E2F1-driven histone demethylase KDM6B enhances thyroid malignancy via manipulating TFEB-dependent autophagy axis.

Aberrant epigenetic modifications or events regulate autophagy to influence tumor progression, which has gained increasing attention. KDM6B is an essential histone demethylase that participates in multiple processes of tumors, but its role in thyroid carcinoma (THCA) remains to be unknown. Here, in this study, we used the MTT assay to screen and validate that KDM6B is an essential demethylase for THCA. KDM6B promotes THCA proliferation, migration, invasion in vitro and in vivo. Transcriptional factor E2F1 directly binds to the promoter region of KDM6B and regulates its mRNA levels in THCA. E2F1 partially depended on KDM6B to exert its oncogenic functions. Mechanistically, KDM6B binds to TFEB promoter region and mediates the demethylation of H3K27me3. KDM6B depended on TFEB to activate a series of lysosomal-related genes. KDM6B enhances autophagy process, as evidenced by elevated p62 and Beclin-1 proteins. KDM6B depended on TFEB-driven autophagy activity to accelerate THCA progression. Lastly, targeting autophagy with 3-MA could notably abrogate growth of KDM6Bhigh THCA, but has mild influence on KDM6Blow THCA. Together, this study identified KDM6B as an essential epigenetic regulator for THCA, functioning as an autophagy regulator. The fundamental mechanisms underlying E2F1/KDM6B/TFEB axis provided novel vulnerabilities for THCA treatment.

Elucidating the spatial determinants of heavy metals pollution in different agricultural soils using geographically weighted regression.

Intensive human activities caused massive socio-economic and land-use changes that directly or indirectly resulted in excessive accumulation of heavy metals in agricultural soils. The goal of our study was to explore the spatial determinants of heavy metals pollution for agricultural soil environment in Sunan economic region of China. We applied geographically weighted regressions (GWR) to measure the spatially varying relationship as well as conducted principal component analysis (PCA) to incorporate multiple variables. The results indicated that our GWR models performed well to identify the determinants of heavy metal pollution in different agricultural soils with relatively high values of local R2. Heavy metal pollution in Sunan economic region was crucially determined by accessibility, varying agricultural inputs as well as the composition and configuration of agricultural landscape, and such impacts exhibited significantly heterogeneity over space and farming practices. For the both agricultural soils, the major variance proportion for our determinants can be grouped into the first four factors (82.64 % for cash-crop soils and 73.065 for cereal-crop soils), indicating the incorporation and interactions between variables determining agricultural soil environment. Our findings yielded valuable insights into understanding the spatially varying 'human-land interrelationship' in rapidly developing areas. Methodologically, our study highlighted the applicability of geographically weighted regression to explore the spatial determinants associated with unwanted environmental outcomes in large areas.

One-stage transanal endorectal pull-through for Hirschsprung disease: experience with 229 neonates.

OBJECTIVE: To evaluate the safety and efficacy of transanal endorectal pull-through (TEPT) and the long-term outcomes in newborns with Hirschsprung disease (HD). METHODS: A total of 229 newborns with HD underwent one-stage TEPT between 2007 and 2020, and the diagnoses were confirmed by rectal biopsy. The perioperative clinical course for all patients was reviewed, and the postoperative short- and long-term outcomes were assessed. RESULTS: A total of 229 neonates (187 male and 42 female) had a median age at TEPT of 17 days (range 6-28 days). Sixty-eight patients (29.7%) underwent TEPT combined with an abdominal approach or laparoscopy. Early postoperative complications (using the Clavien-Dindo grading system) were documented in 36 patients (15.7%), and late postoperative complications were noted in 9 patients (3.9%). The follow-up period in the remaining 165 children ranged from 1.2 to 14.0 years (median 5.0 years). A total of 106 of the patients older than four years old took part in an interview about bowel function, and 85 patients (80.2%) had bowel function scores (BFS) ≥ 18. CONCLUSION: TEPT is effective and safe for HD in the neonatal period and presents with a low rate of complications and an acceptable outcome.

Risk factors of enterostomy in neonates with Hirschsprung disease.

