Development of a dynamical statistical analog ensemble forecast model for landfalling typhoon disasters.

In this report, the development of a Dynamical Statistical Analog Ensemble Forecast model for landfalling typhoon disasters (LTDs) and some applications over coastal China are described. This model consists of the following four elements: (i) obtaining the forecast track of a target landfalling typhoon, (ii) constructing its generalized initial value (GIV), (iii) identifying its analogs based on the GIV, and (iv) assembling typhoon disasters of the analogs. Typhoon track, intensity, and landfall date are introduced in GIV at this early development stage. The pre-assessment results show that the mean threat scores of two important damage levels of LTDs reach 0.48 and 0.55, respectively. Of significance is that most of the damage occurs near the typhoon centers around the time of landfall. These results indicate the promising performance of the model in capturing the main damage characteristics of typhoon disasters, which would help coastal community mitigate damage from destructive typhoons.

Different types of diabetes mellitus and risk of thyroid cancer: A meta-analysis of cohort studies.

Objective: Sex-specific thyroid cancer risk exists in patients diagnosed with diabetes mellitus (DM). However, thyroid cancer risk in different types of DM is still unclear. This meta-analysis aims to identify the real correlation between different types of DM and thyroid cancer risk in both sexes. Methods: Studies were identified by an electronic search of PubMed, EMBASE, and Cochrane Library on 16 January 2022. A random-effects model was used to estimate the relative risks (RRs). The Cochran's Q and I2 statistics were computed to detect heterogeneity between studies. Results: In comparison with non-DM counterparts, patients with DM had a 1.32-fold higher risk of thyroid cancer (95% CI, 1.22-1.44) with 1.26-fold (95% CI, 1.12-1.41) in men and 1.36-fold (95% CI, 1.22-1.52) in women, respectively. Subgroup analysis by the type of DM showed that the RR of thyroid cancer in patients with type 2 diabetes was 1.34 (95% CI, 1.17-1.53) in the study population with 1.32 (95% CI, 1.12-1.54) in men and 1.37 (95% CI, 1.12-1.68) in women, respectively; the RR of thyroid cancer was 1.30 (95% CI, 1.17-1.43) in patients with gestational diabetes; the risk of thyroid cancer in patients with type 1 diabetes was 1.51-fold in women but not in men. Although there were some heterogeneities, it did not affect the above results of this study. Conclusion: This study indicates that, compared with non-DM individuals, patients with any type of DM have an elevated thyroid cancer risk. This positive correlation between type 2 diabetes and thyroid cancer risk exists in both men and women. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42022304028.

Prognostic Factors for Excellent Response to Initial Therapy in Patients With Papillary Thyroid Cancer From a Prospective Multicenter Study.

Prognostic factors for excellent response (ER) to initial therapy in patients with papillary thyroid cancer (PTC) have not been determined. In this study, we investigated the response to initial therapy in PTC patients and independent prognostic factors for ER in a prospective multicenter study in China. A total of 506 PTC patients from nine centers in China were enrolled in this study, all of whom underwent total or near total thyroidectomy with lymph node dissection and subsequent radioiodine therapy. Univariate and multivariable logistic regression analyses were carried out to determine the independent prognostic factors for ER. The optimal cutoff value of the number of metastatic lymph nodes for predicting ER was determined by the receiver operating characteristic curve. A total of 139 patients (27.5%) achieved ER after initial therapy. Extrathyroidal extension, the number of metastatic lymph nodes, and preablative-stimulated thyroglobulin (Ps-Tg) were independent risk factors for ER for the entire population. In a subgroup analysis, extrathyroidal extension and Ps-Tg were independent risk factors for ER in pathological N1a patients, while the number of metastatic lymph nodes and Ps-Tg were independent risk factors for ER in pathological N1b patients. The appropriate cutoff values of the number of metastatic lymph nodes in predicting ER were 5 and 13 for the entire population and pathological N1b PTC patients, respectively. PTC patients with more metastatic lymph nodes were more likely to fail to achieve ER. Extrathyroidal extension, the number of metastatic lymph nodes, and Ps-Tg were important prognostic factors for ER after initial therapy in PTC patients.

A four-enhancer RNA-based prognostic signature for thyroid cancer.

