Differentiated thyroid cancer: effect on quality of life, depression, and anxiety.

CONTEXT: Thyroid cancer is the most common endocrine cancer, the lifelong risk for which is approximately 1%. Despite favorable prognosis and well-tolerated treatment modalities, numerous studies have shown that thyroid cancer survivors have impaired health-related quality of life (HRQoL). Patients are also more frequently affected by depression and anxiety. OBJECTIVE: We aimed to evaluate HRQoL, depression, and anxiety status in female patients with DTC. DESIGN, SUBJECTS, AND METHODS: We compared HRQoL, depression, and anxiety status in 114 female thyroid cancer survivors with 110 healthy subjects via a cross-sectional design. For this purpose, we utilized short-form 36 (SF-36), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: The majority of the patients (82%) were stage I. Fifty-seven patients (51%) received radioiodine treatment. Regarding HRQoL, depression, and anxiety between groups, thyroid cancer survivors did worse on every aspect of SF-36 than the control group (p < 0.05). Thyroid cancer survivors had higher BDI and BAI scores (p < 0.05). In those receiving RAI, the dose of RAI, lymph node dissection, and tumor stage did not affect SF-36, depression, and anxiety scores. Duration since diagnosis also did not affect results. CONCLUSION: Our study further confirms the observation that survivors of DTC have impaired HRQoL. Furthermore, they are more likely to suffer from anxiety and depression.

Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC. EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole-exome sequencing, single-cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms. RESULTS: Implantation of CDDP-resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance. CONCLUSIONS: CDDP resistance and development of DM are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP-resistant head and neck tumors.

Effect of thyroid nodule size on cytology reliability and incidence of malignancy: A large cohort of 1205 patients from a single center.

OBJECTIVE: There is controversy about whether the rates of malignancy and of false-negative malignancy are greater in large nodules. The aim of this study was to determine the reliability of cytology in ≥4cm nodules and to compare malignancy rates between ≥4cm and<4cm nodules. METHODS: The study included 1205 patients who underwent biopsy and subsequent thyroidectomy with the diagnosis of nodular thyroid disease between 2014 and 2019. The patients were separated into two groups, ≥4cm and<4cm, according to the size of the index nodule on ultrasonography. RESULTS: Two hundred and eleven index nodules (17.5%) were ≥4cm. Malignancy rate on definitive pathology was 51% in<4cm nodules and 30% in ≥4cm nodules. Malignancy risk was significantly lower in ≥4cm nodules than <4cm nodules (P<0.001). When<1cm nodules were excluded and 1-4cm and ≥4cm nodules were compared, malignancy risk was also significantly lower in ≥4cm nodules (P=0.001). On definitive pathology, there were 45 false-negative results among cytologically benign nodules. There was no difference in false-negative cytology rate between<4cm and ≥4cm nodules (P=0.209). CONCLUSION: The present study found no decrease in the reliability of cytology in ≥4cm nodules, and there may not be a linear relationship between nodule size and malignancy risk. Therefore, in asymptomatic cytologically benign ≥4cm nodules, surgery may not be recommended based on nodule size alone.

Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

OBJECTIVE: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described. DESIGN: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin. RESULTS: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFßi, mTORi and SRCi) for EpiC groups. CONCLUSION: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.

Machine Learning in Epigenomics: Insights into Cancer Biology and Medicine.

The recent deluge of genome-wide technologies for the mapping of the epigenome and resulting data in cancer samples has provided the opportunity for gaining insights into and understanding the roles of epigenetic processes in cancer. However, the complexity, high-dimensionality, sparsity, and noise associated with these data pose challenges for extensive integrative analyses. Machine Learning (ML) algorithms are particularly suited for epigenomic data analyses due to their flexibility and ability to learn underlying hidden structures. We will discuss four overlapping but distinct major categories under ML: dimensionality reduction, unsupervised methods, supervised methods, and deep learning (DL). We review the preferred use cases of these algorithms in analyses of cancer epigenomics data with the hope to provide an overview of how ML approaches can be used to explore fundamental questions on the roles of epigenome in cancer biology and medicine.

Identification of EMT signaling cross-talk and gene regulatory networks by single-cell RNA sequencing.

The epithelial-to-mesenchymal transition (EMT) plays a critical role during normal development and in cancer progression. EMT is induced by various signaling pathways, including TGF-ß, BMP, Wnt-ß-catenin, NOTCH, Shh, and receptor tyrosine kinases. In this study, we performed single-cell RNA sequencing on MCF10A cells undergoing EMT by TGF-ß1 stimulation. Our comprehensive analysis revealed that cells progress through EMT at different paces. Using pseudotime clustering reconstruction of gene-expression profiles during EMT, we found sequential and parallel activation of EMT signaling pathways. We also observed various transitional cellular states during EMT. We identified regulatory signaling nodes that drive EMT with the expression of important microRNAs and transcription factors. Using a random circuit perturbation methodology, we demonstrate that the NOTCH signaling pathway acts as a key driver of TGF-ß-induced EMT. Furthermore, we demonstrate that the gene signatures of pseudotime clusters corresponding to the intermediate hybrid EMT state are associated with poor patient outcome. Overall, this study provides insight into context-specific drivers of cancer progression and highlights the complexities of the EMT process.

The preventive effect of ellagic acid on brain damage in rats via regulating of Nrf-2, NF-kB and apoptotic pathway.

