Primary synovial sarcoma of the thyroid gland: a CARE compliant case report and literature review.

Rationale: Synovial sarcoma is a subtype of soft tissue sarcoma. Synovial sarcoma in the head and neck region is relatively unusual. Primary synovial sarcoma of the thyroid gland (PSST) is first reported in 2003 by Inako Kikuchi. PSST is extremely rare with only 15 cases documented globally. PSST shows rapid disease progression and a relatively poor prognosis. However, diagnosis and therapy are challenging for clinical surgeons. In this article, we reported the 16th PSST case and reviewed the PSST cases globally for further clinical application. Patient concerns: The patient was referred to us because of gradually worsened dyspnea and dysphagia for 20 days. Physical examination showed a 5 × 4 cm mass with a clear boundary and good mobility. Contrast-enhanced ultrasonography (CEUS) and computed tomography (CT) showed a mass in the isthmus of the thyroid gland. The imageology diagnosis tends to be a benign thyroid nodule. Diagnosis: After surgery, histopathology, immunohistochemistry, and fluorescence, in situ hybridization indicated the mass to be primary synovial sarcoma of the thyroid gland with no local and distant metastasis. Interventions: The patient underwent total thyroidectomy and dissected the lymph nodes in the central compartment. This patient received postoperative chemotherapy (a combination of ifosfamide and epirubicin for five cycles). Patients tolerated chemotherapy well. No recurrence was found during the 9-month follow-up. Lessons: Although PSST is an extremely rare disease, we should raise our awareness when we encounter a rapidly growing, cystic-solid mixed thyroid mass with neck compression symptoms to avoid misdiagnosis. Intraoperatively, surgeons should refine surgical procedures to avoid capsular rupture and tumor local implantation metastasis. Intraoperative frozen section pathology is necessary sometimes, especially when the diagnosis could not be established before surgery.

A Risk Model Developed Based on Necroptosis Predicts Overall Survival for Hepatocellular Carcinoma and Identification of Possible Therapeutic Drugs.

Background: Necroptosis is a form of regulatory cell death (RCD) that attracts and activates immune cells, resulting in pro-tumor or anti-tumor effects. The purpose of this study was to investigate genes associated with necroptosis, to construct a risk score for predicting overall survival in patients with hepatocellular carcinoma, and to find potentially effective drugs. Methods: The three algorithms ssGSEA, EPIC, and ESTIMATE were used to quantify the immune cell infiltration of the samples, differentially expressed genes (DEGs) analysis, and weighted gene co-expression network analysis were used to screen necroptosis related genes. Variables were screened according to random survival forest analysis, and combinations with significant p-values and a low number of genes were defined as prognostic signatures by using log-rank test after gene combination. Based on the sensitivity data of PRISM and CTRP2.0 datasets, we predicted the potential therapeutic agents for high-NRS patients. Results: Seven genes such as TOP2A were used to define necroptosis-related risk score (NRS). The prognostic value of risk score was further validated, where high NRS was identified as a poor prognostic factor and tended to have higher grades of histologic grade, pathologic stage, T stage, BCLC, CLIP, and higher AFP. Higher NRS was also negatively correlated with the abundance of DCs, Neutrophils, Th17 cells, Macrophages, Endothelial, and positively correlated with Th2 cells. Necroptosis is often accompanied by the release of multiple cytokines, and we found that some cytokines were significantly correlated with both NRS and immune cells, suggesting that necroptosis may affect the infiltration of immune cells through cytokines. In addition, we found that TP53 mutations were more common in samples with high NRS, and these mutations may be associated with changes in NRS. Patients with high NRS may be more sensitive to gemcitabine, and gemcitabine may be an effective drug to improve the prognosis of patients with high NRS, which may play a role by inhibiting the expression of TOP2A. Conclusions: We constructed a necroptosis-related scoring model to predict OS in HCC patients, and NRS was associated with immune response, TP53 mutation, and poor clinical classification in HCC patients. In addition, gemcitabine may be an effective drug for high-NRS patients.

Case Report: A papillary thyroid microcarcinoma patient with skip lymph node metastasis and multiple distant metastasis.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Papillary thyroid microcarcinoma (PTMC) is defined as PTC with a diameter less than 1 centimeter. Most lymph nodes of PTC patients have metastasized to the central neck, and a few lymph nodes have metastasized to the lateral neck. Skip lymph node metastasis, that is, lateral cervical lymph node metastasis without central lymph node metastasis, is even less common. Additionally, distant metastasis of PTMC is also rare, mainly occurring in the lung and bone. Here, we reported a case of PTMC patient with skip lymph node metastasis and multiple distant metastasis. The patient presented with a huge shoulder mass and the primary tumor was found to originate from the thyroid. However, the patient only suffered with PTMC via postoperative pathological results, and interestingly, the patient only had skip lymph node metastasis. Thus, we should focus on PTMC patients with lateral cervical lymph nodes metastasis, especially those with skip metastasis. In addition, this case provides a new perspective for us to understand of skip lymph metastasis and distant metastasis of PTMC.

