miR-142-3p encapsulated in T lymphocyte-derived tissue small extracellular vesicles induces Treg function defect and thyrocyte destruction in Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease characterized by lymphocyte infiltration that destroys thyrocyte cells. The aim of the present study was to elucidate the role and mechanisms of tissue small extracellular vesicle (sEV) microRNAs (miRNAs) in the pathogenesis of HT. METHODS: Differentially expressed tissue sEV miRNAs were identified between HT tissue and normal tissue by RNA sequencing in the testing set (n = 20). Subsequently, using quantitative real-time polymerase chain reaction (qRT‒PCR) assays and logistic regression analysis in the validation set (n = 60), the most relevant tissue sEV miRNAs to HT were verified. The parental and recipient cells of that tissue sEV miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of sEV miRNAs that contribute to the development of HT. RESULTS: We identified that miR-142-3p encapsulated in T lymphocyte-derived tissue sEVs can induce Treg function defect and thyrocyte destruction through an intact response loop. Inactivation of miR-142-3p can effectively protect non-obese diabetic (NOD).H-2h4 mice from HT development display reduced lymphocyte infiltration, lower antibody titers, and higher Treg cells. Looking at the mechanisms underlying sEV action on thyrocyte destruction, we found that the strong deleterious effect mediated by tissue sEV miR-142-3p is due to its ability to block the activation of the ERK1/2 signaling pathway by downregulating RAC1. CONCLUSIONS: Our findings highlight the fact that tissue sEV-mediated miR-142-3p transfer can serve as a communication mode between T lymphocytes and thyrocyte cells in HT, favoring the progression of HT.

A nomogram model based on the preoperative clinical characteristics of papillary thyroid carcinoma with Hashimoto's thyroiditis to predict central lymph node metastasis.

OBJECTIVE: Preoperative prediction of central lymph node (LN) metastasis in papillary thyroid carcinoma (PTC) with Hashimoto's thyroiditis (HT) provides an important basis for surgical decision-making, especially regarding the extent of tumour resection. We aimed to develop and validate a nomogram model for the preoperative assessment of central LN metastasis. METHODS: We retrospectively collected the data of 994 PTC patients with HT who underwent surgery at the West China Hospital from January 2008 to December 2017. Among them, 606 patients who underwent surgeries relatively earlier comprised the training cohort for nomogram development, while the other 388 who underwent surgeries relatively later formed the validation cohort to validate the model's performance. Univariate and multivariate logistic regression analyses were conducted using the data of the two respective cohorts, as well as the data of the combined cohort. The relevant preoperative potential risk factors include demographic characteristics, medical history information, thyroid function test, ultrasound characteristics and BRAF V600E gene detection. A nomogram model was subsequently developed. The performance, discrimination and calibration of the nomogram model were assessed in the training and validation cohorts and in the combined cohort. RESULTS: The central LN metastasis rate of PTC with HT was 49.7% (301/606) and 48.7% (193/388) in the training and validation cohorts, respectively. The univariate and multivariate logistic regression analyses indicated that younger age, normal body mass index, BRAF V600E mutation, larger maximum diameter, left lobe tumour, aspect ratio >1, capsular invasion and calcification were significant risk factors for central LN metastasis in PTC patients with HT. The preoperative nomogram showed good calibration and discrimination for the training and validation cohorts, as well as for the combined data set. CONCLUSION: The nomogram we developed and validated with a comprehensive set of preoperative factors is effective in predicting central LN metastasis in PTC patients with HT.

The effectiveness of the combined problem-based learning (PBL) and case-based learning (CBL) teaching method in the clinical practical teaching of thyroid disease.

