cancer has become the most frequent endocrine-related malignancy. Currently, a mounting body of evidences support the clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers. However, the functions and molecular mechanisms of PARP inhibitors in thyroid cancers (TCs) are not fully understood. Here, on the one hand, we revealed that niraparib promotes the accumulation of DNA damage in TCs. On the other hand, we indicated that niraparib inhibits the transcription of DIMT1 through promoting Pol II pausing in a PAR-dependent manner, subsequently leading to a global translation inhibition in TCs. Meanwhile, we found that niraparib activates the NF-κB signaling pathway by inhibiting the PARylation of p65, which decreases its ubiquitination and degradation level through E3 ubiquitin ligase RNF146. Moreover, bortezomib (a small molecule inhibitor of the NF-κB signaling pathway) could significantly enhance the anti-tumor effect of niraparib on TCs in vitro and in vivo. Our findings provide mechanistic supports for the efficacy of PARP inhibitors in cancer cells lacking BRCA-mutant.

Anlotinib in patients with medullary thyroid carcinoma with negative prognostic factors: A sub-analysis based on the ALTER01031 study.

Background: Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer; however, it accounted for 13.4% of the disease-specific mortalities. ALTER01031 (NCT02586350) was a randomised, placebo-controlled phase 2b trial that evaluated the efficacy and safety of anlotinib in locally advanced or metastatic MTC. This post hoc analysis aimed to evaluate the efficacy and safety of anlotinib in older patients and those with bone metastases using ALTER01031. Methods: In ALTER01031, anlotinib significantly prolonged the median progression-free survival (PFS) from 11.1 months to 20.7 months compared with placebo in the whole population. Patients who were older (≥ 50 years) or had bone metastases were selected. PFS and overall survival (OS) were estimated and compared between patients receiving anlotinib or placebo in each subgroup. A sub-analysis of tumour response and safety was also performed. Results: Patients with older age or bone metastases experienced rapid disease progression as the median PFS was 6.8 months and 7.0 months respectively in the placebo group. Anlotinib significantly improved the median PFS to 17.5 months (P = 0.002) and 20.7 months (P = 0.029) with hazard ratio (HR) of 0.31 (95% CI, 0.15-0.68) and 0.44 (95% CI, 0.20-0.94) compared with placebo. Significant benefit in OS was observed in patients with older age after a longer follow-up (HR = 0.47 [95% CI, 0.22-0.99], P = 0.041). The safety profile of these subgroups was similar to that of the entire population. Conclusion: This sub-analysis demonstrated significant survival benefits and favourable safety of anlotinib in patients with MTC who had old age or bone metastases, supporting the feasibility of anlotinib in these patients.

EGFR inhibition enhances the antitumor efficacy of a selective BRAF V600E inhibitor in thyroid cancer cell lines.

BRAF V600E is the most common genetic alteration in thyroid cancer and is indicative of a relatively poor prognosis. A selective inhibitor of BRAF V600E has been proposed as a novel treatment for patients with thyroid cancer exhibiting BRAF V600E mutations. However, this inhibitor has demonstrated a limited therapeutic effect. In the present study, possible adaptive mechanisms of resistance of thyroid cancer cells to the specific BRAF V600E inhibitor, PLX4032, were investigated. MTT assays were performed to determine the anti-proliferative efficiencies and half maximal inhibitory concentration (IC50) of inhibitory treatments. The level of phosphorylated ERK was used to evaluate the activity of the mitogen assisted protein kinase (MAPK) pathway. Flow cytometry was performed to evaluate the rate of apoptosis. The IC50 measurements of PLX4032 in K1 and BCPAP cells were 0.550 and 1.772 µM, respectively. Co-treatment with an endothelial growth factor receptor (EGFR) inhibitor decreased the IC50 of PLX4032 to 0.206 µM, and prolonged the inhibitory effect of PLX4032 in K1 cells. In cells treated with PLX4032 alone, the MAPK pathway was reactivated after 24 h. However, the addition of an EGFR inhibitor suppressed this reactivation and increased the rate of apoptosis. In summary, the present study demonstrated that thyroid cancer harboring the BRAF V600E mutation was resistant to a selective BRAF inhibitor due to reactivation of the MAPK pathway. Co-treatment with an EGFR inhibitor increased antitumor efficacy and suppressed resistance to the BRAF V600E inhibitor.

miR-24 promotes the proliferation, migration and invasion in human tongue squamous cell carcinoma by targeting FBXW7.