DALY trend and predictive analysis of COPD in China and its provinces: Findings from the global burden of disease study.

Background: Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease in the world, especially in China. Few studies have explored the trend of COPD in China and its provinces. This study aimed to demonstrate and predict the trend of COPD DALY in China and its provinces based on the global burden of disease (GBD) data. Methods: The data on COPD disability-adjusted life year (DALY) were collected from GBD 2017, GBD 2019, and the National Bureau of Statistics of China. The age-standardized rate (ASR) was used to evaluate the trend of COPD DALY by gender, age, and risk factors in China and its provinces. In addition, the trend of COPD considering the aging population in the next 10 years was also predicted. Results: In China, the COPD DALY was 20.4 million in 2017, which decreased to 24.16% from 1990 to 2017. Most provinces showed a downward trend, with the exception of Taiwan which increased by 127.78%. The ASR of DALY was 1445.53 per 100,000 people in 2017 and demonstrated a significant decrease. Among all provinces, only Taiwan (97.78%) and Hubei (2.21%) demonstrated an increased trend of ASR. In addition, Tibet ranked third with a decline of 56.95%, although its ASR was the highest in 1990. Smoking and air pollution were the main risk factors for COPD and varied with regions, gender, and age. The proportion of COPD DALY attributable to smoking was higher in the middle-aged and elderly male population and did not decrease in China. Moreover, the ASR attributable to air pollution of the elderly decreased significantly in China. Socio-demographic index (SDI) and educational level were also found to be related to ASR. By predicting the ASR trend in the next 10 years, we found that the ASR attributable to smoking might increase significantly among men. The ASR attributable to air pollution showed a significant decrease in women. Unfortunately, ASR attributable to second-hand smoke was found to increase in women. Conclusion: Chronic obstructive pulmonary disease is the leading contributor to the burden of global diseases. Although China and its provinces demonstrated a downward trend of COPD DALY, some provinces still faced challenges. Moreover, ASR attributable to risk factors was different in regions, gender, age, and years. The predicted trend of COPD was also different. Therefore, more targeted strategies should be formulated to reduce the burden of COPD in China and its provinces.

The global burden of thyroid cancer and its attributable risk factor in 195 countries and territories: A systematic analysis for the Global Burden of Disease Study.

BACKGROUND: Thyroid cancer is a growing threat to human health. Few studies have explored trends of thyroid cancer and relationships with social development factors. In this study, we explored the trend and relationship based on GBD. METHODS: By using GBD study, we obtained detailed data of thyroid cancer. Incidence, mortality and DALY were used to assess epidemiological characteristics. ASR and EAPC were used to estimate the trend. RESULTS: Globally, the incidence significantly increased from 1990 to 2017, especially in high-income regions. Males and middle SDI region demonstrated a higher increase of age-standardized incidence rates. Unlike incidence trend, mortality trend showed a minor increase, and even showed a decreasing trend in some regions such as Eastern Sub-Saharan Africa. Additionally, the DALY trend also demonstrated a slightly increase with an EAPC of 0.77 (95% CI 0.73-0.81). More significant increase of DALY was found in males, middle SDI region and high-income Asia Pacific. The incidence of thyroid cancer peaked in middle-aged people, while the mortality and DALY peaked in elder-aged. Moreover, the proportion of thyroid cancer deaths contributable to high BMI was highest in developed countries and middle-aged people. CONCLUSIONS: Thyroid cancer is a public health problem worldwide. Over-diagnosis might be partly responsible for its rising trend. It remains us to revise the guidelines to avoid unnecessary burdens. Moreover, we should pay attention to the risk factors of thyroid cancer. More targeted measures should be formulated to improve potential environmental and lifestyle-related factors which might contribute to rising trend of thyroid cancer.

TRIM29 Reverses Oxaliplatin Resistance of P53 Mutant Colon Cancer Cell.