BACKGROUND: This study aimed to evaluate the effectiveness and efficiency of PBL-CBL combined teaching in thyroid surgery and make observations from the students' perspectives, based on their satisfaction with the learning process. METHODS: We prospectively enrolled 354 fourth-year students majoring in clinical medicine, along with 232 residents, from September 2014 to June 2019. These participants were randomly allocated into either the combined PBL-CBL teaching group or the traditional lecture-based classroom group to attend a course about thyroid nodules. Both pre- and post-class quizzes were conducted. An anonymous questionnaire was also administered to both groups to evaluate the students' perceptions and experiences. We compared the two teaching methods among all the students as well as with the fourth-year students and residents in subgroups. RESULTS: The traditional group's pre-class quiz scores were significantly higher than the PBL-CBL group's (as determined by a two-tailed t-test at a 95% confidence interval, T = 16.483, P < 0.001). After class, in the PBL-CBL group, the mean total quiz score and the basic knowledge and case analysis scores increased significantly (P < 0.001). The PBL-CBL group's performance improvement was significantly higher than the traditional group's (increasing from 52.76 to 70.51 vs. from 67.03 to 71.97). Furthermore, the scores for learning motivation, understanding, student-teacher interaction, the final examination, communication skills, clinical thinking skills, self-learning skills, teamwork skills, and knowledge absorption, as measured by the survey, were significantly higher in the PBL-CBL group than in the traditional group (P < 0.001). Meanwhile, the survey scores representing the amount of students' free time the course consumed were significantly lower in the PBL-CBL group than in the traditional group (P < 0.001). CONCLUSIONS: PBL combined with CBL may be an effective method for improving medical students' and residents' performance and enhancing their clinical skills.

Comparing ChatGPT's and surgeon's responses to thyroid-related questions from patients.

BACKGROUND: For some common thyroid-related conditions with high prevalence and long follow-up times, ChatGPT can be used to respond to common thyroid-related questions. In this cross-sectional study, we assessed the ability of ChatGPT (version GPT-4.0) to provide accurate, comprehensive, compassionate, and satisfactory responses to common thyroid-related questions. STUDY DESIGN: First, we obtained 28 thyroid-related questions from the Huayitong app, which together with the two interfering questions eventually formed 30 questions. Then, these questions were responded to by ChatGPT (on July 19, 2023), junior specialist and senior specialist (on July 20, 2023) separately. Finally, 26 patients and 11 thyroid surgeons evaluated those responses on four dimensions: accuracy, comprehensiveness, compassion, and satisfaction. RESULTS: Among the 30 questions and responses, ChatGPT's speed of response was faster than that of the junior specialist (8.69 [7.53-9.48] vs. 4.33 [4.05-4.60], P <.001) and senior specialist (8.69 [7.53-9.48] vs. 4.22 [3.36-4.76], P <.001). The word count of the ChatGPT's responses was greater than that of both junior specialist (341.50 [301.00-384.25] vs. 74.50 [51.75-84.75], P <0.001) and senior specialist (341.50 [301.00-384.25] vs. 104.00 [63.75-177.75], P <0.001). ChatGPT received higher scores than junior specialist and senior specialist in terms of accuracy, comprehensiveness, compassion and satisfaction in responding to common thyroid-related questions. CONCLUSIONS: ChatGPT performed better than junior specialist and senior specialist in answering common thyroid-related questions, but further research is needed to validate the logical ability of the ChatGPT for complex thyroid questions.

Generation of a Mouse Spontaneous Autoimmune Thyroiditis Model.

In recent years, Hashimoto's thyroiditis (HT) has become the most common autoimmune thyroid disease. It is characterized by lymphocyte infiltration and the detection of specific serum autoantibodies. Although the potential mechanism is still not clear, the risk of Hashimoto's thyroiditis is related to genetic and environmental factors. At present, there are several types of models of autoimmune thyroiditis, including experimental autoimmune thyroiditis (EAT) and spontaneous autoimmune thyroiditis (SAT). EAT in mice is a common model for HT, which is immunized with lipopolysaccharide (LPS) combined with thyroglobulin (Tg) or supplemented with complete Freund's adjuvant (CFA). The EAT mouse model is widely established in many types of mice. However, the disease progression is more likely associated with the Tg antibody response, which may vary in different experiments. SAT is also widely used in the study of HT in the NOD.H-2h4 mouse. The NOD.H2h4 mouse is a new strain obtained from the cross of the nonobese diabetic (NOD) mouse with the B10.A(4R), which is significantly induced for HT with or without feeding iodine. During the induction, the NOD.H-2h4 mouse has a high level of TgAb accompanied by lymphocyte infiltration in the thyroid follicular tissue. However, for this type of mouse model, there are few studies to comprehensively evaluate the pathological process during the induction of iodine. A SAT mouse model for HT research is established in this study, and the pathologic changing process is evaluated after a long period of iodine induction. Through this model, researchers can better understand the pathological development of HT and screen new treatment methods for HT.

Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma.

BACKGROUND: Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. METHODS: 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. RESULTS: Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated ß-catenin signaling pathway in LCSCs. CONCLUSIONS: LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.

