Lysine acetyltransferase 14 mediates TGF-ß-induced fibrosis in ovarian endometrioma via co-operation with serum response factor.

BACKGROUND: Fibrogenesis within ovarian endometrioma (endometrioma), mainly induced by transforming growth factor-ß (TGF-ß), is characterized by myofibroblast over-activation and excessive extracellular matrix (ECM) deposition, contributing to endometrioma-associated symptoms such as infertility by impairing ovarian reserve and oocyte quality. However, the precise molecular mechanisms that underpin the endometrioma- associated fibrosis progression induced by TGF-ß remain poorly understood. METHODS: The expression level of lysine acetyltransferase 14 (KAT14) was validated in endometrium biopsies from patients with endometrioma and healthy controls, and the transcription level of KAT14 was further confirmed by analyzing a published single-cell transcriptome (scRNA-seq) dataset of endometriosis. We used overexpression, knockout, and knockdown approaches in immortalized human endometrial stromal cells (HESCs) or human primary ectopic endometrial stromal cells (EcESCs) to determine the role of KAT14 in TGF-ß-induced fibrosis. Furthermore, an adeno-associated virus (AAV) carrying KAT14-shRNA was used in an endometriosis mice model to assess the role of KAT14 in vivo. RESULTS: KAT14 was upregulated in ectopic lesions from endometrioma patients and predominantly expressed in activated fibroblasts. In vitro studies showed that KAT14 overexpression significantly promoted a TGF-ß-induced profibrotic response in endometrial stromal cells, while KAT14 silencing showed adverse effects that could be rescued by KAT14 re-enhancement. In vivo, Kat14 knockdown ameliorated fibrosis in the ectopic lesions of the endometriosis mouse model. Mechanistically, we showed that KAT14 directly interacted with serum response factor (SRF) to promote the expression of α-smooth muscle actin (α-SMA) by increasing histone H4 acetylation at promoter regions; this is necessary for TGF-ß-induced ECM production and myofibroblast differentiation. In addition, the knockdown or pharmacological inhibition of SRF significantly attenuated KAT14-mediating profibrotic effects under TGF-ß treatment. Notably, the KAT14/SRF complex was abundant in endometrioma samples and positively correlated with α-SMA expression, further supporting the key role of KAT14/SRF complex in the progression of endometrioma-associated fibrogenesis. CONCLUSION: Our results shed light on KAT14 as a key effector of TGF-ß-induced ECM production and myofibroblast differentiation in EcESCs by promoting histone H4 acetylation via co-operating with SRF, representing a potential therapeutic target for endometrioma-associated fibrosis.

Association of blood cadmium levels and all-cause mortality among adults with rheumatoid arthritis: The NHANES cohort study.

BACKGROUND: The potential impact of environmental cadmium exposure on the prognosis of patients with rheumatoid arthritis (RA) remains unclear, despite its known association with various adverse health outcomes. METHODS: In this study, a total of 1285 RA patients were included in the National Health and Nutrition Examination Survey (NHANES) conducted between 2003 and 2016. The Cox regression model was employed to investigate the relationship between blood cadmium levels and the risk of all-cause mortality in RA patients. RESULTS: During a mean follow-up duration of 105.9 months, 341 patient deaths were recorded. After adjusting for multiple factors, elevated blood cadmium was strongly correlated with an increased risk of all-cause mortality in patients with RA. With one unit rise in natural logarithm-transformed blood cadmium concentrations, the risk of patient death increased by 107%. The adjusted hazard ratios for each quartile of blood cadmium demonstrated a significant upward trend (P < 0.001). A linear dose-response relationship of blood cadmium concentrations with all-cause mortality was also distinctive (P < 0.001). Consistent findings were ascertained when conducting stratified analyses by age, gender, race, education level, body mass index, smoking status, and drinking status. CONCLUSIONS: Elevated blood cadmium levels may serve as a risk factor for increased death risk in RA patients.

Histone acetyltransferase CSRP2BP promotes the epithelial-mesenchymal transition and metastasis of cervical cancer cells by activating N-cadherin.

