PurposeThe novel coronavirus COVID-19, has caused a worldwide pandemic, impairing several human organs and systems. Whether COVID-19 affects human thyroid function remains unknown.MethodsEighty-four hospitalized COVID-19 patients in the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) were retrospectively enrolled in this study, among which 22 cases had complete records of thyroid hormones. In addition, 91 other patients with pneumonia and 807 healthy subjects were included as controls.ResultsWe found that levels of total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were lower in COVID-19 patients than healthy group (p < 0.001). Besides, TSH level in COVID-19 patients was obviously lower than non-COVID-19 patients (p < 0.001). Within the group of COVID-19, 61.9% (52/84) patients presented with thyroid function abnormalities and the proportion of thyroid dysfunction was higher in severe cases than mild/moderate cases (74.6 vs. 23.8%, p < 0.001). Patients with thyroid dysfunction tended to have longer viral nucleic acid cleaning time (14.1 ± 9.4 vs. 10.6 ± 8.3 days, p = 0.088). To note, thyroid dysfunction was also associated with decreased lymphocytes (p < 0.001) and increased CRP (p = 0.002). The correlation between TT3 and TSH level seemed to be positive rather than negative in the early stage, and gradually turned to be negatively related over time.ConclusionThyroid function abnormalities are common in COVID-19 patients, especially in severe cases. This might be partially explained by nonthyroidal illness syndrome.

BACKGROUND Bilaterality is common in papillary thyroid cancer (PTC), but its clinical and prognostic implications are still controversial, and it remains unclear whether its behavior is more aggressive than multifocality. METHODS The clinicopathologic features of 2211 consecutive patients with PTC who underwent surgical treatment at the authors’ institute between 1997 and 2011 were reviewed. Among these surgical patients, 425 (19.2%) had bilateral PTCs, and 1786 had unilateral PTCs. The patients who had unilateral PTCs were subdivided into a group with unilateral‐multifocal PTCs (210 patients) and a group with solitary PTCs (1576 patients). The 10‐year disease‐free survival (DFS) rates were calculated to compare the prognosis between groups. B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) mutation status was examined by direct DNA sequencing. RESULTS Patients who had bilateral PTCs were likely to have larger tumors, higher rates of extrathyroid extension and lymph node metastasis, and more advanced tumor stage than those who had unilateral‐multifocal PTCs. Multivariate analysis identified only lymph node metastasis as an independent risk factor for PTC recurrence (P < .001). The 10‐year DFS rate for patients with bilateral PTCs was much lower than that for those with unilateral‐multifocal and solitary PTCs (78.8% vs 85.7% and 89.3%, respectively; P = .005). It is noteworthy that patients who had bilateral PTCs with lymph node metastasis had the worst prognosis in terms of DFS. Incidence of the BRAF V600E mutation (valine to glutamic acid mutation at position 600) was higher in the bilateral PTC group than that in the unilateral and unilateral‐multifocal PTC groups. CONCLUSIONS The current results provide initial evidence that bilateral PTCs are more aggressive than unilateral‐multifocal PTCs, and patients who have bilateral disease have more advanced stage and shorter DFS. The poorer outcome of patients with bilateral PTCs may be caused in part by their high incidence of lymph node metastasis. Cancer 2016;122:198–206. © 2015 American Cancer Society.

Background: The novel coronavirus COVID-19, has caused a worldwide pandemic, impairing several human organs and systems. Whether COVID-19 affects human thyroid function remains unknown. Methods: 84 hospitalized COVID-19 patients in the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) were respectively enrolled in this study. In addition, 91 other patients with pneumonia and 807 healthy subjects were included as controls. Findings: We found that the levels of TT3 and TSH were lower in COVID-19 patients than control groups (p<0.001). Within the group of COVID-19 patients, 61.9% patients (52/84) presented with thyroid function abnormalities. We found a larger proportion of patients in severe condition exhibited thyroid dysfunction than mild/moderate cases (74.6% vs. 23.8%, p < 0.001). Patients with thyroid dysfunction tended to have increased interval time for negative conversion of viral nucleic acid (14.1 ± 9.4 vs. 10.6 ± 8.3 days, p = 0.088). To note, thyroid dysfunction was also associated with decreased lymphocytes (p < 0.001) and increased CRP (p = 0.002). In 7 patients with dynamic changes of thyroid function, we observed the levels of TT3 and TSH gradually increased and reached normal range without thyroid hormone replacement at Day 30 post-admission. The correlation between TT3 and TSH level seemed to be positive rather than negative in the early stage, and gradually turned to be negatively related over time. Interpretations: Thyroid function abnormalities are common in COVID-19 patients, especially in severe cases. This might be caused by virus attack and damage to the thyroid-pituitary axis. Therefore, more attention should be paid to thyroid function during treatment of COVID-19, and close follow-up is also needed after discharge.

