Homogentisic acid metabolism inhibits papillary thyroid carcinoma proliferation through ROS and p21-induced cell cycle arrest.

Thyroid cancer is one of the most common primary endocrine malignancies worldwide, and papillary thyroid carcinoma (PTC) is the predominant histological type observed therein. Although PTC has been studied extensively, our understanding of the altered metabolism and metabolic profile of PTC tumors is limited. We identified that the content of metabolite homogentisic acid (HGA) in PTC tissues was lower than that in adjacent non-cancerous tissues. We evaluated the potential of HGA as a novel molecular marker in the diagnosis of PTC tumors, as well as its ability to indicate the degree of malignancy. Studies have further shown that HGA contributes to reactive oxygen species (ROS) associated oxidative stress, leading to toxicity and inhibition of proliferation. In addition, HGA caused an increase in p21 expression levels in PTC cells and induced G1 arrest. Moreover, we found that the low HGA content in PTC tumors was due to the low expression levels of tyrosine aminotransferase (TAT) and p-hydroxyphenylpyruvate hydroxylase (HPD), which catalyze the conversion of tyrosine to HGA. The low expression levels of TAT and HPD are strongly associated with a higher probability of PTC tumor invasion and metastasis. Our study demonstrates that HGA could be used to diagnose PTC and provides mechanisms linking altered HGA levels to the biological behavior of PTC tumors.

FTO-mediated epigenetic upregulation of LINC01559 confers cell resistance to docetaxel in breast carcinoma by suppressing miR-1343-3p.

This study was to explore the regulatory effect of long non-coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO-mediated demethylation in an m6A-YTHDF2-dependent manner. Additionally, Dual-luciferase reporter assay confirmed the binding ability between LINC01559 and miR-1343-3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR-1343-3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO-mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR-1343-3p.

Histone deacetylase inhibitor panobinostat in combination with rapamycin confers enhanced efficacy against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for about 15% of diagnosed breast cancer patients, which has a poor survival outcome owing to a lack of effective therapies. This study aimed to explore the in vitro and in vivo efficiency of histone deacetylase (HDAC) inhibitor panobinostat (PANO) in combination with mTOR inhibitor rapamycin (RAPA) against TNBC. TNBC cells were treated with PANO, RAPA alone or the combination of drugs, then cell growth and apoptosis were evaluated by CCK-8, colony formation and flow cytometry. Cell migration and invasion were detected by wound healing assay and transwell assay, respectively. ROS production was detected by DCFH-DA staining. Western blotting was performed to detect protein levels. In vivo tumor growth was assessed in nude mice. The expression of cleaved caspase-3 and Ki-67 in tumor tissues was detected by immunofluorescence staining. H&E staining was conducted to observe the pathological changes in heart, liver, and kidney tissues. The combination of PANO and RAPA exerted a stronger role in repressing growth, migration, invasion, and inducing apoptosis of TNBC cells compared with monotherapy. Furthermore, this combination presented a more effective anti-cancer efficacy than a single treatment in the xenograft model without apparent toxic side effects. Importantly, mechanistic studies indicated that PANO and RAPA combination led to ROS overproduction, which subsequently activated endoplasmic reticulum stress. Conclusion: PANO in combination with RAPA exhibits enhanced efficacy against TNBC, which may be considered a promising therapeutic candidate.

Application of competing risk model in the prognostic prediction study of patients with follicular thyroid carcinoma.

BACKGROUND: Follicular thyroid carcinoma (FTC) is an indolent carcinoma. The cumulative incidence of death from patients with FTC and the nomogram built based on the competing risks model have not been described. METHODS: The data from patients diagnosed with primary FTC were identified and extracted from the surveillance, epidemiology, and end results (SEER) program (1988-2015). The cumulative incidence function was utilized to calculate the likelihood of death resulting from thyroid cancer and other causes, respectively. Gray's test was used to examine the difference in the cumulative incidence of death between the groups. A tenfold cross-validation was applied to assess the discrimination and calibration of the model. RESULTS: A total of 9210 patients diagnosed with primary FTC were included. The median follow-up time was 92 months (1-347 months). The 5-year, 10-year, and 20-year probabilities of death from FTC were 2.84%, 5.23%, and 8.61%, respectively. The age at diagnosis, sex, tumor size, pathological subtypes, tumor extension, lymph node involvement, as well as surgical and radiotherapy methods used, were related to the cumulative incidence of death. Multivariate analysis identified several risk factors for patient survival. The model behaved well in terms of performance. A nomogram based on the model allowed the prediction of the probability of death among patients with FTC. CONCLUSIONS: The prognosis of FTC is excellent. The likelihood of death caused by thyroid cancer increases with age. Male sex, tumors larger than 4 cm, invasion, extrathyroidal extension, lymph node involvement, and distant metastases increase the risk of dying of thyroid carcinoma. The nomogram constructed on the basis of the model is potentially useful for both clinicians and patients.