Enhancer RNAs (eRNAs) can serve as an independent prognostic factor for poor outcomes of cancer patients. The purpose of this study was to identify a vital eRNA signature that has prognostic value for thyroid cancer based on GTEx and TCGA screening. We downloaded gene expression data and clinical data of thyroid cancer included in the GTEx and TCGA databases and conducted data consolidation. eRNA expression data were extracted, and subjected to differential analysis and cluster analysis. Univariate Cox regression was used to screen the prognostic factors of thyroid cancer. Multivariate Cox regression was applied for prognostic risk assessment model construction, with the efficacy evaluated by receiver operating characteristic (ROC) curve. Downstream regulatory genes of candidate eRNAs were determined using correlation analysis. There were 79 differentially expressed eRNAs associated with thyroid cancer. These differentially expressed eRNAs could assign all thyroid cancer samples into three molecular subtypes, which showed a strong link to lymph node metastasis (N stage) of thyroid cancer patients. Additionally, four key eRNAs AC141930.1, NBDY, MEG3 and AP002358.1 closely related to the prognosis of thyroid cancer patients. The risk model based on the four eRNAs predicted the prognosis of thyroid cancer patients effectively. TPO, MGST2, THBS2 and SLC25A47P1 were potential downstream regulators of the four eRNAs involved in the development of thyroid cancer. Collectively, our data suggest that a four-eRNA signature consisting of AC141930.1, NBDY, MEG3 and AP002358.1 can accurately predict the prognosis of thyroid cancer patients.

AUF1 Promotes Proliferation and Invasion of Thyroid Cancer via Downregulation of ZBTB2 and Subsequent TRIM58.

The pathogenesis of papillary thyroid cancer (PTC), the most common type of thyroid cancer, is not yet fully understood. This limits the therapeutic options for approximately 7% of invasive PTC patients. The critical role of AUF1 in the progression of thyroid cancer was first reported in 2009, however, its molecular mechanism remained unclear. Our study used CRISPR/Cas 9 system to knockdown AUF1 in IHH4 and TPC1 cells. We noticed that the expression of TRIM58 and ZBTB2 were increased in the AUF1 knockdown IHH4 and TPC1 cells. When TRIM58 and ZBTB2 were inhibited by small hairpin RNAs (shRNAs) against TRIM58 (shTRIM58) and ZBTB2 (shZBTB2), respectively, the proliferation, migration, and invasion ability of the AUF1-knockdown IHH4 and TPC1 cells were increased. In addition, two ZBTB2 binding sites (-719~-709 and -677~-668) on TRIM58 promoter and two AUF1 binding sites (1250-1256 and 1258-1265) on ZBTB2 3'-UTR were identified. These results suggested that AUF1 affecting thyroid cancer cells via regulating the expression of ZBTB2 and TRIM58.

HYOU1 facilitates proliferation, invasion and glycolysis of papillary thyroid cancer via stabilizing LDHB mRNA.

HYOU1 is upregulated in many kinds of cancer cells, and its high expression is associated with tumour invasiveness and poor prognosis. However, the role of HYOU1 in papillary thyroid cancer (PTC) development and progression remains to be elucidated. Here, we reported that HYOU1 was highly expressed in human PTC and associated with poor prognosis. HYOU1 silencing suppressed the proliferation, migration and invasion of PTC cells. Mechanistic analyses showed that HYOU1 silencing promoted oxidative phosphorylation while inhibited aerobic glycolysis via downregulating LDHB at the posttranscriptional level. We further confirmed that the 3'UTR of LDHB mRNA is the indirect target of HYOU1 silencing and HYOU1 silencing increased miR-375-3p levels. While LDHB overexpression significantly suppressed the inhibitory effects of HYOU1 silencing on aerobic glycolysis, proliferation, migration and invasion in PTC cells. Taken together, our findings suggest that HYOU1 promotes glycolysis and malignant progression in PTC cells via upregulating LDHB expression, providing a potential target for developing novel anticancer agents.

TRIM29 inhibits miR-873-5P biogenesis via CYTOR to upregulate fibronectin 1 and promotes invasion of papillary thyroid cancer cells.

Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence, has a strong propensity for neck lymph node metastasis. Limited treatment options are available for patients with advanced or recurrent metastatic disease, resulting in a poor prognosis. Tripartite motif protein 29 (TRIM29) is dysregulated in various cancer and functions as oncogene or tumor suppressor in discrete cancers. In this study, we found that both TRIM29 and fibronectin 1 (FN1) were upregulated with positive correlation in PTC tissues. Neither overexpression nor downregulation of TRIM29 altered the proliferation of PTC cells significantly. Overexpression of TRIM29 significantly promotes, while knockdown of TRIM29 significantly decreases migration and invasion by regulating FN1 expression in PTC cells. In terms of mechanism, we found that TRIM29 altered the stability of FN1 mRNA via regulation of miR-873-5p expression. The current study also demonstrated that long non-coding RNA (LncRNA) CYTOR suppressed maturation of miR-873-5p via interaction with premiR-873, and TRIM29 decreased miR-873-5p via upregulation of CYTOR. This study suggests that involvement of TRIM29 in migration and invasion in PTC cells may reveal potential metastatic mechanism of PTC and represent a novel therapeutic target and strategy.

BAG5 promotes invasion of papillary thyroid cancer cells via upregulation of fibronectin 1 at the translational level.

Papillary thyroid cancer (PTC), the most common thyroid malignancy, has a strong propensity for neck lymph node metastasis, which will increase the risk of local recurrence and decrease the survival in some high-risk groups. Hence, it is essential to set up a reliable biomarker to predict lymph node metastasis. BAG5 is a unique member of the BAG cochaperone family because it consists of more than one BAG domain, which acts as modulator of chaperone activity. In this study, we found that expression of BAG5 was significantly increased in PTC cells and tissues. Neither overexpression nor downregulation of BAG5 altered the proliferation of PTC cells. On the contrary, overexpression of BAG5 significantly promoted, while knockdown of BAG5 significantly decreased migration and invasion of PTC cells. Along with this, fibronectin 1 (FN1) was significantly increased and decreased in cells that overexpress or downregulate BAG5, respectively. Mechanistically, we found that BAG5 modulated FN1 expression at the translational level and promoted invasion via suppression of miR-144-3p, which targeted the 3' untranslational region (UTR) of FN1 transcript. This study suggests that BAG5 is an important regulator of migration and invasion in PTC cells and may represent a novel therapeutic target for intervening in PTC progression.

Systematic identification of CDC34 that functions to stabilize EGFR and promote lung carcinogenesis.

BACKGROUND: How the oncoprotein epidermal growth factor receptor (EGFR) evades proteolytic degradation and accumulates in non-small cell lung cancer (NSCLC) remains unclear, and ubiquitin pathway genes (UPGs) that are critical to NSCLC needs to be systematically identified. METHODS: A total of 696 UPGs (including E1, E2, E3, and deubiquitinases) were silenced by small interfering RNA (siRNA) library in NSCLC cells, the candidates were verified, and their significance was evaluated in patients with NSCLC. The effects of a candidate gene on EGFR were investigated in vitro and in vivo. FINDINGS: We report 31 candidates that are required for cell proliferation, with the E2 ubiquitin conjugase CDC34 as the most significant one. CDC34 is elevated in tumor tissues in 76 of 114 (66.7%) NSCLCs and inversely associated with prognosis, is higher in smoker patients than nonsmoker patients, and is induced by tobacco carcinogens in normal human lung epithelial cells. Forced expression of CDC34 promotes, whereas knockdown of CDC34 inhibits, NSCLC cell proliferation in vitro and in vivo. CDC34 competes with c-Cbl to bind Y1045 to inhibit polyubiquitination and degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del (exon 19)-driven lung tumor growth in mouse models, knockdown of CDC34 significantly inhibits tumor formation. INTERPRETATION: These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to stabilize substrates, and CDC34 represents an attractive therapeutic target for NSCLCs. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, and the CAMS Innovation Fund for Medical Sciences.

BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase.