BACKGROUND: Dysregulated epithelial-mesenchymal transition (EMT) is involved in cervical cancer metastasis and associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. METHODS: We systematically investigated the expression patterns of histone acetylation genes and their correlations with the EMT pathway in cervical cancer. The expression of CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effects of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were examined by cell growth curve, EdU assay, flow cytometry and xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effects of CSRP2BP on cell invasion and metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays were used to uncover the molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and metastasis. RESULTS: We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effects. In addition, CSRP2BP promoted resistance to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, cooperated with the transcription factor SMAD4 to bind to the SEB2 sequence in the N-cadherin gene promotor and upregulated N-cadherin transcription. Consequently, CSRP2BP promoted cervical cancer cell EMT and metastasis through activating N-cadherin. CONCLUSIONS: This study demonstrates that the histone acetyltransferase CSRP2BP promotes cervical cancer metastasis partially through increasing the EMT and suggests that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.

Age-based factors modulating the required thyroxine dose to achieve thyrotropin suppression in intermediate-and high-risk papillary thyroid cancer.

Background: Guidelines widely recommend thyrotropin suppression to reduce the risk of recurrence in intermediate- and high-risk papillary thyroid cancer (PTC) after total thyroidectomy. However, an insufficient or excessive dosage may result in a number of symptoms/complications especially in older patients. Patients and methods: We constructed a retrospective cohort including 551 PTC patient encounters. Using propensity score matching and logistic regression models, we determined the independent risk factors affecting levothyroxine therapy at different ages. Our outcomes included: expected TSH level and an unexpected TSH level, which was based on the initial thyroid-stimulating hormone (TSH) goal< 0.1 mIU/L with usual dosage of L-T4 (1.6 µg/kg/day). Results: From our analysis, more than 70% of patients undergoing total thyroidectomy did not achieve the expected TSH level using an empirical medication regimen, and the effect of the drug was affected by age (odds ratio [OR], 1.063; 95% CI, 1.032-1.094), preoperative TSH level (OR, 0.554; 95% CI, 0.436-0.704) and preoperative fT3 level (OR, 0.820; 95% CI, 0.727-0.925). In patients with age < 55 years old, preoperative TSH level (OR, 0.588; 95% CI, 0.459-0.753), and preoperative fT3 level (OR, 0.859; 95% CI, 0.746-0.990) were two independent protective factors, while, in patients with age ≥ 55 years old, only preoperative TSH level (OR, 0.490; 95% CI, 0.278-0.861) was the independent protective factors to achieve expected TSH level. Conclusion: Our retrospective analysis suggested the following significant risk factors of getting TSH suppression in PTC patients: age (≥55 years), lower preoperative TSH and fT3 levels.

Radiosensitization of Nasopharyngeal Carcinoma by Graphene Oxide Nanosheets to Reduce Bcl-2 Level.

There are many treatments for nasopharyngeal carcinoma (NPC), but none of them are very effective. Radiotherapy is used extensively in NPC treatment, but radioresistance is a major problem. Graphene oxide (GO) has been previously studied in cancer treatment, and this study is aimed to explore its role in radiosensitization of NPC. Therefore, graphene oxide nanosheets were prepared, and the relationship between GO and radioresistance was explored. The GO nanosheets were synthesized by a modified Hummers' method. The morphologies of the GO nanosheets were characterized by field-emission environmental scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The morphological changes and radiosensitivity of C666-1 and HK-1 cells with or without the GO nanosheets were observed by an inverted fluorescence microscopy and laser scanning confocal microscopy (LSCM). Colony formation assay and Western Blot were applied for analysis of NPC radiosensitivity. The as-synthesized GO nanosheets have lateral dimensions (sizes ∼1 µm) and exhibit a thin wrinkled two-dimensional lamellar structure with slight folds and crimped edges (thickness values ∼1 nm). C666-1 cells with the GO was significantly changed the morphology of cells postirradiation. The full field of view visualized by a microscope showed the shadow of dead cells or cell debris. The synthesized graphene oxide nanosheets inhibited cell proliferation, promoted cell apoptosis, and inhibited the expression of Bcl-2 in C666-1 and HK-1 cells but increased the level of Bax. The GO nanosheets could affect the cell apoptosis and reduce the pro-survival protein Bcl-2 related to the intrinsic mitochondrial pathway. The GO nanosheets could enhance radiosensitivity, which might be a radioactive material in NPC cells.