Targeting tumor-associated macrophages for cancer treatment.

Tumor-associated macrophages (TAMs) are abundant, nearly accounting for 30-50% of stromal cells in the tumor microenvironment. TAMs exhibit an immunosuppressive M2-like phenotype in advanced cancer, which plays a crucial role in tumor growth, invasion and migration, angiogenesis and immunosuppression. Consequently, the TAM-targeting therapies are particularly of significance in anti-cancer strategies. The application of TAMs as anti-cancer targets is expected to break through traditional tumor-associated therapies and achieves favorable clinical effect. However, the heterogeneity of TAMs makes the strategy of targeting TAMs variable and uncertain. Discovering the subset specificity of TAMs might be a future option for targeting TAMs therapy. Herein, the review focuses on highlighting the different modalities to modulate TAM's functions, including promoting the phagocytosis of TAMs, TAMs depletion, blocking TAMs recruitment, TAMs reprogramming and suppressing immunosuppressive tumor microenvironment. We also discuss about several ways to improve the efficacy of TAM-targeting therapy from the perspective of combination therapy and specificity of TAMs subgroups.

Non-Linear Correlation Between Tumor Size and Survival Outcomes for Parathyroid Carcinoma: A SEER Population-Based Cohort Study.

Background: Parathyroid carcinoma (PC) is a rare malignancy without a commonly acknowledged prognostic assessment and treatment system. This study captures how independent prognostic factors and tumor size correlate with outcomes in patients with PC. Methods: The Surveillance, Epidemiology, and End Results database was used to perform a retrospective analysis on PC patients from 2000 to 2018. Univariate and multivariable survival analyses were performed to evaluate cancer-specific survival (CSS) and overall survival (OS), to identify independent prognostic factors in the PC patient population. A generalized additive model was applied to conduct smooth curve fitting and to examine the association between tumor size and relative risk of death. Results: A total of 590 patients were included. The 5- and 10-year OS were 80.8% and 67.1%, respectively. 5- and 10-year CSS was estimated to be 93.6% and 92.1%, respectively. The association between tumor size and relative risk of death can be generalized as a U-shaped curve. The mortality risk reaches its lowest point when tumor diameter approaches 2cm. At a tumor diameter cutoff of 3cm for CSS and 4cm for OS, there is an abrupt drop in survival rates. Multivariate Cox analysis revealed age, no surgery, and debulking surgery as consistent predictors of lower OS and CSS. Conclusions: A non-linear correlation between tumor size and death risk has been identified in patients with PC, along with an accurate size threshold at which survival rates sharply decrease. Further investigation is needed to determine if these trends are seen in other malignancies with promising prognoses.

Comparative efficacy of different ultrasound-guided ablation for the treatment of benign thyroid nodules: Systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Percutaneous ablation is currently deemed an additionally treatment option for benign thyroid nodules in the world, but possibly different effect among the ablation modalities is not clear. So we aim to evaluate the efficacy and complications of thermal/chemical ablation by network meta-analysis. MATERIALS AND METHODS: In the network meta-analysis, PubMed, EMBASE and the Cochrane Library databases were searched from 1980 to 2020. Studies of adults with thyroid benign nodules under percutaneous ablation therapy were included. Percentage mean volume change, symptom score change, cosmetic score change and complications were evaluated by network meta-analysis. RESULTS: In the network meta-analysis, Radiofrequency Ablation(RFA) with 2 treatment sessions group was associated with the highest reduction for the mean volume change during 6-month follow-up (MD = 79.09 and 95% CrI:48.23-89.94). There is no significant difference in the incidence of complications. Subgroup analysis showed that 2 sessions of Radiofrequency Ablation (RFA) ranks the highest probability (surface under the cumulative ranking curve (SUCRA) values 77.9) of being the most efficacious treatment for solid or predominantly solid benign nodules. Ethanol ablation (EA) ranked first (SUCRA value 81.1) in the treatment for cyst or predominantly cyst benign nodules. CONCLUSION: RFA appears to be superior to other US-guided percutaneous ablation in reducing benign thyroid nodule volume during short- and long-term follow-up. In the subgroup analysis, RFA with 2 treatment sessions showed the most significant effectiveness for solid benign thyroid nodules and EA showed more effectiveness to decrease the volume of cyst benign thyroid nodules.

