Microscopic extrathyroidal extension does not affect the prognosis of patients with papillary thyroid carcinoma: A propensity score matching analysis.

Background: Extrathyroidal extension (ETE) in papillary thyroid carcinoma (PTC) can be divided into two categories based on different degrees of invasion: microscopic ETE (micro-ETE) and macroscopic ETE (macro-ETE). At present, there is a consensus that macro-ETE significantly affects PTC prognosis, while the prognostic significance of micro-ETE remains controversial. Methods: The clinicopathological and follow-up data for PTC patients who underwent surgical treatment at the Hangzhou First People's Hospital between 2015 and 2018 were retrospectively analyzed. According to the degree of ETE, patients were divided into three groups: non-ETE, micro-ETE and macro-ETE. Cox regression analysis was performed to evaluate the effect of ETE on recurrence-free survival (RFS). The propensity score matching (PSM) method was used to reduce the interference of confounding factors, and Kaplan-Meier curves were utilized to compare the RFS. Results: Both micro- and macro-ETE were associated with some aggressive tumor features, including tumor size, multifocality, and lymph node metastasis. Univariate and multivariate Cox regression analyses showed that macro-ETE was an independent risk factor for recurrence, while micro-ETE was not associated with recurrence. The K-M curves showed that RFS for micro-ETE and non-ETE were not statistically different before and after PSM, while RFS for macro-ETE was significantly shorter than that for non-ETE. Conclusion: The presence of micro-ETE in PTC did not affect prognosis of patients, suggesting that its treatment should be consistent with the treatment for intrathyroidal tumors. The surgical method and the necessity for radioiodine therapy should be carefully evaluated to reduce overtreatment.

MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation.

BACKGROUND: Gastric cancer (GC) is associated with high mortality and heterogeneity and poses a great threat to humans. Gene therapies for the receptor tyrosine kinase RON and its spliceosomes are attracting increasing amounts of attention due to their unique characteristics. However, little is known about the mechanism involved in the formation of the RON mRNA alternative spliceosome RONΔ160. METHODS: Fourteen human GC tissue samples and six normal gastric tissue samples were subjected to label-free relative quantitative proteomics analysis, and MAGOH was identified as a candidate protein for subsequent studies. The expression of MAGOH in clinical specimens was verified by quantitative real-time PCR and western blotting. We then determined the biological function of MAGOH in GC through in vitro and in vivo experiments. RNA pulldown, RNA sequencing and RNA immunoprecipitation (RIP) were subsequently conducted to uncover the underlying mechanism by which MAGOH regulated the formation of RONΔ160. RESULTS: Proteomic analysis revealed that MAGOH, which is located at key nodes and participates in RNA processing and mRNA splicing, was upregulated in GC tissue and GC cell lines and was associated with poor prognosis. Functional analysis showed that MAGOH promoted the proliferation, migration and invasion of GC cells in vitro and in vivo. Mechanistically, MAGOH inhibited the expression of hnRNPA1 and reduced the binding of hnRNPA1 to RON mRNA, thereby promoting the formation of RONΔ160 to activate the PI3K/AKT signaling pathway and consequently facilitating GC progression. CONCLUSIONS: Our study revealed that MAGOH could promote the formation of RONΔ160 and activate the PI3K/AKT signaling pathway through the inhibition of hnRNPA1 expression. We elucidate a novel mechanism and potential therapeutic targets for the growth and metastasis of GC based on the MAGOH-RONΔ160 axis, and these findings have important guiding significance and clinical value for the future development of effective therapeutic strategies for GC.

Surface Lattice Modulation through Chemical Delithiation toward a Stable Nickel-Rich Layered Oxide Cathode.