Repeat Breast-Conserving Surgery Versus Salvage Mastectomy for Ipsilateral Breast Tumour Recurrence After Breast-Conserving Surgery in Breast Cancer Patients: A Meta-Analysis.

BACKGROUND: Salvage mastectomy (SM) is the standard surgery for ipsilateral breast tumour recurrence (IBTR). However, whether repeat breast-conserving surgery (RBCS) is an alternative method remains unclear. We performed a meta-analysis to compare the effects of RBCS and SM after IBTR for breast-conserving surgery (BCS). METHODS: We searched PubMed, Cochrane, Wiley Online and Embase for controlled studies comparing RBCS and SM after IBTR for BCS (published between 1993 and 2019, published in English). Our main endpoints were the secondary local recurrence rate (SLRR), distant metastasis rate (DMR) and overall survival (OS). We used a random-effects model or fixed-effects model for data pooling. RESULTS: Fifteen of the 424 eligible studies were ultimately included, and all studies were retrospective cohort studies (n=2532 participants). 1) SLRR: The SLRR of RBCS was higher than SM (pooled relative rate (pRR) = 1.87, 95% CI 1.22 - 2.86, P=0.004). Stratified analysis was performed according to whether radiotherapy was performed after salvage surgery (radiotherapy group: 2ndRT, no radiotherapy group: no-2ndRT), and the following results were revealed: pRR=0.43 (95% CI 0.20-0.95, P=0.04) for group 2ndRT; and pRR=2.30 (95% CI 1.72-3.06, P<0.00001) for group no-2ndRT. These results showed that the main cause of heterogeneity was salvage radiotherapy. 2) DMR: No significant difference in the DMR was observed between RBCS and SM (pRR = 0.61, 95% CI 0.37 - 1.01, P=0.05). 3) OS: No significant difference in OS was observed between RBCS and SM (pRR=0.65, 95% CI 0.39 - 1.08, P=0.10). CONCLUSIONS: The SLRR of RBCS was higher than SM for ITBR after BCS, but survival was not affected. RBCS may be used as an alternative for IBTR patients after BCS with strict control for several indications, such as tumor size, recurrence interval and biological behavior, and attaching importance to subsequent salvage radiotherapy and systematic therapy.

Loss of ID3 drives papillary thyroid cancer metastasis by targeting E47-mediated epithelial to mesenchymal transition.

Papillary thyroid cancer (PTC) is the main histological type of thyroid cancer and accounts for almost all increased cases worldwide. Patients with PTC exhibit a favorable prognosis, but the fact that PTC is often accompanied by a high prevalence of lymph node metastasis (LNM) means that the overall recurrence-free survival rate in PTC patients is relatively low. Herein, we identified that ID3 expression is subdued in PTC tissues and closely associated with LNM and a poor disease-free survival outcome in PTC patients. The main contributor to this gene repression is the hypermethylation of the CpG island at the promoter of ID3. Besides, we uncovered that a loss of ID3 promotes invasion and migration of PTC cells, while an ectopic overexpression of ID3 inhibits invasion and migration. Mechanistically, ID3 exhibits tumor suppressor functions in PTC cells by interacting with E47 to form heterodimers that prevent E47 binding to CDH1 promoter and maintaining CDH1 transcription and epithelial phenotype in PTC cells. Taken together, our study demonstrates that ID3 plays a tumor suppressor role in PTC and impedes metastasis by inhibiting E47-mediated epithelial to mesenchymal transition.

Chemotherapy-induced changes of cerebral activity in resting-state functional magnetic resonance imaging and cerebral white matter in diffusion tensor imaging.

While chemotherapy related cognitive disorder has been described in many studies, but we still lack relatively reliable and objective diagnostic tools, and there are few similar studies in Asian patients. We recruited Asian breast cancer patients to perform a cohort study to uncover chemotherapy related cognitive disorder by using resting-state functioning magnetic resonance imaging (RS-fMRI) and magnetic resonance diffusion tensor imaging (DTI) combined with neuropsychologic assessments. This is the first prospective study which combines RS-fMRI and DTI to detect chemotherapy related cognitive disorder. The neuropsychologic tests and MRI were performed before and after the chemotherapy. The healthy controls were tested at matched times. The chemotherapy-treated group performed worse on memory and we found significant changes in the cerebellum, right orbitofrontal area, right middle and superior temporal gyrus, right subcentral area, left dorsolateral prefrontal cortex, and precentral gyrus in RS-fMRI after chemotherapy. We found changes in the fornix and superior fronto-occipital fasciculus with DTI. There was a correlation between some cognitive function and MRI measurements in the correlation analysis, but it was not significant after false discovery rate (FDR) multiple testing corrections. The results indicate that RS-fMRI and DTI may be a prospective application for assessing chemotherapy related cognitive disorder.