The aim of this study was to investigate the neuroprotective role of ellagic acid (EA) on CCl4 -induced brain injury in rats. In this study, the rats were divided into four groups. Groups: (1) Control group; (2) EA group; (3) CCl4 group; (4) EA + CCl4 group. In brain tissue, tumor necrosis factor-α (TNF-α), nuclear factor kappa b (NF-kB), cyclooxygenase-2 (COX-2), nuclear erythroid related factor 2 (Nrf-2), cysteine-aspartic acid protease (caspase-3), VEGF (vascular endothelial growth factor) and B-cell lymphoma-2 (bcl-2) protein expression levels were analyzed by western blotting. MDA (malondialdehyde), catalase enzyme activity (CAT) and glutathione (GSH) analysis were determined by spectrophotometer. In our findings, EA ameliorated Nrf-2 and caspase-3 protein expression levels, GSH and catalase activities, NF-kB, TNF-α, VEGF, Bcl-2, COX-2 protein expression levels and MDA levels in CCl4 intoxicated rats. These results suggest that EA demonstrated the neuroprotective effect on CCl4 -induced brain damage in rats. PRACTICAL APPLICATIONS: Ellagic acid has different biological activities, these are; antioxidant, anti-inflammatory, antidepressant, antifibrosis, anticancer, neuroprotective and hepatoprotective. For example it was reported that EA protects the cells against DNA injury induced by free radicals and it can prevent the traumatic brain injury. These results obtained from this study reveals that EA has a protective effect against rat brain damage and it may be used as an alternative drugs for the brain injury treatment in future.

Guided intraoperative scintigraphic tumor targeting of metastatic cervical lymph nodes in patients with differentiated thyroid cancer: a single-center report.

OBJECTIVE: Our aim was to present our experiences related to performing neck surgery using the guided intraoperative scintigraphic tumor targeting (GOSTT) procedure for patients who had locally recurrent or persistent differentiated thyroid cancer (DTC) and who had undergone previous thyroid surgery. SUBJECTS AND METHODS: We retrospectively evaluated 11 patients who had locally recurrent or persistent DTC, who had undergone previous surgery, and for whom reoperation was planned for metastatic cervical lymph nodes (LNs). We performed the neck surgery using the GOSTT procedure on all patients and at a single academic institution. RESULTS: The 11 patients had a total of 26 LNs, as marked with a radiotracer, and those LNs' mean size was 14.7 ± 8.2 mm (range: 5-34 mm). Histopathological examinations revealed DTC metastasis in all 26 of the preoperatively marked LNs. Of the 11 patients, only one needed a reoperation in the neck; she had another successful surgery (also using the GOSTT procedure). In the evaluation of the patients' final status, all were disease-free in their necks. There also were no GOSTT-associated postoperative complications. CONCLUSION: The GOSTT procedure is a useful, successful, inexpensive, and comfortable procedure for marking and mapping metastatic LNs, especially in DTC patients who have undergone previous surgery.

Guided intraoperative scintigraphic tumor targeting of metastatic cervical lymph nodes in patients with differentiated thyroid cancer: a single-center report

ABSTRACT Objective: Our aim was to present our experiences related to performing neck surgery using the guided intraoperative scintigraphic tumor targeting (GOSTT) procedure for patients who had locally recurrent or persistent differentiated thyroid cancer (DTC) and who had undergone previous thyroid surgery. Subjects and methods: We retrospectively evaluated 11 patients who had locally recurrent or persistent DTC, who had undergone previous surgery, and for whom reoperation was planned for metastatic cervical lymph nodes (LNs). We performed the neck surgery using the GOSTT procedure on all patients and at a single academic institution. Results: The 11 patients had a total of 26 LNs, as marked with a radiotracer, and those LNs' mean size was 14.7 ± 8.2 mm (range: 5-34 mm). Histopathological examinations revealed DTC metastasis in all 26 of the preoperatively marked LNs. Of the 11 patients, only one needed a reoperation in the neck; she had another successful surgery (also using the GOSTT procedure). In the evaluation of the patients' final status, all were disease-free in their necks. There also were no GOSTT-associated postoperative complications. Conclusion: The GOSTT procedure is a useful, successful, inexpensive, and comfortable procedure for marking and mapping metastatic LNs, especially in DTC patients who have undergone previous surgery.

GDF-15 and Hepcidin Levels in Nonanemic Patients with Impaired Glucose Tolerance.

Aims. Growth Differentiation Factor-15 (GDF-15) has been suggested as one of the regulators of hepcidin, an important regulatory peptide for iron deposition. Current data is conflicting about the relationship between hepcidin and disorders of glucose metabolism. We aimed to investigate serum hepcidin and GDF-15 concentrations and their associations with each other, in nonanemic subjects with impaired glucose tolerance (IGT) in comparison with the nonanemic subjects with normal glucose tolerance (NGT). Methods. Thirty-seven subjects with IGT and 32 control subjects with NGT, who were age-, gender-, and body mass index- (BMI-) matched, were included in the study. Results. Serum GDF-15 levels were significantly higher in IGT compared to NGT. There were no differences in hepcidin, interleukin-6, and high sensitive C-reactive protein levels between the groups. We found a positive correlation between GDF-15 and hepcidin levels. There were also positive correlations between GDF-15 and age, uric acid, creatinine, and area under the curve for glucose (AUC-G). Hepcidin was correlated positively with ferritin levels. In the multiple regression analysis, GDF-15 concentrations were independently associated with age, uric acid, and AUC-G. Conclusions. Impaired glucose tolerance is associated with increased GDF-15 levels even in the absence of anemia, but the levels of hepcidin are not significantly altered in prediabetic state.