Nickel-rich layered oxides (NLOs) are considered as one of the most promising cathode materials for next-generation high-energy lithium-ion batteries (LIBs), yet their practical applications are currently challenged by the unsatisfactory cyclability and reliability owing to their inherent interfacial and structural instability. Herein, we demonstrate an approach to reverse the unstable nature of NLOs through surface solid reaction, by which the reconstructed surface lattice turns stable and robust against both side reactions and chemophysical breakdown, resulting in improved cycling performance. Specifically, conformal La(OH)3 nanoshells are built with their thicknesses controlled at nanometer accuracy, which act as a Li+ capturer and induce controlled reaction with the NLO surface lattices, thereby transforming the particle crust into an epitaxial layer with localized Ni/Li disordering, where lithium deficiency and nickel stabilization are both achieved by transforming oxidative Ni3+ into stable Ni2+. An optimized balance between surface stabilization and charge transfer is demonstrated by a representative NLO material, namely, LiNi0.83Co0.07Mn0.1O2, whose surface engineering leads to a highly improved capacity retention and excellent rate capability with a strong capability to inhibit the crack of NLO particles. Our study highlights the importance of surface chemistry in determining chemical and structural behaviors and paves a research avenue in controlling the surface lattice for the stabilization of NLOs toward reliable high-energy LIBs.

Blood immune indexes can predict lateral lymph node metastasis of thyroid papillary carcinoma.

Objective: To explore the clinical significance of blood immune indexes in predicting lateral lymph node metastasis (LLNM) of thyroid papillary carcinoma (PTC). Methods: The pathological data and preoperative blood samples of 713 patients that underwent thyroid surgery at affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine from January 2013 to June 2021 were collected as the model group. The pathological data and preoperative blood samples of 177 patients that underwent thyroid surgery in the same hospital from July 2021 to October 2021 were collected as the external validation group. Univariate and multivariate logistic regression analyses were used to determine the independent risk factors of LLNM in PTC patients. A predictive model for assessing LLNM in PTC patients was established and externally validated using the external data. Results: According to univariate and multivariate logistic regression analyses, tumor diameter (P < 0.001, odds ratios (OR): 1.205, 95% confidence interval (CI): 1.162-1.249) and the preoperative systemic immune-inflammation index (SII) (P = 0.032, OR: 1.001, 95% CI: 1.000-1.002) were independent risk factors for distinguishing LLNM in PTC patients. When the Youden index was the highest, the area under the curve (AUC) was 0.860 (P < 0.001, 95% CI: 0.821-0.898). The externally validated AUC was 0.827 (P < 0.001, 95% CI: 0.724-0.929), the specificity was 86.4%, and the sensitivity was 69.6%. The calibration curve and the decision curve indicated that the model had good diagnostic value. Conclusion: Blood immune indexes can reflect the occurrence of LLNM and the biological behavior of PTC. The predictive model established in combination with SII and tumor diameter can effectively predict the occurrence of LLNM in PTC patients.

Total tumor diameter is a better indicator of multifocal papillary thyroid microcarcinoma: A propensity score matching analysis.

Background: Accurate evaluation of the risk of papillary thyroid microcarcinoma (PTMC) is the key to treatment. However, the maximum diameter (MD), which is currently used in various staging systems, may not truly reflect the aggressiveness of multifocal tumors. Methods: Clinical and pathological data for 1001 patients with papillary thyroid carcinoma who underwent surgery at the Hangzhou First People's Hospital were retrospectively analyzed. First, the relationship between total tumor diameter (TTD) and clinicopathological features in multifocal PTMC was explored. Then, patients were divided into subgroups according to the TTD. The baseline was consistent after using the propensity score matching method, and the differences between groups were compared. In addition, the effectiveness of TTD and MD in evaluating central lymph node metastasis (CLNM) was analyzed and compared. Results: TTD is associated with a range of clinicopathological features, including lymph node metastasis, extrathyroidal extension, and risk stratification. Assuming the same MD and number of foci, the invasiveness of multifocal PTMC with TTD >1 cm was significantly higher than that with TTD <1 cm, and even higher than unifocal non-PTMC. Moreover, the efficiency of TTD in predicting CLNM was also significantly higher than that of MD. Conclusion: For multifocal PTMC, TTD is a more realistic indicator of tumor biological characteristics than MD. The aggressiveness of PTMC with TTD >1 cm was significantly enhanced, and surgical treatment should be actively sought in such cases.