Background: Oxaliplatin is the first-choice chemotherapy method for patients with advanced colon cancer. However, its resistance leads to treatment failure for many patients. In our experiments, we aim to elucidate the associations among TRIM29 protein, mutant P53, and the resistance of colon cancer cells to oxaliplatin. Methods: HCT116 and HT-29 cells were cultured and transfected with plasmids pIRES2-ZsGreen1-TRIM29-flag. Western blot and real-time qRT-PCR were utilized to examine the protein and mRNA expressions of TRIM29 and other related markers, respectively. MTT assay was utilized to determine the cell growth rate and generate the inhibition curve. Continuous culture in low-concentration oxaliplatin was conducted to construct oxaliplatin-resistant cell lines. The coimmunoprecipitation method and immunofluorescence detection were used to examine the interaction between TRIM29 and mutant P53 protein in HT29 cells. Results: We successfully transfected pIRES2-ZsGreen1-TRIM29-flag into HCT116 and HT29 cells, which were utilized in the whole experiments. TRIM29 significantly increased the sensitivity of P53 mutant colon cancer cell HT29 to oxaliplatin. The oxaliplatin-resistant model of P53 mutant colon cancer cell HT29 was successfully constructed. TRIM29 physically bound with mutant P53 and retained it in the cytoplasm from the nucleus, which inhibited its transcription function of downstream genes such as MDR1. In addition, TRIM29 successfully reversed the resistance of HT29-OX resistant cell model to oxaliplatin. Conclusion: In mutant P53 colon cancer cell HT29, TRIM29 greatly increased the sensitivity of HT29 to oxaliplatin and reverse oxaliplatin resistance. The underlying mechanism is TRIM29 may increase the sensitivity of HT29 to oxaliplatin by blocking the transcriptional function of mutant P53, which inhibits the transcription function of its downstream gene such as MDR1.

Intra-platelet serotonin and YAP contributed to poor prognosis of hepatocellular carcinoma.

AIMS: Intra-platelet 5-HT (IP 5-HT) and YAP exhibit an important role in hepatocellular carcinoma (HCC). The aim of the study was to investigate whether IP 5-HT and YAP could affect the progression and prognosis of HCC. METHODS: 5-HT level and YAP expression were measured and were compared between HCC patients and control patients. By grouping HCC patients, we analyzed clinical indicators and survival. The predictive nomogram was established by R software according to the risk factors obtained from multivariate analysis. RESULTS: Higher IP 5-HT level and higher YAP expression were associated with poorer prognosis. In addition, they were also associated with BCLC stages. Higher IP 5-HT was found to be related with higher international normalized ratio (INR) (p = 0.040), more death (p = 0.015) and higher YAP expression (p < 0.001). Similarly, higher YAP expression was proved to be associated with lower platelet counts (PLT) (p = 0.032), smaller tumor size (p = 0.017), more death (p < 0.001) and higher IP 5-HT (p < 0.001). In addition, alkaline phosphatase (ALP), YAP and tumor size were proved to be independent risk factors. By using risk factors, we have established a prognostic prediction nomogram for HCC patients. In the prognostic prediction nomogram, patients with higher scores would have poorer prognosis. CONCLUSIONS: IP 5-HT and YAP might affect the progression and prognosis of HCC through synergistic effect. Moreover, IP 5-HT might affect HCC by regulating YAP expression. Thus, both of them might be potential therapeutic targets. By establishing the prognostic prediction nomogram, we could improve the prediction system.

LncRNA XLOC_006390 promotes pancreatic carcinogenesis and glutamate metabolism by stabilizing c-Myc.

The role of lncRNAs in the regulation of glutamate metabolism and metabolic reprogramming of pancreatic cancer (PC) during nutrient deprivation is largely unknown. Our study found that alpha-ketoglutarate (aKG) levels were significantly reduced in the absence of XLOC_006390. We subsequently confirmed that the decrease in aKG was mainly due to the downregulation of glutamate dehydrogenase 1 (GDH1) at the mRNA level. Therefore, we first screened transcription factors targeting the GDH1 gene promoter and confirmed that c-Myc regulates GDH1 transcription. c-Myc binds to the promoter of GDH1 and activates its transcription. Downregulation of GDH1 mRNA levels by XLOC_006390 deletion could be rescued by overexpression of c-Myc. Overexpression of XLOC_006390 promoted the protein stability of c-Myc by blocking its ubiquitination. Clinically, XLOC_006390 was positively correlated with the mRNA level of GDH1, and c-Myc positively regulated GDH1 gene expression, which was tightly associated with PC patient prognosis. The dysregulated lncRNA/c-Myc axis increased glutamate metabolism, promoting PC progression to a higher stage. Therefore, XLOC_006390/c-Myc may be a potential target for PC, and its abnormal activation also indicates the progression of PC.

Serotonin and YAP/VGLL4 Balance Correlated with Progression and Poor Prognosis of Hepatocellular Carcinoma.