PURPOSE: This study was aiming to explore the risk factors contributing to enterostomy in neonates with Hirschsprung disease (HD) to provide a reference for clinicians to make treatment decisions. METHODS: Medical records of 284 patients diagnosed with HD during the neonatal period were retrospectively analyzed. The patients were divided into 2 groups based on operative intervention (one stage transanal pull-through, versus enterotomy and staged transanal pull-through). Univariate and multivariable logistic regression analysis was performed to identify risk factors contributing to enterostomy. RESULTS: The incidence of enterostomy was 12.0% (34/284) in neonates with HD. Univariate and multivariate logistic regression analysis showed that serum albumin < 25.4 g/L, radiographic results as subphrenic free air, and level of aganglionosis with long-segment or total colonic aganglionosis (TCA) were independent risk factors of enterostomy in neonates, with OR of 42.045 (6.131, 288.319), 285.558 (26.651, 3059.694) and 15.573 (4.319, 56.157), respectively. CONCLUSIONS: The low serum albumin level, bowel perforation, and level of aganglionosis with long-segment or TCA could influence the occurrence of enterostomy in neonates with HD.

[Analysis and Prediction of Health Risk from Heavy Metals in Drinking Water Sources Based on Time Series Model].

Health risk analysis can predict and control the risks posed by heavy metals, especially in drinking water, which is a highly sensitive environmental receptors. In order to evaluate heavy metal pollution in drinking water, the monthly average concentrations of As, Cd, Cu, Hg, Ni, and Zn were used to assess the health risk between January 2015 and December 2018 in a drinking water source. Furthermore, Spearman rank correlation coefficient and the ARIMA model were used to analyze temporal variations. The results showed that the monthly average concentrations of heavy metals exceeded the class Ⅲ values as specified by Chinese environmental quality standard for surface water(GB 3838-2002), especially Hg with a minimum monthly average four times more than that set by the standard limits. Overall, the order of carcinogenic risk of As and Cd was decreased; the non-carcinogenic risk of Zn, Cu, Ni, Pb, and Hg was increased. Further, the comprehensive non-carcinogenic risk for adults was lower than 1 throughout the study period except February 2015, when the comprehensive non-carcinogenic risk for children was lower than or close to 1 after October 2017, and the comprehensive carcinogenic risk for children was more than 10-4. Meanwhile, the children's health risks are higher than that for adults, with the main health risk characteristic factors of As, Cd, and Hg. The Spearman rank correlation coefficient were -0.714069, -0.773122, and -0.62234, indicating the significant downward trend from 2015 to 2018. However, the children's comprehensive carcinogenic risk, whose average value was 0.000234 much more than 10-4, had significant upward trend in 2018 with Spearman rank correlation coefficient 0.902098. The ARIMA(3,1,3) model was able to predict the comprehensive carcinogenic risk for children from heavy metals in drinking water, and the result indicated the children comprehensive carcinogenic risk should be monitored to ensure levels between 0.000200 and 0.000302. The study has positive significance for risk warning and environmental management compared to the analysis and prediction of health risk from heavy metals in drinking water sources based on time series models.

Risk Factors for Severe Hypocalcemia in Patients with Secondary Hyperparathyroidism after Total Parathyroidectomy.

BACKGROUND: Hypocalcemia is the most common complication of total parathyroidectomy in secondary hyperparathyroidism (SHPT) and is associated with adverse consequences such as spasms, epilepsy, and arrhythmia and even death if the serum calcium level decreases rapidly. Previous studies have identified several risk factors for postoperative severe hypocalcemia (SH) in patients with SHPT, but the sample sizes were small and thus the results may not be reliable. OBJECTIVES: This study was performed to investigate the risk factors for SH after total parathyroidectomy without autotransplantation (tPTX) in a large sample of patients with uremic hyperparathyroidism. METHODS: We retrospectively investigated the records of 1,095 patients with SHPT treated with tPTX between January 2008 and December 2018. Based on the postoperative serum calcium concentration, the patients were grouped into SH and non-SH groups. The clinical characteristics and biochemical results were analyzed, and binary logistic regression analysis was used to identify the risk factors for SH. RESULTS: After surgery, 25.9% of the patients developed SH. Age, diastolic blood pressure (DBP), heart rate, frequency of bone pain, weight of resected glands, preoperative serum calcium, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and hemoglobin levels differed between the two groups. Binary logistic regression analyses identified preoperative serum calcium, iPTH, and ALP levels as independent predictors of SH after surgery. CONCLUSIONS: The preoperative serum calcium, iPTH, and ALP levels can be used to assess the risk of postoperative SH in patients with SHPT. Such patients should thus be monitored closely in order to initiate prompt interventions to avoid SH.

Potential role of iodine excess in papillary thyroid cancer and benign thyroid tumor: A case-control study.