Bcl-2 associated athanogene 3 (BAG3) is an important molecule that maintains oncogenic features of cancer cells via diverse mechanisms. One of the important functions assigned to BAG3 is implicated in selective macroautophagy/autophagy, which attracts much attention recently. However, the mechanism underlying regulation of autophagy by BAG3 has not been well defined. Here, we describe that BAG3 enhances autophagy via promotion of glutamine consumption and glutaminolysis. Glutaminolysis initiates with deamination of glutamine by glutaminase (GLS), by which yields glutamate and ammonia in mitochondria. The current study demonstrates that BAG3 stabilizes GLS via prohibition its interaction with SIRT5, thereby hindering its desuccinylation at Lys158 and Lys164 sites. As an underlying molecular mechanism, we demonstrate that BAG3 interacts with GLS and decreases SIRT5 expression. The current study also demonstrates that occupation by succinyl at Lys158 and Lys164 sites prohibits its Lys48-linked ubiquitination, thereby preventing its subsequent proteasomal degradation. Collectively, the current study demonstrates that BAG3 enhances autophagy via stabilizing GLS and promoting glutaminolysis. For the first time, this study reports that succinylation competes with ubiquitination to regulate proteasomal GLS degradation.

Genome-wide identification of transcription factors that are critical to non-small cell lung cancer.

To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs.

[Effect of HCO3- on Nitrogen Removal Efficiency in Partial Nitritation-ANAMMOX Process].

The effect of HCO3- on nitrogen removal efficiency in partial nitritation-ANAMMOX process was studied by using the combined process of partial nitritation and ANAMMOX has been started and achieved the stable operation of nitrogen removal. The results showed that, when the ratio of C/N decreased from 2 to 0.17 in influent, the nitrogen removal rate decreased from 1.3 kg- ( M3 x d)(-1) to 0.40 kg x (M3 x d)(-1), the decrease range arrived at 69.3%. The nitrogen conversion efficiency was limited, because of the added amount of HCO3- was decreased, which leading to the pH value declined sharply in nitritation and ANAMMOX zone. In the partial nitritation-ANAMMOX process, the effect of HCO3- limitation on activity of ammonium oxidizing bacteria, ANAMMOX bacteria and nitrifying bacteria was decreased in turn. When the C/N ratio increased to 1, the nitrogen removal rate of combined process was quickly restored to 1 kg x (m3 x d)(-1). It indicated that short HCO3- limitation on nitrogen conversion efficiency of the combined process can be fast recovery. The resulted also showed that the relationship between influent C/N ratio and nitrogen removal efficiency has obvious relativity in partial nitritation-ANAMMOX process.

[Effect of gas-lift device on the morphology and performance of ANAMMOX sludge].

The upflow reactor with gas-lift device was started up by inoculating ANAMMOX sludge granules of less than 0.9 mm. The effects of gas lift device system on the morphology and performance of ANAMMOX sludge were studied by using the nitrogen gas produced in ANAMMOX to drive the effluent circulation in the reactor. The results showed that, the airlift circulation function was not clear in the startup stage of the reactor, because the nitrogen gas production was very low. At the same time, the ANAMMOX granular sludge was easy to condensate. When the load rate of nitrogen removal reached 3.4 kg x (m3 x d)(-1), the function of gas lift was significant, resulting in gradually increased effluent self-circulation, and the granules were dispersed and grew gradually. After 183d of operation, the granular sludge was dominated by the granules with sizes of 1.6-2.5 mm, which accounted for 53.2% of the total sludge volume. The MLVSS content increased with the increase of sludge particle size. The gas lift device had the same function as the external reflux pump, and was helpful for sludge granulation in the ANAMMOX reactor, while reducing power consumption and the cost of the equipment.

[Numerical simulation of dynamic characteristic of exhalation valve plate in pressure oxygen mask].

Objective. To find out the reason of "dithering" of exhalation valve plate in pressure oxygen mask under high overpressure condition. Method. Dynamic model of the exhalation valve plate in pressure oxygen mask was established. Aerodynamic force on the plate was determined by flowfield computing. The dynamic characteristic of the exhalation valve plate was analyzed by experimental measurement [correction of measurment] integrated with numerical simulation. Result. The movement of valve plate could be simulated with the method proposed, and the course of the"dithering" was found out. Conclusion. The "dithering" of the valve plate can be averted by cutting down the area of the film or increasing the diameter of the valve pedestal moderately.