Nuclear m6 A reader YTHDC1 suppresses proximal alternative polyadenylation sites by interfering with the 3' processing machinery.

N6-methyladenosine (m6 A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m6 A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here, we show that YTHDC1, a nuclear m6 A reader, can suppress proximal APA sites and produce longer 3' UTR transcripts by binding to their upstream m6 A sites. YTHDC1 can directly interact with the 3' end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m6 A sites can promote liquid-liquid phase separation of YTHDC1 and FIP1L1, which may play an important role in their interaction and APA regulation. Collectively, YTHDC1 as an m6 A "reader" links m6 A modification with pre-mRNA 3' end processing, providing a new mechanism for APA regulation.

Association of Ozone Exposures with the risk of thyroid nodules in Hunan Province: a population-based cohort study.

BACKGROUND: Increasing evidence associates air pollution with thyroid dysfunction, whereas the potential relationship between exposure to ozone (O3) and Thyroid Nodules (TNs) is unclear. METHODS: This retrospective cohort study investigated the association between O3 exposure and TNs in Hunan province, enrolling 191,357 Chinese adults who lived in Hunan province from January 2009 to December 2019 and received voluntary medical examinations. Individual exposure levels to O3 from 2010 to 2019 were measured on account of participants' residential addresses at the district level. Associations of O3 exposure with the risk of incidental TNs were assessed by restricted cubic splines and surveyed as odds ratios after adjusting for demographic factors. RESULTS: In total, 81,900 adults were newly diagnosed with TNs during the study period. Age-standardized TNs detection rate in Hunan province increased from 25.9 to 46.3% between 2010 and 2019, with the greatest annual percent change being 8.1 [95% CI, 7.3-8.8]. A similar trend has been found in all tumor sizes, ages, and both sexes. O3 exposure presented a statistically significant dose-dependent positive correlation (greater than 0.036 ppm) with TNs. Similarly, long-term exposure to high levels of O3 (1-year average O3 concentrations exceeding 0.0417 ppm) was found positively associated with increased TSH levels. CONCLUSIONS: High-level O3 exposure in the long term was associated with an increase in TSH. Consequently, increased TSH was related to the increased risk of TNs. Being exposed to high-level O3 in the long term was related to the increased detection rates of TNs in Hunan province, which could be mediated by TSH.

A Prognostic Model of Differentiated Thyroid Cancer Based on Up-Regulated Glycolysis-Related Genes.

Objective: This study aims to identify reliable prognostic biomarkers for differentiated thyroid cancer (DTC) based on glycolysis-related genes (GRGs), and to construct a glycolysis-related gene model for predicting the prognosis of DTC patients. Methods: We retrospectively analyzed the transcriptomic profiles and clinical parameters of 838 thyroid cancer patients from 6 public datasets. Single factor Cox proportional risk regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) were applied to screen genes related to prognosis based on 2528 GRGs. Then, an optimal prognostic model was developed as well as evaluated by Kaplan-Meier and ROC curves. In addition, the underlying molecular mechanisms in different risk subgroups were also explored via The Cancer Genome Atlas (TCGA) Pan-Cancer study. Results: The glycolysis risk score (GRS) outperformed conventional clinicopathological features for recurrence-free survival prediction. The GRS model identified four candidate genes (ADM, MKI67, CD44 and TYMS), and an accurate predictive model of relapse in DTC patients was established that was highly correlated with prognosis (AUC of 0.767). In vitro assays revealed that high expression of those genes increased DTC cancer cell viability and invasion. Functional enrichment analysis indicated that these signature GRGs are involved in remodelling the tumour microenvironment, which has been demonstrated in pan-cancers. Finally, we generated an integrated decision tree and nomogram based on the GRS model and clinicopathological features to optimize risk stratification (AUC of the composite model was 0.815). Conclusions: The GRG signature-based predictive model may help clinicians provide a prognosis for DTC patients with a high risk of recurrence after surgery and provide further personalized treatment to decrease the chance of relapse.