BACKGROUND AND OBJECTIVES: The relationship between nutritional status of iodine and thyroid tumor is unclear. We investigated the association between urinary iodine concentration and thyroid function in patients with papillary thyroid cancer, benign thyroid tumor and healthy individuals. METHODS AND STUDY DESIGN: We compared the biomarkers of thyroid function and urinary iodine concentration within and between each group. A regression analysis was used to identify risk factors for papillary thyroid cancer. Correlation analysis was performed to determine whether any significant correlation exists between urinary iodine concentration and thyroid function biomarkers. RESULTS: The iodine nutrition statuses of these three groups were adequate (median urinary iodine concentration= 100-199 µg/L). However, the median urinary iodine concentration of papillary thyroid cancer (174.7 µg/L) and benign thyroid tumor (165.04 µg/L) groups was significantly higher than that of the healthy control group (135.8 µg/L) (p<0.05). The regression analysis showed that thyroglobulin antibody was an independent risk factor for papillary thyroid cancer. After adjusting for age and gender, the association between thyroglobulin antibody and urinary iodine concentration was significant (ß: 0.002; p<0.05). In subgroup analyses, significant correlations was noted only in the papillary thyroid cancer group (adjusted ß: 0.002; 95% confidence interval: 0.000- 0.003). CONCLUSIONS: Excessive iodine in patients with thyroid tumors may affect thyroglobulin antibody, which may be an independent risk factor for papillary thyroid cancer.

[Assessment and Spatial Characteristics Analysis of Human Health Risk of Heavy Metals in Cultivated Soil].

Spatial characteristics analysis of the human health risk posed by heavy metals in cultivated soils is of great significance, with the potential to prevent and control soil pollution, protect human health, provide a basis for risk management, etc. In this paper, a methodological system, including a USEPA health risk assessment model, differentiation and factor detector within a geographical detector, and optimized initial model of rank-size theory, was constructed from a geographical perspective. Taking a city in Jiangsu province as the research object, we obtained the spatial differentiation and relative level of human health risk of Cr, Pb, Hg, and Cd in cultivated land by using the methodological system constructed and SPSS and ArcGIS software. The average concentrations of heavy metals (mg·kg-1) in the research area were Cr (65.207 mg·kg-1), Pb (25.486 mg·kg-1), Cd (0.238 mg·kg-1), and Hg (0.045 mg·kg-1), which were lower than the risk control standards for soil contamination of agricultural land in China. The children's non-cancer risk of Cr and Pb and the cancer risk to children and adults of Cr were 2.914385, 1.337503, 4.312679×10-6, and 8.137130×10-6, respectively, all of which exceeded the maximum acceptable limit in the research. Meanwhile, the spatial differentiation (q) of heavy metal health risk was between 0.005523 and 0.204238, which indicated that the high health risk posed by heavy metals should be paid attention to. The health risk rankings (R) of the children's non-cancer risk of Cr and Pb and the cancer risk of Cr in subregions 1, 2, 3, and 4 approached or exceeded 1, and were higher than in subregions 5, 6, and 7, for which R was lower than 0.1. The R values indicated than the high health risk is concentrated in the research region. This research has great significance in measuring the health risk of heavy metals in cultivated soil at different scales, and in forming control strategies with local conditions.

Effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection for papillary thyroid carcinoma.

BACKGROUND: The purpose of present study is to assess the effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection (CND) for papillary thyroid carcinoma (PTC). METHODS: A classification of IPGs according to their location and vascular features was developed, and, based on this classification, a CND procedure was designed, and IPGs and their vascular were actively localized and strategically preserved. A total of 197 patients with PTC who underwent a total thyroidectomy and concomitant CND were enrolled. Eighty-nine patients with traditional meticulous fascia dissection were allocated to group A, and 108 patients with active location and vascular preservation of IPGs were allocated to group B. Those with inferior parathyroid glands auto-transplantation in each group were assigned as group At (18) and group Bt (12). Variables including serum intact parathyroid hormone (PTH), total calcium, the incidence of transient, and permanent hypoparathyroidism were studied. RESULTS: Compared with group A, serum intact PTH (P < 0.001) and total calcium levels (P < 0.05) in group B significantly improved on the first postoperative day, and the incidence of transient hypoparathyroidism significantly dropped in group B (P < 0.001). A total of 170 patients in the two groups had complete follow-up data. The incidence of permanent hypoparathyroidism significantly decreased in group B, from 8.8% to 1.0% (P = 0.017). However, there were no significant differences in all variables between group Bt and group At. CONCLUSION: Active location and vascular preservation of inferior parathyroid glands effectively protected the function of IPGs in CND for PTC.