Risk factors of skip lateral cervical lymph node metastasis in papillary thyroid carcinoma: a systematic review and meta-analysis.

OBJECTIVE: To analyze and explore the risk factors of skip lateral cervical lymph node metastasis (SLLNM) in papillary thyroid carcinoma (PTC). METHODS: PubMed, Web of Science, Embase, Cochrane, Wanfang, China National Knowledge Infrastructure, and China Science and Technology Journal databases, updated to April 4, 2021, were systematically searched for literature on the risk factors of SLLNM in PTC. The meta-analysis was completed using Stata 15.0 software after quality evaluation. The odds ratio (OR) and 95% confidence interval (CI) of each variable were calculated using fixed or random-effects models, and the publication bias was evaluated by the Egger's test. RESULTS: A total of 28 studies with 10,682 cases were included in our meta-analysis; 1592 (14.90%) cases were positive for SLLNM. The meta-analysis showed that female sex (OR = 1.16, 95% CI = 1.02-1.31, P = 0.021), age ≥45 (OR = 1.60, 95% CI = 1.19-2.15, P = 0.002), tumor diameter ≤10 mm (OR = 2.23, 95% CI = 1.62-3.06, P < 0.001), and upper location of tumor (OR = 3.60, 95% CI = 2.65-4.89, P < 0.001) were risk factors for SLLNM in PTC patients. Hashimoto's thyroiditis (OR = 1.02, 95% CI = 0.88-1.19, P = 0.777), multifocality (OR = 0.98, 95% CI = 0.75-1.28, P = 0.873), bilateral tumors (OR = 0.92, 95% CI = 0.70-1.19, P = 0.515), extrathyroidal extensions (OR = 1.07, 95% CI = 0.83-1.39, P = 0.598), and capsular invasion (OR = 0.93, 95% CI = 0.65-1.31, P = 0.660) were not closely related to SLLNM risk. CONCLUSION: This study confirmed significant associations between SLLNM and female sex, age ≥45, tumor diameter ≤10 mm, and upper location of the tumor.

A Novel Pyroptosis-Related Gene Signature for Prediction of Disease-Free Survival in Papillary Thyroid Carcinoma.

BACKGROUND: The incidence and recurrence rate of papillary thyroid carcinoma (PTC) are high. Thus, it is critical to accurately identify patients at high risk of recurrence. Pyroptosis is a type of programmed cell death closely related to the progression and prognosis of cancer. However, the role of pyroptosis in PTC remains unclear. METHODS: Transcriptome data for PTC patients were obtained from The Cancer Genome Atlas database. The expression level of pyroptosis-related genes (PRGs) in PTC and normal tissues was identified. Based on these differentially expressed genes, a risk score model of disease-free survival (DFS) was established using least absolute shrinkage and selection operator Cox regression. In-cluster and quantitative real-time PCR validations were carried out. A nomogram, in combination with clinical factors, was also established. In addition, its relationship with immune characteristics and tumor gene mutations is discussed. RESULTS: A risk score model with four PRGs, including CASP6, CASP9, IL-18, and NOD1, was established. The samples were divided into high- and low-risk clusters, according to the risk score, revealing significant differences in DFS between the two clusters. A nomogram was established combining age, lymph node metastasis and extrathyroidal extension. The area under the curve (AUC) of predicting one-, five-, and 10-year DFS in PTC patients was 0.745, 0.801, and 0.803, respectively. The low-risk cluster showed higher levels of immune infiltration and immune checkpoint gene expression, while the high-risk cluster demonstrated a higher tumor mutation burden. CONCLUSION: A predictive DFS model was established, based on PRGs, which may aid in identifying patients at high risk of recurrence. The present study helps to better understand the role of pyroptosis in the progression and prognosis of PTC.