Methylation-Driven Gene PLAU as a Potential Prognostic Marker for Differential Thyroid Carcinoma.

Purpose: Aberrant DNA methylation plays a crucial role in the tumorigenesis of differentiated thyroid cancer (DTC); nevertheless, the factors leading to the local and regional recurrence of DTC are not well understood. This study aimed to establish the connection between DNA methylation-driven genes and the recurrence of DTC. Methods: RNA sequencing profiles and DNA methylation profiles of DTC were downloaded from The Cancer Genome Atlas (TCGA) database. Combined application of the methylmix R package and univariate Cox regression analyses were used to screen and distinguish prognosis-related methylation-driven genes. Multivariate Cox regression analyses were utilized to identify the target genes that were closely associated with the recurrence of DTC. Then, correlations between the expression levels of the target genes and the clinicopathological features were verified, as well as their potential biological functions. Results: A total of 168 Methylation-driven genes were differentially expressed in thyroid cancer, among which 10 genes (GSTO2, GSTM5, GSTM1, GPX7, FGF2, LIF, PLAU, BCL10, SHARPIN and TNFRSF1A) were identified as Hub genes. We selected PLAU for further analysis because PLAU was most strongly correlated with DTC recurrence and the DNA methylation levels of PLAU were closely associated with multiple clinicopathological features of DTC. PLAU was significantly upregulated in DTC, and patients with a high expression level of PLAU had a higher risk of recurrence (p < 0.05). Functional predictions suggested that PLAU-related genes were mainly involved in the regulation of immune-related signaling pathways. Moreover, the mRNA level of PLAU was found to be positively correlated with the cell markers of neutrophils and dendritic cells. In addition, we found that two DNA methylation sites (cg06829584, cg19399285) were associated with abnormal expression of PLAU in DTC. Conclusion: The methylation-driven gene PLAU is an independent risk factor for the recurrence of DTC and it functions as an oncogene through the regulation of immune-related signaling pathways, which offers new insight into the molecular mechanisms of thyroid cancer and provides new possibilities for individualized treatment of thyroid cancer patients.

Down-regulating GRP78 reverses pirarubicin resistance of triple negative breast cancer by miR-495-3p mimics and involves the p-AKT/mTOR pathway.

Due to the lack of known therapeutic targets for triple-negative breast cancer (TNBC), chemotherapy is the only available pharmacological treatment. Pirarubicin (tetrahydropyranyl Adriamycin, THP) is the most commonly used anthracycline chemotherapy agent. However, TNBC has a high recurrence rate after chemotherapy, and the mechanisms of chemoresistance and recurrence are not entirely understood. To study the chemoresistance mechanisms, we first screened compounds on a pirarubicin-resistant cell line (MDA-MB-231R) derived from MDA-MB-231. The drug resistance index of MDA-MB-231R cells was approximately five times higher than that of MDA-MB-231 cells. MDA-MB-231R cells have higher GRP78 and lower miR-495-3p expression levels than MDA-MB-231 cells. Transfecting MDA-MB-231R cells with a siGRP78 plasmid reduced GRP78 expression, which restored pirarubicin sensitivity. Besides, transfecting MDA-MB-231R cells with miR-495-3p mimics increased miR-495-3p expression, which also reversed pirarubicin chemoresistance. Cell counting kit-8 (CCK-8), EdU, wound healing, and Transwell assays showed that the miR-495-3p mimics also inhibited cell proliferation and migration. Based on our results, miR-495-3p mimics could down-regulate GRP78 expression via the p-AKT/mTOR signaling pathway in TNBC cells. Remarkably, chemo-resistant and chemo-sensitive TNBC tissues had opposite trends in GRP78 and miR-495-3p expressions. The lower the GRP78 and the higher the miR-495-3p expression, the better prognosis in TNBC patients. Therefore, the mechanism of pirarubicin resistance might involve the miR-495-3p/GRP78/Akt axis, which would provide a possible strategy for treating TNBC.