LncRNA ENST00000539653 acts as an oncogenic factor via MAPK signalling in papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent type of thyroid malignancy. In this study, we investigated the mechanisms whereby long non-coding RNAs (lncRNAs) are associated with PTC pathogenesis. METHODS: Microarray analysis was used to determine differentially expressed lncRNAs between paired PTC tissues and normal adjacent thyroid tissues. Quantitative RT-PCR was used for validation in 86 PTC cases. Small interfering RNA (siRNA) transfection assays were then performed to assess how a novel lncRNA affected key proliferation and cell death pathways in IHH4 PTC cells. RESULTS: We identified 1878 differentially expressed lncRNAs versus matched control samples (fold change ≥2.0, P < 0.05), of which 429 were upregulated and 1449 were downregulated. ENST00000539653.1 (ENS-653), one of the top hits in this microarray, was selected for further study. Higher ENS-653 expression was observed in PTC tissue samples versus adjacent normal tissues, and was associated with a larger tumor size and a more advanced clinical stage. In the Cancer Genome Atlas (TCGA) PTC cohort, higher ENS-653 expression was correlated with more frequent BRAF (V600E) mutation and poorer disease-free survival. Furthermore, ENS-653 downregulation reduced the proliferation of PTC cells and led to G1-S arrest, but had no impact on apoptosis. ENS-653 downregulation also inactivated ERK1/2 and ERK5, causing partial MAPK cascade suppression. CONCLUSION: ENS-653 exhibits oncogenic properties in PTC, and could be a diagnostic and/or prognostic PTC biomarker, in addition to possibly being a future target for therapy.

Flow behavior of N2 huff and puff process for enhanced oil recovery in tight oil reservoirs.

In the present work, the potential of N2 huff and puff process to enhance the recovery of tight oil reservoir was evaluated. N2 huff and puff experiments were performed in micromodels and cores to investigate the flow behaviors of different cycles. The results showed that, in the first cycle, N2 was dispersed in the oil, forming the foamy oil flow. In the second cycle, the dispersed gas bubbles gradually coalesced into the continuous gas phase. In the third cycle, N2 was produced in the form of continuous gas phase. The results from the coreflood tests showed that, the primary recovery was only 5.32%, while the recoveries for the three N2 huff and puff cycles were 15.1%, 8.53% and 3.22%, respectively.The recovery and the pressure gradient in the first cycle were high. With the increase of huff and puff cycles, and the oil recovery and the pressure gradient rapidly decreased. The oil recovery of N2 huff and puff has been found to increase as the N2 injection pressure and the soaking time increased. These results showed that, the properly designed and controlled N2 huff and puff process can lead to enhanced recovery of tight oil reservoirs.

Effect of parathyroid hormone on serum magnesium levels: the neglected relationship in hemodialysis patients with secondary hyperparathyroidism.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is an important complication in patients with end-stage renal disease. Since recent studies have shown that magnesium (Mg) disturbance plays an important role in CKD-MBD and cardiovascular mortality, the interest on magnesium has grown recently. Although much concern focused on the effect of Mg on parathyroid hormone (PTH) levels, however, the influence of PTH on serum Mg levels is nearly unexplored. To evaluate the effect of PTH on serum Mg levels, we first described the relationship between serum Mg and PTH in secondary hyperparathyroidism. Besides, we also monitored the changes of serum Mg concentration after parathyroidectomy (PTX) in 23 patients. In our study, we found that hypermagnesemia (>2.5 mg/dL) occurred in up to 44% of cases and hypomagnesemia did not present. No statistically significant correlations were found between serum Mg levels and PTH (r = -0.143, p = 0.134). Correlation analysis and regression analysis suggested that the derangement of magnesium homeostasis was consistent with the derangement of calcium/phosphorus homeostasis. However, after PTX, serum magnesium levels dropped immediately after the surgery, minimally at the first day and gradually restored from the third day. The changes of serum Mg after surgery was positive correlated with the changes of serum phosphate (r = 0.558, p = 0.003). Taken altogether, our data suggested that the therapeutic strategies to achieve optimum serum magnesium levels in CKD-MBD should take into account the varying stages of disease development since PTH could also influence magnesium metabolism and this problem might be important in severe secondary hyperparathyroidism.