The Prediction of Metastases of Lateral Cervical Lymph Node in Medullary Thyroid Carcinoma.

Purpose: Development and validation of a nomogram for the prediction of lateral lymph node metastasis (LLNM) in medullary thyroid carcinoma (MTC). Methods: We retrospectively reviewed the clinical features of patients with MTC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 and in our Department of Surgical Oncology, Hangzhou First People's Hospital between 2009 and 2019. The log-rank test was used to compare the difference in the Kaplan-Meier (K-M) curves in recurrence and survival. The nomogram was developed to predict the risk of LLNM in MTC patients. The prediction efficiency of the predictive model was assessed by area under the curve (AUC) and concordance index (C-index) and calibration curves. Decision curve analysis (DCA) was performed to determine the clinic value of the predictive model. Result: A total of 714 patients in the SEER database and 35 patients in our department were enrolled in our study. Patients with LLNM had worse recurrence rate and cancer-specific survival (CSS) compared with patients without LLNM. Five clinical characteristics including sex, tumor size, multifocality, extrathyroidal extension, and distant metastasis were identified to be associated with LLNM in MTC patients, which were used to develop a nomogram. Our prediction model had satisfied discrimination with a C-index of 0.825, supported by both training set and internal testing set with a C-index of 0.825, and 0.816, respectively. DCA was further made to evaluate the clinical utility of this nomogram for predicting LLNM. Conclusions: Male sex, tumor size >38mm, multifocality, extrathyroidal extension, and distant metastasis in MTC patients were significant risk factors for predicting LLNM.

Extranodal Extension Is an Independent Prognostic Factor in Papillary Thyroid Cancer: A Propensity Score Matching Analysis.

Purpose: To investigate the prognostic significance of extranodal extension (ENE) in papillary thyroid cancer (PTC). Methods: Seven hundred forty-three PTC patients were enrolled in the study from January 2014 to December 2017. The patients were dichotomized according to the presence of ENE. Logistic analysis was used to compare differences between the two groups. Kaplan-Meier (K-M) curve and propensity score matching (PSM) analyses were used for recurrence-free survival (RFS) comparisons. Cox regression was performed to analyze the effects of ENE on RFS in PTC. Results: Thirty-four patients (4.58%) had ENE. Univariate analysis showed that age, tumor size, extrathyroidal extension, and nodal stage were associated with ENE. Further logistic regression analysis showed that age, extrathyroidal extension, and nodal stage remained statistically significant. Evaluation of K-M curves showed a statistically significant difference between the two groups before and after PSM. Cox regression showed that tumor size and ENE were independent risk factors for RFS. Conclusions: Age ≥55 years, extrathyroidal extension, and lateral cervical lymph node metastasis were identified as independent risk factors for ENE. ENE is an independent prognostic factor in PTC.

A meta-analysis of risk factors for lymph node posterior to the right recurrent laryngeal nerve metastasis in papillary thyroid carcinoma.

BACKGROUND: Whether the lymph node posterior to the right recurrent laryngeal nerve (LN-prRLN) should be dissected is still controversial. This meta-analysis aimed to assess the risk factors for LN-prRLN metastasis in papillary thyroid carcinoma (PTC). METHODS: We retrieved relevant studies published before May 2020 from the Wanfang Data, CNKI, PubMed, Embase, Web of Science and Cochrane Library databases. Heterogeneity was assessed with the Q-test and inconsistency index and sensitivity analysis and subgroup analysis were then used to find the source of heterogeneity. Begg test and generate a funnel chart to assess publication bias. RESULTS: We retrieved 236 articles, 14 articles were selected as the subjects of our research. Fourteen studies involving 10,580 patients were analysed in this study. The LN-prRLN metastasis rate was 9.22% (975/10,580). The results of the meta-analysis showed that sex (P<0.001), age (P<0.001), tumour size (P<0.001), multifocality (P<0.001), capsular invasion (P=0.04), extrathyroidal extension (P<0.001), superficial central lymph node (VIa-LN) metastasis (P<0.001), and lateral lymph node (LLN) metastasis (P<0.001) were correlated with LN-prRLN metastasis. DISCUSSION: Male sex, age ≤45 years, tumour size >1 cm, multifocality, capsular invasion or extrathyroidal extension, and VIa-LN metastasis or LLN metastasis in PTC patients were significant risk factors for predicting LN-prRLN metastasis. B ultrasound and CT scans are expected to predict LN-prRLN metastasis in the future. REGISTRATION: This research is registered on the PROSPERO website (registration number: CRD42020200898).