Comprehensive Analysis of Prognostic Alternative Splicing Signature Reveals Recurrence Predictor for Papillary Thyroid Cancer.

BACKGROUND: Alternative splicing (AS) plays a key role in the diversity of proteins and is closely associated with tumorigenicity. The aim of this study was to systemically analyze RNA alternative splicing (AS) and identify its prognostic value for papillary thyroid cancer (PTC). METHODS: AS percent-splice-in (PSI) data of 430 patients with PTC were downloaded from the TCGA SpliceSeq database. We successfully identified recurrence-free survival (RFS)-associated AS events through univariate Cox regression, LASSO regression and multivariate regression and then constructed different types of prognostic prediction models. Gene function enrichment analysis revealed the relevant signaling pathways involved in RFS-related AS events. Simultaneously, a regulatory network diagram of AS and splicing factors (SFs) was established. RESULTS: We identified 1397 RFS-related AS events which could be used as the potential prognostic biomarkers for PTC. Based on these RFS-related AS events, we constructed a ten-AS event prognostic prediction signature that could distinguish high-and low-risk patients and was highly capable of predicting PTC patient prognosis. ROC curve analysis revealed the excellent predictive ability of the ten-AS events model, with an area under the curve (AUC) value of 0.889; the highest prediction intensity for one-year RFS was 0.923, indicating that the model could be used as a prognostic biomarker for PTC. In addition, the nomogram constructed by the risk score of the ten-AS model also showed high predictive efficiency for the prognosis of PTC patients. Finally, the constructed SF-AS network diagram revealed the regulatory role of SFs in PTC. CONCLUSION: Through the limited analysis, AS events could be regarded as reliable prognostic biomarkers for PTC. The splicing correlation network also provided new insight into the potential molecular mechanisms of PTC.

Effects of marital status on survival of medullary thyroid cancer stratified by age.

PURPOSE: Marital status has emerged as an important influence on several cancer outcomes, but its role in medullary thyroid cancer (MTC) remains unclear. This study was to explore the effects of marital status on the prognosis of MTC patients and to determine whether its effects vary by age. PATIENTS AND METHODS: We retrospectively extracted 1344 eligible patients diagnosed with MTC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Based on the marital status, we divided those patients into married and unmarried groups. We compared the difference in overall survival (OS) and cancer-specific survival (CSS) between married and unmarried via the Kaplan-Meier analysis. Univariate and multivariate Cox proportional models were performed to identify the prognostic factors of OS and CSS. RESULTS: There were 1344 MTC eligible patients in a total of which 883 (65.7%) were married and 461 (34.3%) were unmarried. The comparison observed between married and unmarried patients was as follows: male (45.2% vs. 28.0%), age (≥52 years) (55.9% vs. 44.6%), White (86.7% vs. 78.7%), and undergo surgery (97.7% vs. 93.3%). Multivariate analysis revealed unmarried status as a risk factor independently associated with worse OS (HR: 2.15, 95% CI: 1.59-2.92) rate and CSS (HR: 1.70, 95% CI: 1.17-2.47) rate. In a further analysis stratified by age, there was no significant difference in OS and CSS between married and unmarried patients younger than 52 years. For the remaining group with 52 years old and higher, unmarried patients showed significantly higher risk of OS and CSS than married patients at all stages of the pathology except M1 stage. CONCLUSION: Married patients with MTC have a better prognosis than unmarried ones. Age can affect the association between marital status and the survival of MTC, and married elders may benefit more than youngers.

A Prediction Model for Contralateral Central Neck Lymph Node Metastases in Unilateral Papillary Thyroid Cancer.