Disease Severity Determines Timing of Initiating Continuous Renal Replacement Therapies: A Systematic Review and Meta-Analysis.

Background: Timing of initiating continuous renal replacement therapies (CRRTs) among the patients with acute kidney injury (AKI) in intensive care units (ICU) has been discussed over decades, but the definition of early and late CRRT initiation is still unclear. Methods: The English language randomized controlled trials (RCTs) and cohort studies were searched through MEDLINE, EMBASE, and Cochrane Library on July 19, 2019, by the two researchers independently. The study characteristics; early and late definitions; outcomes, such as all-cause, in-hospital, 28- or 30-, 60-, 90-day mortality; and renal recovery were extracted from the 18 eligible studies. Pooled relative risk ratios (RRs) and 95% CIs were estimated with the fixed effects model and random effects model as appropriate. This study is registered with PROSPERO (CRD 42020158653). Results: Eighteen studies including 3,914 patients showed benefit in earlier CRRT (n = 1,882) over later CRRT (n = 2,032) in all-cause mortality (RR 0.78, 95% CI 0.66-0.92), in-hospital mortality (RR 0.81, 95% CI 0.67-0.99), and 28- or 30-day mortality (RR 0.81, 95% CI 0.74-0.88), but in 60- and 90-day mortalities, no significant benefit was observed. The subgroup analysis showed significant benefit in the disease-severity-based subgroups on early CRRT initiation in terms of in-hospital mortality and 28- or 30-day mortality rather than the time-based subgroups. Moreover, early CRRT was found to have beneficial effects on renal recovery after CRRT (RR 1.21, 95% CI 1.01-1.45). Conclusions: Overall, compared with late CRRT, early CRRT is beneficial for short-term survival and renal recovery, especially when the timing was defined based on the disease severity. CRRT initiation on Acute Kidney Injury Network (AKIN) stage 1 or Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE)-Risk or less may lead to a better prognosis.

The comparison of different antiviral therapies on the prognosis of hepatitis B virus-related hepatocellular carcinoma after curative treatments: A network meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of different nucleos(t)ide analogues in the prognosis of HBV-related hepatocellular carcinoma (HCC) patients after curative treatment by network meta-analysis. METHODS: Literature retrieval was conducted in globally recognized databases, namely, PubMed, EMBASE, Cochrane Library databases, and Science Citation Index Expanded, to address relative studies investigating nucleot(s)ide analogues for HBV-related HCC patients after curative resection. Relative parametric data, including 1-, 3-, and 5-year overall survival rate and 1-, 3-, and 5-year recurrence-free survival rate were quantitatively pooled and estimated. The inconsistency factor, the cumulative ranking curve, and the publication bias were evaluated. RESULTS: Fourteen observational studies of 2481 adults performed between 2000 and 2019 were eligible. In terms of overall survival, ADV (Adefovir dipivoxil) (Odds ratio (OR): 2.35, 95% confidence interval (CI): 1.17-4.73), Lamivudine (OR: 2.08, 95% CI: 1.78-5.58), and Entecavir (OR: 2.14, 95% CI: 1.59-2.88) were found to be more beneficial than control group while ADV has the highest probability of having the most efficacious treatment (SCURA values 66.3) for 5-year overall survival. In late recurrence-free survival, ADV (OR = 1.88, 95% CI: 1.77-4.60), Entecavir (OR = 1.96, 95% CI: 1.36-2.55), and Lamivudine (OR = 1.73, 95% CI: 1.06-2.82) all had better significant prognosis than patients without antiviral therapy postoperatively and patients with ADV as postoperative antiviral therapy has significantly recurrence-free survival benefit at 5-year follow-up compared to those undertaking Entecavir (OR = 1.96, 95% CI: 1.52-7.38) and Lamivudine (OR = 1.39, 95% CI: 1.09-3.01). Moreover, the application of ADV possessed the highest possibility of having the best clinical effects on 1- (surface under the cumulative ranking probabilities (SUCRA), 64.7), 3- (SUCRA, 64.7), and 5-year (SUCRA, 70.4) recurrence survival rate for HBV-related HCC patients. CONCLUSIONS: Patients with postoperative nucleos(t)ide analogues antiviral therapy had better survival benefit than those without antiviral therapy for HBV-related HCC patients after curative treatment. Additionally, nucleotide analogues like ADV and Tenofovir disoproxil fumarate has better impact on early and late recurrence-free survival of patients after curative treatment than those undertaking nucleoside analogues.