Risk factors for lateral cervical lymph node metastasis in medullary thyroid carcinoma.

: To investigate risk factors of lateral cervical lymph node metastasis (LLNM) in patients with medullary thyroid carcinoma (MTC). : Published studies regarding clinicopathological factors of LLNM in MTC were searched in PubMed, Web of Science, Embase, Cochrane library, Wanfang date and CNKI. Statistical analysis was performed using Stata 14.0 software. The mean and standard deviation from the sample size, range, median, and interquartile range was estimated. Odds ratio () or standard mean difference () with 95% confidence interval () of related factors were analyzed by fixed/random-effects models. Egger's test and Begg's test were applied to assess the publication bias of the literature. This study was registered with PROSPERO (CRD42021254955). : Fifteen studies involving 1424 patients were included in the analysis, among whom 543 cases had LLNM (38.13%). Meta-analysis revealed that an increased risk of LLNM was associated with male gender (1.64, 95%: 1.29-2.09, 4.06, 0.01), tumor diameter≥1cm (5.09, 95%: 2.43-10.67, 4.31, 0.01), multifocality (2.55, 95%: 1.79-3.61, 5.22, 0.01), capsule invasion (7.80, 95%: 4.84-12.55, 8.46, 0.01), extracapsular extension (9.46, : 5.66-15.81, 8.58, 0.01), cervical central lymph node metastasis (23.58, : 9.44-58.87, 6.77, 0.01), elevated preoperative calcitonin (1.17,95%: 0.67-1.67, 4.56, 0.01), spiculated margin on ultrasonography (4.32, 95%: 2.43-7.68, 4.99, 0.01), irregular shape on ultrasonography (6.81, : 3.64-12.73, 6.01, 0.01); while age ≥ 45 years (=1.22, 95%: 0.65-2.29, 0.62, >0.05), elevated preoperative carcinoembryonic antigen (0.95, : -0.48-2.38, 1.30, >0.05) and calcification on ultrasonography (1.28, 95%: 0.75-2.18, 0.92, >0.05) were not associated with LLNM. : Male gender, tumor diameter≥multifocality, capsule invasion, extracapsular extension, central lymph node metastasis, elevated preoperative calcitonin, spiculated margin and irregular shape on ultrasonography are risk factors for LLNM in MTC, when these clinical and ultrasonic features are present, lateral neck lymph node dissection is recommended.

Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex.

Checkpoints are biochemical pathways that provide cells a mechanism to detect DNA damage and respond by arresting the cell cycle to allow DNA repair. The conserved checkpoint kinase, Chk1, regulates mitotic progression in response to DNA damage by blocking the activation of Cdk1/cyclin B. In this study, we investigate the regulatory interaction between Chk1 and members of the Atm family of kinases and the functional role of the C-terminal non-catalytic domains of Chk1. Chk1 stimulates the kinase activity of DNA-PK (protein kinase) complexes, which leads to increased phosphorylation of p53 on Ser-15 and Ser-37. In addition, Chk1 stimulates DNA-PK-dependent end-joining reactions in vitro. We also show that Chk1 protein complexes bind to single-stranded DNA and DNA ends. These results indicate a connection between components that regulate the checkpoint pathways and DNA-PK complex proteins, which have a role in the repair of double strand breaks.