The health problems caused by the frequent relapse of papillary thyroid carcinoma (PTC) remain a worldwide concern since the morbidity rate of PTC ranks the highest among thyroid cancers. Residues from contralateral central lymph node metastases (con-CLNM) are the key reason for persistence or recurrence of unilateral papillary thyroid carcinoma (uni-PTC); however, the ability to assess the status of con-CLNM in uni-PTC patients is limited. To clarify the risk factors of con-CLNM, a total of 250 patients with uni-PTC who underwent total thyroidectomy and bilateral central lymph node dissection were recruited in this study. We compared the clinical, sonographic, and pathological characteristics of patients with con-CLNM to those without con-CLNM and established a nomogram for con-CLNM in uni-PTC. We found that male sex, without Hashimoto's thyroiditis, present capsular invasion, with ipsilateral lateral lymph node metastases, and the ratio of ipsilateral central lymph node metastases ≥0.16 were independent con-CLNM predictors of uni-PTC (ORs: 2.797, 0.430, 2.538, 2.202, and 26.588; 95% CIs: 1.182-6.617, 0.211-0.876, 1.223-5.267, 1.064-4.557, and 7.596-93.069, respectively). Additionally, a preoperative nomogram for the prediction of con-CLNM based on these risk factors showed good discrimination (C-index 0.881; 95% CI: 0.840-0.923; sensitivity 85.3%; specificity 76.0%) and good agreement via the calibration plot. Our study provided a way to quantitatively and accurately predict whether con-CLNM occurred in patients with uni-PTC, which may guide surgeons to evaluate the nodal status and perform tailored therapeutic central lymph node dissection.

ELABELA alleviates syncytiotrophoblast hypoxia/reoxygenation injury and preeclampsia-like symptoms in mice by reducing apoptosis.

INTRODUCTION: Preeclampsia (PE) is associated with increased syncytiotrophoblast apoptosis. ELABELA (ELA) is a circulating hormone secreted by the placenta. Here, we investigated the involvement of ELA in the pathogenesis of PE. METHODS: We measured ELA expression in the placental villi of patients with severe PE and healthy controls. A cellular model of hypoxia and reoxygenation was used to simulate PE hypoxia, and changes in the proliferation and apoptosis of trophoblasts in response to different ELA concentrations were measured. In addition, we used NG-nitro-l-arginine methyl ester (l-NAME) to generate a mouse model of pregnancy-induced hypertension and explore whether ELA can improve the symptoms of PE. RESULTS: ELA expression was decreased in severe PE. ELA promoted the proliferation of BeWo cells and improved the decreased cell proliferation rate after hypoxia/reoxygenation injury. ELA reversed the phenotypes of l-NAME-induced PE mice and regulated the expression of mouse placental apoptosis factors. DISCUSSION: ELA reduced apoptosis in BeWo cells and improved PE-like symptoms in mice, suggesting its value as a potential novel treatment for PE.

Phylotranscriptomic insights into Asteraceae diversity, polyploidy, and morphological innovation.

Biodiversity is not evenly distributed among related groups, raising questions about the factors contributing to such disparities. The sunflower family (Asteraceae, >26,000 species) is among the largest and most diverse plant families, but its species diversity is concentrated in a few subfamilies, providing an opportunity to study the factors affecting biodiversity. Phylotranscriptomic analyses here of 244 transcriptomes and genomes produced a phylogeny with strong support for the monophyly of Asteraceae and the monophyly of most subfamilies and tribes. This phylogeny provides a reference for detecting changes in diversification rates and possible factors affecting Asteraceae diversity, which include global climate shifts, whole-genome duplications (WGDs), and morphological evolution. The origin of Asteraceae was estimated at ~83 Mya, with most subfamilies having diverged before the Cretaceous-Paleocene boundary. Phylotranscriptomic analyses supported the existence of 41 WGDs in Asteraceae. Changes to herbaceousness and capitulescence with multiple flower-like capitula, often with distinct florets and scaly pappus/receptacular bracts, are associated with multiple upshifts in diversification rate. WGDs might have contributed to the survival of early Asteraceae by providing new genetic materials to support morphological transitions. The resulting competitive advantage for adapting to different niches would have increased biodiversity in Asteraceae.

Kinase gene fusions: roles and therapeutic value in progressive and refractory papillary thyroid cancer.