Relationship between parathyroid mass and parathyroid hormone level in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: To evaluate the influence of parathyroid mass on the regulation of parathyroid hormone (PTH) secretion, we investigated the relationship between the resected parathyroid gland in total parathyroidectomy and the parathyroid hormone level in hemodialysis patients with secondary hyperparathyroidism. METHODS: From January 2009 to July 2014, 223 patients undergoing total parathyroidectomy were included. The size and the weight of parathyroid gland were measured during the operation. RESULTS: 874 parathyroid glands were removed. A positive correlation was identified between the size and the weight of resected parathyroid glands. We found that both the preoperative PTH and the reduction of PTH were significantly correlated with the size and the weight of parathyroid glands in a positive manner. However, in the subgroup of patients with PTH < 1000 pg/ml, no significant correlation was found. CONCLUSIONS: Larger parathyroid gland secretes more PTH and high level of serum PTH usually indicated that surgical removal might be required. However, since PTH levels could be influenced by the pharmaceutical drug, the large size of parathyroid gland might be used as a much more appropriate guide that indicates the requirement of surgery treatment even when the parathyroid hormone was less than 1000 pg/ml.

Tracheoesophageal fistula after primary repair of type C esophageal atresia in the neonatal period: recurrent or missed second congenital fistula.

PURPOSE: The aim of the study is to investigate whether a tracheoesophageal fistula (TEF) found after the primary repair of type C esophageal atresia (EA) is a recannulation of the original fistula, a missed proximal fistula, or other rare foregut malformation. METHODS: Between 2000 and 2009, 143 different types of patients with EA were admitted in our hospital. Seven patients (2 from our series, 5 referred to us by other hospitals with the history of primary repair of type C EA) had late presenting TEF. Esophagogram, 3-dimensional computed tomographic (CT) reconstruction, bronchoscopy, and reoperation were performed to confirm the TEF. Their medical records were reviewed and summarized. RESULTS: Persistent feeding or respiratory problems were the common symptom. The mean age of the first appearance was 17 ± 26 (1-63) months. Preoperative diagnosis was made by esophagograms and bronchoscopy in 6 patients. Reoperations were performed in all patients through thoracotomy. Missed proximal TEF shown as a distinct fistula above the primary anastomosis without much adhesion was confirmed in 5 cases. A recurrent TEF was found in 1 case. A case of communicating bronchopulmonary foregut malformation was confirmed by 3-dimensional CT reconstruction and reoperation. CONCLUSION: A missed proximal TEF after repair of EA may be misdiagnosed as a recurrent TEF. Accurate preoperative diagnosis depends on combined evaluations of radiologic contrast study, 3-dimensional CT, and bronchoscopy.

Diagnostic scoring system of Hirschsprung's disease in the neonatal period.

OBJECTIVE: Eighty to ninety percent of Hirschsprung's disease (HD) patients present in newborns. However, the diagnosis of HD in the neonatal period remains difficult. Our present study aims to propose a diagnostic scoring system and hope this will increase early diagnosis of HD and avoid unnecessary rectal biopsy. METHODS: In the first study period, 57 suspected HD patients (0-3 months) completed our predetermined study protocol in which barium enema (BE), rectal manometry (RM) and full-thickness rectal biopsy were performed. Symptoms, signs and investigations were analysed for their correlation with HD diagnosis. A HD diagnostic scoring system was developed according to the statistical results and was assessed in 74 patients in the second study period. RESULTS: Forty-five patients were diagnosed with HD in the first study period. A HD scoring system was developed in which delayed meconium, tight anus, BE and RM were diagnostic factors. A cut-off point of 3 provided 84% of HD patients score >3, whereas 75% non-HD patients score

Analysis of postoperative reoperation for congenital duodenal obstruction.

OBJECTIVE: To analyse the risk factors for reoperation after initial surgical repair of congenital duodenal obstruction and demonstrate that they can be decreased with more careful attention and more advanced techniques during surgery. METHODS: The records of newborns and infants (aged 0-2 months) who had surgical therapy for congenital duodenal obstruction in the past 30 years were reviewed and analysed. Of the 298 patients, 132 (44%) were boys and 166 (56%) were girls. All patients who underwent repeat surgery postoperatively were evaluated by the reasons for surgery. The number of patients with various combination lesions of congenital duodenal obstruction was also calculated and the relationship to postoperative reoperation was analysed. RESULTS: Twenty patients (6.7%) had congenital duodenal obstruction with combination lesions including duodenal web, malrotation, annular pancreas and multiple duodenal web. Twelve patients required further operation 5 days to 2 years postoperatively for complications (n = 5) and other duodenal atresias that were not discovered initially (n = 7). CONCLUSION: More than half of reoperated patients (7/12) had multiple lesions of duodenal obstruction that were missed during the primary operation. The postoperative reoperation rate for congenital duodenal obstruction could be decreased with more careful attention to operative details and more preoperative and intraoperative evaluation of the gastrointestinal tract.