The different effects of adefovir dipivoxil and telbivudine on the prognosis of hepatitis b virus-related hepatocellular carcinoma patients after curative resection.

Numerous studies suggested that antiviral therapy could reduce the recurrence in hepatocellular carcinoma (HCC) patients after hepatectomy. The impact of nucleotide and nucleoside analogues on prognosis of chronic hepatitis B (CHB) related HCC remains to be explored. We aimed to investigate the role of the telbivudine and adefovir dipivoxil on the prognosis of CHB-related HCC patients after hepatectomy.One hundred eighty-eight CHB-related patients who received hepatectomy from February 2010 to February 2017 were divided into telbivudine (LdT) and adefovir dipivoxil (ADV) groups. The characteristics and survival information of both groups were retrospectively compared and analyzed.One hundred eleven and 77 patients received telbivudine and adefovir dipivoxil monotherapy, respectively. Alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg), serum HBV-DNA level were compared between groups. OS and DFS in ADV-treatment group were significantly better than it in LdT-treatment group (P < .05). In the subgroups analysis, we found that ADV treatment was significantly associated with better DFS and OS among patients with cirrhosis, HBeAg-negative patients, or those with detectable HBV-DNA.CHB-related HCC patients receiving long-term ADV-treatment had a better OS and DFS than patients receiving LdT-treatment after hepatectomy.

Nomograms to Predict the Individual Survival of Patients with Solitary Hepatocellular Carcinoma after Hepatectomy.

BACKGROUND/AIMS: Solitary hepatocellular carcinoma (HCC) is a subgroup of HCCs. We aimed to establish nomograms for predicting the survival of solitary HCC patients after hepatectomy. METHODS: A total of 538 solitary HCC patients were randomly classified into training and validation sets. A Cox model was used to identify predictors of overall survival (OS) in the training set. A nomogram was generated based on these predictors and was validated using the validation set. RESULTS: Tumor size, microvascular invasion, and major vascular invasion were significantly associated with OS in the training set. Nomograms were developed based on these predictors in the multivariate analysis. The C-index was 0.75 for the OS nomogram and 0.72 for the recurrence-free survival nomogram. Compared to the index of conventional staging systems for predicting survival (0.71 for Barcelona Clinic Liver Cancer, 0.66 for the seventh American Joint Committee on Cancer, 0.68 for Cancer of the Liver Italian Program, and 0.70 for Hong Kong Liver Cancer), the index of the OS nomogram was significantly higher. Moreover, the calibration curve fitted well between the predicted and observed survival rate. Similarly, in the validation set, the nomogram discrimination was superior to those of the four staging systems (p<0.001). CONCLUSIONS: The nomograms demonstrated good discrimination performance in predicting 3- and 5-year survival rates for solitary HCCs after hepatectomy.

Prognostic nomograms for patients with resectable hepatocelluar carcinoma incorporating systemic inflammation and tumor characteristics.

BACKGROUND: The model to predict the prognosis of resectable hepatocelluar carcinoma (HCC) has not been determined. METHODS: Predictors were selected using Cox model. Nomograms were generated in the training set and validated in the validation set. The predictive ability of the nomogram was determined by concordance index and calibration curve. RESULTS: Independent factors for overall survival including alpha-fetoprotein level (hazard ratio (HR):1.292), tumor size (HR:1.092), tumor number (HR:1.472), microvascular invasion (HR:1.660), neutrophil to lymphocyte count ratio (NLR) (HR:1.428), major vascular invasion (HR:2.485) and satellite lesions(HR:1.392) were selected into the nomogram for survival. The c-index in the training set and validation set were 0.767 and 0.719, respectively, which were statistically higher than those of the four conventional staging systems.(Barcelona Clinic Liver Cancer: 0.644 and 0.609; the seventh American Joint Committee on Cancer: 0.678 and 0.674; Cancer of the Liver Italian Program: 0.692 and 0.648; Hong Kong Liver Cancer: 0.689 and 0.639, p < 0.001 for all). A nomogram for predicting 3- and 5-year recurrence free survival was generated with the c-index of 0.746 for the training set and 0.718 for the validation set, respectively. CONCLUSIONS: We have generated nomograms predicting prognosis for HCC treated by hepatectomy with a higher predictive power.