The incidence of papillary thyroid cancer (PTC), the major type of thyroid cancer, is increasing rapidly around the world, and its pathogenesis is still unclear. There is poor prognosis for PTC involved in rapidly progressive tumors and resistance to radioiodine therapy. Kinase gene fusions have been discovered to be present in a wide variety of malignant tumors, and an increasing number of novel types have been detected in PTC, especially progressive tumors. As a tumor-driving event, kinase fusions are constitutively activated or overexpress their kinase function, conferring oncogenic potential, and their frequency is second only to BRAFV600E mutation in PTC. Diverse forms of kinase fusions have been observed and are associated with specific pathological features of PTC (usually at an advanced stage), and clinical trials of therapeutic strategies targeting kinase gene fusions are feasible for radioiodine-resistant PTC. This review summarizes the roles of kinase gene fusions in PTC and the value of clinical therapy of targeting fusions in progressive or refractory PTC, and discusses the future perspectives and challenges related to kinase gene fusions in PTC patients.

Predictive Factors for Level V Lymph Node Metastases in Papillary Thyroid Carcinoma with BRAFV600E Mutation and Clinicopathological Features.

BACKGROUND: Therapeutic lateral neck dissection (LND) is recommended in papillary thyroid carcinoma (PTC) patients with clinically lateral lymph node metastasis (LLNM), whether underwent level V LND remains controversial for lacking of sensitive predicting system. BRAFV600E mutation is associated with aggressive tumor behavior, recurrence, and disease-specific mortality of PTC. However, the relationship between BRAFV600E mutation and level V LNM is unclear. METHODS: Univariate and multivariate analyses were retrospectively conducted on the potential predictive factors of 252 PTC patients who underwent initial treatment of neck lymph node dissection from September 2015 to October 2018 in our institute. BRAFV600E mutation and the clinicopathological characteristics of the two groups were compared. RESULTS: LLNM was presented in 208 (82.5%) patients and level II-V LNM was present in 42.8%, 71.2%, 85.1%, 17.8% patients, respectively. BRAFV600E mutation was observed in 188 (74.6%) patients and was significantly associated with patients' age, lymphocytic thyroiditis, capsule invasion, bilateral central lymph node metastasis (CLNM) and level V LNM in PTC. Univariate analysis revealed that lymphocytic thyroiditis, tumor size, number of CLNM, Level II LNM, Level III LNM, simultaneous Level II+III, simultaneous Level III+IV and simultaneous Level II+III+IV were significantly correlated with Level V LNM. In addition, multivariate analysis revealed that tumor size ≥2.5 cm, number of CLNM≥3, level II metastases and BRAFV600E mutation were independent Level V LNM predictors (odds ratio 3.910, 3.660, 8.410, 0.439; 95% CI 1.737-10.135, 1.054-12.713, 1.233-57.355, 0.280-0.827, respectively). CONCLUSION: In summary, we presented several independent predictive factors for level V LNM in PTC patients. We constructed a risk prediction model consisting of tumor size ≥2.5 cm, number of CLNM≥3 and level II metastases and BRAFV600E mutation that may guide surgeons to evaluate the nodal status in PTC and perform tailored therapeutic LND.

Epidemiology and Outcome Analysis of 470 Patients with Hand Burns: A Five-Year Retrospective Study in a Major Burn Center in Southwest China.

BACKGROUND This retrospective study aimed to investigate the epidemiology of burns to the hand, including the causes, demographic data, management, and outcome in a single center in Southwest China between 2012 and 2017. MATERIAL AND METHODS A retrospective study included 470 patients with hand burns who were treated at a single hospital in Southwest China between 2012 and 2017. Demographic, injury-related, and clinical data were obtained from the clinical electronic data collection system. RESULTS In 470 patients, men were more commonly admitted to hospital with hand burns (73.62%). Children under 10 years (29.57%) were the main patient group. Hospital admissions occurred in the coldest months, from December to March (55.11%). In 60.21% of cases, hand burns occurred outside the workplace. Fire (40.42%), electricity (30.85%), and hot liquids (20.21%) were the main causes of hand burns. Data from 428 patients showed that burns with a larger total body surface area and deeper burns were associated with surgery and amputation. Burn depth was a risk factor for skin grafting, and lack of burn cooling before hospital admission increased the risk of amputation. Data from 117 patients with localized burns showed that full-thickness burns and lack of cooling before admission were associated with an increased hospital stay. CONCLUSIONS The findings suggest that in Southwest China, prevention programs for children aged 0-9 years, injuries occurring in winter and non-workplace sites, and fire burns were imperative.