YAP-TEAD complex plays an important role in tumorigenesis. 5-HT is proved to upregulate YAP expression by our previous study and VGLL4 is found to compete with YAP for binding to TEAD in several of cancers. Here, we investigated whether 5-HT could affect progression and prognosis of hepatocellular carcinoma (HCC) patients and regulate YAP/VGLL4 balance. We found that 5-HT and YAP/VGLL4 ratio were higher in HCC patients and closely related with progression and poor prognosis. Furthermore, 5-HT level, YAP/VGLL4 ratio and tumor size were proved as independent risk factors of HCC patients in our study. Based on the independent risk factors, nomogram was established to exactly predict prognosis of HCC patients. Additionally, the study revealed that a higher total point of the nomogram was closely correlated with poorer prognosis. As a result, 5-HT might contribute to the progression and poor prognosis of hepatocellular carcinoma via regulating YAP/VGLL4 balance. Therefore, the established nomogram based on the independent risk factors may become an important part of HCC prediction system and YAP/VGLL4 balance may be a potential therapeutic target in future.

Pharmacological inhibition of TRPV4 channel suppresses malignant biological behavior of hepatocellular carcinoma via modulation of ERK signaling pathway.

TRPV4 (transient receptor potential vanilloid 4), a member of the TRP superfamily, has been reported to correlate with several different forms of cancers. However, the role of TRPV4 in human hepatocellular carcinoma (HCC) remains unclear. The present study demonstrated that elevated expression of TRPV4 was shown in HCC tumor tissues when compared with paired non-tumoral livers both in protein and mRNA levels. Furthermore, the enhanced expression of TRPV4 was highly associated with histological grade (P = 0.036) and the number of tumors (P = 0.045). Pharmacological inhibition of TRPV4 channels in HCC cells with the specific antagonist HC-067047 suppressed cell proliferation, induced apoptosis and decreased the migration capability by attenuating the epithelial-mesenchymal transition (EMT) process in vitro. The p-ERK expression was apparently repressed after treatment with the TRPV4 antagonist, further blockade of the ERK pathway with U0126 could significantly aggravate HCC cells apoptosis. In NOD-SCID mouse xenograft models, intraperitoneal injection of HC-067047 could obviously suppress tumor growth and induce apoptosis in vivo. Together, our studies showed that the antitumor effects caused by TRPV4 channel inhibition in HCC cell lines might be attributed to the suppression of EMT process and inactivation of p-ERK which induced subsequent cell apoptosis. Thus, pharmacological inhibition of TRPV4 channel may be an option for HCC treatment.

Synergistic effect of nutlin-3 combined with aspirin in hepatocellular carcinoma HepG2 cells through activation of Bcl-2/Bax signaling pathway.

Aspirin as an antitumor drug has been studied in various malignancies with regards to its effects on apoptosis, proliferation, metastasis and senescence of tumor cells. However, the clinical application is limited by its side effects. Nutlin­3 is a novel antitumor compound, which has not been clinically approved. The present study investigated the value of combining aspirin and nutlin­3 on hepatocellular carcinoma (HCC) cells. MTT was performed to detect the proliferation of HepG2 cells treated with aspirin or/and nutlin­3. Transwell invasion assays were performed to estimate the invasion ability of HepG2 cells treated with aspirin or/and nutlin­3. Then the apoptotic analysis of HepG2 cells evaluated the synergistic effect of aspirin and nutlin­3. Apoptosis markers, including B­cell lymphoma 2 (Bcl­2), Bcl­2­associated X protein (Bax), caspase­3, caspase­8 and caspase­9 were estimated by western blot analysis at various time points. In addition, a Xenograft mouse model was established by infection with HepG2 cells, and aspirin and/or nutlin­3 was administrated to verify the anti­apoptotic effect of the two drugs in vivo. A high dose of aspirin and nutlin­3 inhibit the proliferation and apoptosis of HepG2 cells. The antitumor effect was enhanced with the combined treatment of the two drugs, particularly in the group with a low concentration of aspirin and nutlin­3. Nutlin­3 was able to increase the level of Bax in HepG2 cells treated with aspirin significantly after treatment for 8 h. When treated with a low concentration of aspirin and nutlin­3, the level of Bax in HepG2 cells was enhanced for 2 h. In the animal model, tumor volume and tumor angiogenesis were significantly decreased in combination group compared with other groups (P<0.01). Although there were side effects in the group treated with aspirin alone, no side effects were observed in the combination group. Nutlin­3 enhanced the apoptotic effect of a low dose of aspirin by upregulating Bax expression in the HepG2 cell line and in vivo. The synergistic effect of nutlin­3 in aspirin antitumor therapy contributed to diminishing the dose of aspirin required and decreased the occurrence of adverse drug events in HCC through targeting the Bcl­2/Bax signaling pathway.