Recent studies suggest that aberrant expression of miR-24 is linked to various human cancers, including tongue squamous cell carcinoma (TSCC). F-box and WD-40 domain protein 7 (FBXW7), a tumor-suppressor gene, is responsible for the degradation of several proto-oncogenes. However, the function and mechanism of miR-24 and FBXW7 in TSCC remains unclear. In the present study, we found that miR-24 was increased in TSCC tissues and cell lines, and that upregulation of miR-24 was associated with advanced clinical stage and a shorter overall survival of TSCC patients. Inhibition of miR-24 significantly suppressed the proliferation, migration and invasion of TSCC cells in vitro. Furthermore, miR-24 repressed FBXW7 expression by directly binding to the 3-untranslated region of FBXW7. Moreover, the suppression of FBXW7 increased the proliferation, migration and invasion of TSCC cells, and the restoration of FBXW7 substantially attenuated the oncogenic effects of miR-24. In conclusion, our results demonstrated that upregulation of miR-24 was associated with tumor progression and poor prognosis in TSCC patients, and that overexpression of miR-24 was correlated with the proliferation, migration and invasion of TSCC cells in vitro, at least partially through regulation of its functional target FBXW7. Thus, miR-24 may serve as a novel potential biomarker for the prognosis of TSCC patients.

TLR3 correlated with cervical lymph node metastasis in patients with papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the most rapidly increasing endocrine malignancy worldwide. Although less aggressive than the majority malignancies, PTC exhibits extensive cervical lymph node metastasis in early stage of PTC. However, the underlying molecular mechanism of this early-metastasis remains unknown. Toll like receptors (TLRs) constitute a crucial component of the innate immune response to bacterial and viral pathogens. Emerging evidence suggests that TLRs play important roles in cancer progression, invasion and immune evasion, whereas whether TLRs have any role in PTC remains to be clarified. In this study, we found that TLR3 was present in both PTC specimen and various thyroid cancer cell lines. Further IHC analysis of 63 PTC patients revealed that TLR3 expression was associated with cervical metastasis, but not correlated with patients' TNM staging, extrathyroidal invasion. In addition, TLR3 promoted migration of K1 cells in vitro. Activation of TLR3 increased cancer stem cell marker and migration promoting CD44 expression in vitro, indicating that TLR3 might promote metastasis of PTC via modulating CD44 expression. Taken together, our data revealed that TLR3 is correlated with cervical metastasis of PTC and might be an essential prognostic indicator and target for PTC metastasis.

[Hurthle cell thyroid tumor: an analysis of 28 cases].

OBJECTIVE: To explore the clinical features and the combined treatment modality of Hurthle cell thyroid tumor (HCT). METHODS: Twenty-eight cases of HCT treated between 2001 and 2009 were analyzed retrospectively. RESULTS: The age of the patients ranged from 18 to 72 years (with a median of 46.5 years); 22 females and 6 males. The main symptoms were thyroid solitary node or mass (22 cases) and multiple nodule (6 cases), 2 cases with cervical lymph node metastasis. All of the patients underwent surgery, 11 cases with thyroid lobectomy, 11 cases with thyroid lobectomy plus isthmusectomy, 4 cases with subtotal thyroidectomy, and 2 cases with thyroid lobectomy plus isthmusectomy and combined with modified radical cervical lymph node dissection. Postoperative pathological examination showed that 22 cases were Hurthle cell adenomas and 6 cases were Hurthle cell carcinomas, 1 of them with cervical lymph node metastasis. Twenty-one patients with Hurthle cell adenomas were followed up for 6 months to 7.5 years (with a median of 45 months) and 6 patients with Hurthle cell carcinomas for 3 to 8 years (with a median of 54 months), with no recurrence and death case. CONCLUSIONS: HCT is a potential malignant neoplasm. There are some difficulties in the diagnosis of HCT by frozen section. Surgery is an effective treatment for HCT. L-Thyroxine can be used to inhibit TSH excretion.