Preoperative Sonographic and Clinicopathological Predictors for Solitary Lateral Neck Node Metastasis in Papillary Thyroid Carcinoma: A Retrospective Study.

BACKGROUND: Cervical lymph node metastasis (LNM) is an independent risk factor for poor prognosis of papillary thyroid carcinoma (PTC), but the scope of PTC lateral neck dissection (LND) is controversial. Solitary lateral lymph node metastasis (SLNM) is a special type of PTC with lateral LNM. Currently, study on the preoperative clinical characteristics of SLNM has been seldomly reported. This study evaluated the preoperative characteristics for predicting the SLNM of PTC. METHODS: We included 391 patients diagnosed with PTC between May 2011 and July 2017. Among those patients, 44 had SLNM and 347 had multiple lateral neck node metastasis (MLNM). The clinicopathologic characteristics and other central lymph node metastasis risk factors were retrospectively analyzed. RESULTS: Univariate analysis revealed that age and tumor size (≤1 cm) were significantly correlated with SLNM. In ROC curve analysis, the optimal cutoff age of preoperative predictors for the prediction of SLNM was 46.5 years (AUC=0.623, 0.536-0.710). Besides, the frequency and mean number of CLNM was significantly less in the SLNM than MLNM group. The oval and round tumor shape and well-defined margin of the tumor were more common in the SLNM group (p =0.001; p=0.024, respectively). In addition, multivariate analysis revealed that age ≥47, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape were independent SLNM predictors of PTCs (odds ratio 2.386, 0.173, 0.284, 0.239, 0.188; 95% CI 1.07-5.140, 0.058-0.840, 0.066-0.926, 0.091-0.437, 0.167-0.864, respectively). CONCLUSION: This study supported that SLNM is more likely to happen in PTC patients with age ≥47 years, capsular invasion, no extrathyroidal extension, with central lymph node metastases and irregular shape. That denotes, selective single level neck dissection can be considered as an alternative to systemic lateral neck dissection in those patients.

Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.

OBJECTIVE: Pre-eclampsia (PE) is one of the malignant metabolic diseases that complicate pregnancy. Gut dysbiosis has been identified for causing metabolic diseases, but the role of gut microbiome in the pathogenesis of PE remains unknown. DESIGN: We performed a case-control study to compare the faecal microbiome of PE and normotensive pregnant women by 16S ribosomal RNA (rRNA) sequencing. To address the causative relationship between gut dysbiosis and PE, we used faecal microbiota transplantation (FMT) in an antibiotic-treated mouse model. Finally, we determined the microbiome translocation and immune responses in human and mouse placental samples by 16S rRNA sequencing, quantitative PCR and in situ hybridisation. RESULTS: Patients with PE showed reduced bacterial diversity with obvious dysbiosis. Opportunistic pathogens, particularly Fusobacterium and Veillonella, were enriched, whereas beneficial bacteria, including Faecalibacterium and Akkermansia, were markedly depleted in the PE group. The abundances of these discriminative bacteria were correlated with blood pressure (BP), proteinuria, aminotransferase and creatinine levels. On successful colonisation, the gut microbiome from patients with PE triggered a dramatic, increased pregestational BP of recipient mice, which further increased after gestation. In addition, the PE-transplanted group showed increased proteinuria, embryonic resorption and lower fetal and placental weights. Their T regulatory/helper-17 balance in the small intestine and spleen was disturbed with more severe intestinal leakage. In the placenta of both patients with PE and PE-FMT mice, the total bacteria, Fusobacterium, and inflammatory cytokine levels were significantly increased. CONCLUSIONS: This study suggests that the gut microbiome of patients with PE is dysbiotic and contributes to disease pathogenesis.