5-HT Drives Mortality in Sepsis Induced by Cecal Ligation and Puncture in Mice.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality. 5-Hydroxytryptamine (5-HT) is an important regulatory factor in inflammation. The aim of this study is to investigate the role of 5-HT on cecal ligation and puncture- (CLP-) induced sepsis in the mouse model. CLP was performed on C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout (KO) mice. The results showed that the 5-HT-sufficient group mice had a significantly lower survival rate than the 5-HT-deficient group in CLP-induced sepsis and septic shock. The KO-CLP sepsis group received a lower clinical score than the WT-CLP sepsis group. Meanwhile, the body temperature of mice in the KO-CLP sepsis group was higher than that in the WT-CLP sepsis group and was much closer to the normal body temperature 24 hours after CLP. The tissue histopathology analysis revealed that 5-HT markedly exacerbated histological damages in the peritoneum, lung, liver, kidney, intestinal tissue, and heart in sepsis. Moreover, significant lower levels of TNF-α, IL-6, bacterial loads, MPO, and ROS were discovered in the KO-CLP sepsis group in contrast to the WT-CLP sepsis group. In conclusion, 5-HT drives mortality and exacerbates organ dysfunction by promoting serum cytokines and bacterial loads as well as facilitating oxidative stress in the process of sepsis.

Effects and related mechanisms of serotonin on malignant biological behavior of hepatocellular carcinoma via regulation of Yap.

5-hydroxytryptamine (5-HT, serotonin) and Yes-associated protein (Yap), which act as a mitogen and an oncogene, respectively, play an important role in tumors. Here, we investigated whether 5-HT could affect the hepatocarcinogenic process via promoting the activation and expression of Yap, as well as the possible underlying molecular mechanisms. We found that 5-HT promoted hepatoma cell proliferation, invasion and metastasis via regulating Yap expression in vitro and in vivo, and Yap knockdown had opposite effects. Furthermore, 5-HT activated 5-HT2BR to promote Yap expression via upregulating the pERK level. Inhibitors of 5-HT2BR and ERK attenuated the overexpression of Yap and promotional effects of 5-HT in vitro and in vivo. As a result, 5-HT affected the malignant biological behavior of hepatoma cells via the 5-HT-5-HT2BR-pERK-Yap axis. Therefore, 5-HT and Yap may be prognostic predictors and potential therapeutic targets for HCC patients in the future.

Circulating miRNA-21-5p as a diagnostic biomarker for pancreatic cancer: evidence from comprehensive miRNA expression profiling analysis and clinical validation.

Pancreatic cancer (PC) is a highly fatal disease worldwide and is often misdiagnosed in its early stages. The exploration of novel non-invasive biomarkers will definitely benefit PC patients. Recently, circulating miRNAs in body fluids are emerging as non-invasive biomarkers for PC diagnosis. In this study, we first conducted comprehensive robust rank aggregation (RRA) analysis based on 21 published miRome profiling studies. We statistically identified and clinically validated a miRNA expression pattern in PC patients. These miRNAs consisted of four up-regulated (hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-210-3p and hsa-miR-155-5p) and three down-regulated miRNAs (hsa-miR-217, hsa-miR-148a-3p and hsa-miR-375). Among them, hsa-miR-21-5p was one of the most highly expressed miRNAs in the serum of PC patients. Our validation test further suggested a relatively high accuracy of serum hsa-miR-21-5p levels in the diagnosis of PC, with a sensitivity of 0.77 and a specificity of 0.80. Finally, a diagnostic meta-analysis based on 9 studies also revealed favorable sensitivity and specificity of circulating hsa-miR-21-5p for the diagnosis of PC (pooled sensitivity and specificity were 0.76 and 0.74, respectively), which was consistent with our findings. Taken together, as one of the most aberrantly expressed miRNAs in PC, circulating hsa-miR-21-5p might be a promising serum biomarker in patients with PC.

Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis.

MicroRNAs play an important role in liver cancer genesis and progression. In this study, we identified down-regulation of miR-146b-5p associated with tumor growth, metastasis and poor survival in hepatocellular carcinoma (HCC) patients. miR-146b-5p could suppress proliferation, migration, and invasion and induced apoptosis in vitro and in vivo. Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC. In general, our results indicate that miR-146b-5p inhibits tumor growth and metastasis of HCC by targeting TRAF6 mediated Akt phosphorylation.