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice.

Aberrant expression of G protein-coupled receptors (GPCRs) is frequently associated with tumorigenesis. G Protein-coupled receptor class C group 5 member A (GPRC5A) is a member of the GPCR superfamily, is expressed preferentially in lung tissues, and is regulated by various entities at multiple levels. GPRC5A exerts a tumor suppressive role in lung cancer and GPRC5A deletion promotes lung tumor initiation and progression. Recent advances have highlighted that GPRC5A dysregulation is found in various human cancers and is related to many tumor-associated signaling pathways, including the cyclic adenosine monophosphate (cAMP), nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT) 3, and focal adhesion kinase (FAK)/Src signaling. This review aimed to summarize our updated view on the biology and regulation of GPRC5A, its expression in human cancers, and the linked signaling pathways. A better comprehension of the underlying cellular and molecular mechanisms of GPRC5A will provide novel insights into its potential diagnostic and therapeutic value.

Background and Objectives. The clinicopathological risk factors to predict recurrence of papillary thyroid cancer (PTC) patients remain controversial. Methods. PTC patients treated with thyroidectomy between January 1997 and December 2011 at the First Affiliated Hospital of Zhejiang University (Zhejiang cohort) were included. Multivariate Cox regression analysis was conducted to identify independent recurrence predictors. Then, the nomogram model for predicting probability of recurrence was built. Results. According to Zhejiang cohort (N = 1,697), we found that the 10-year event-free survival (EFS) rates of PTC patients with early-stage (TNM stages I, II, and III) were not well discriminated (91.6%, 89.0%, and 90.7%; P=0.768). The multivariate Cox model identified age, bilaterality, tumor size, and nodal status as independent risk factors for tumor recurrence in PTC patients with TNM stages I–III. We then developed a nomogram with the C-index 0.70 (95% CI, 0.64 to 0.76), which was significantly higher (P<0.0001) than the AJCC staging system (0.52). In the validation group, the C-index remained at a similar level. Conclusions. In this study, we build up a new recurrence predicting system and establish a nomogram for early-stage PTC patients. This prognostic model may better predict individualized outcomes and conduct personalized treatments.

Estrogen receptor-alpha36 (ER-α36) is a 36-kDa variant of estrogen receptor-alpha (ER-α) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66). ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-α66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues. Thus, dysregulation of ER-α36 is closely associated with plenty of diseases including cancers. ER-α36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-α36 in endocrine therapy resistance. Therefore, ER-α36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-α36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.

Fine-needle aspiration (FNA) is a reliable method for preoperative diagnosis of thyroid nodules; however, about 10%–40% nodules are classified as indeterminate. The BRAFV600E mutation is the most promising marker for thyroid FNA. This meta-analysis was conducted to investigate the diagnostic value of BRAFV600E analysis in thyroid FNA, especially the indeterminate cases. Systematic searches were performed in PubMed, Web of Science, Scopus, Ovid, Elsevier, and the Cochrane Library databases for relevant studies prior to June 2015, and a total of 88 studies were ultimately included in this meta-analysis. Compared with FNA cytology, the synergism of BRAFV600E testing increased the diagnostic sensitivity from 81.4% to 87.4% and decreased the false-negative rate from 8% to 5.2%. In the indeterminate group, the mutation rate of BRAFV600E was 23% and varied in different subcategories (43.2% in suspicious for malignant cells [SMC], 13.77% in atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS], and 4.43% in follicular neoplasm/suspicious for follicular neoplasm [FN/SFN]). The sensitivity of BRAFV600E analysis was higher in SMC than that in AUS/FLUS and FN/SFN cases (59.4% vs 40.1% vs 19.5% respectively), while specificity was opposite (86.1% vs 99.5% vs 99.7% respectively). The areas under the summary receiver-operating characteristic curve also confirmed the diagnostic value of BRAFV600E testing in SMC and AUS/FLUS rather than FN/SFN cases. Therefore, BRAFV600E analysis can improve the diagnostic accuracy of thyroid FNA, especially indeterminate cases classified as SMC, and select malignancy to guide the extent of surgery.