The role of TFEB-mediated autophagy-lysosome dysfunction in manganese neurotoxicity.

Excessive long-term manganese intake can inflict irreversible damage to the nervous system, with a predominant effect on the substantia nigra-striatum pathway. Through a mouse model simulating manganese exposure, we delved into its implications on the central nervous motor system, uncovering autophagy-lysosome dysfunction as a pivotal factor in manganese-induced neurotoxicity. Our research illuminated the molecular mechanisms behind TFEB's role in manganese-triggered neuronal autophagy dysfunction, offering insights into the cellular and molecular mechanisms of manganese-induced abnormal protein accumulation. This study lays a significant theoretical foundation for future endeavors aimed at safeguarding against manganese neurotoxicity. Furthermore, TFEB emerges as a potential early molecular biomarker for manganese exposure, providing a solid basis for preemptive protection and clinical treatment for populations exposed to manganese.

METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.

Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role of mitochondria in ferroptosis regulation, the underlying mechanisms remain elusive. This study reveals that the mitochondrial protein METTL17 governs mitochondrial function in colorectal cancer (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes that METTL17 expression positively correlates with ferroptosis resistance in cancer cells and is up-regulated in CRC. Depletion of METTL17 sensitizes CRC cells to ferroptosis, impairs cell proliferation, migration, invasion, xenograft tumor growth, and AOM/DSS-induced CRC tumorigenesis. Furthermore, suppression of METTL17 disrupts mitochondrial function, energy metabolism, and enhances intracellular and mitochondrial lipid peroxidation and ROS levels during ferroptotic stress. Mechanistically, METTL17 inhibition significantly reduces mitochondrial RNA methylation, including m4C, m5C, m3C, m7G, and m6A, leading to impaired translation of mitochondrial protein-coding genes. Additionally, the interacting proteins associated with METTL17 are essential for mitochondrial gene expression, and their knockdown sensitizes CRC cells to ferroptosis and inhibits cell proliferation. Notably, combined targeting of METTL17 and ferroptosis in a therapeutic approach effectively suppresses CRC xenograft growth in vivo. This study uncovers the METTL17-mediated defense mechanism for cell survival and ferroptosis in mitochondria, highlighting METTL17 as a potential therapeutic target for CRC.

Radiation exposure in augmented fluoroscopic bronchoscopy procedures: a comprehensive analysis for patients and physicians.

Cancer is a major health challenge and causes millions of deaths worldwide each year, and the incidence of lung cancer has increased. Augmented fluoroscopic bronchoscopy (AFB) procedures, which combine bronchoscopy and fluoroscopy, are crucial for diagnosing and treating lung cancer. However, fluoroscopy exposes patients and physicians to radiation, and therefore, the procedure requires careful monitoring. The National Council on Radiation Protection and Measurement and the International Commission on Radiological Protection have emphasised the importance of monitoring patient doses and ensuring occupational radiation safety. The present study evaluated radiation doses during AFB procedures, focusing on patient skin doses, the effective dose, and the personal dose equivalent to the eye lens for physicians. Skin doses were measured using thermoluminescent dosimeters. Peak skin doses were observed on the sides of the patients' arms, particularly on the side closest to the x-ray tube. Differences in the procedures and experience of physicians between the two hospitals involved in this study were investigated. AFB procedures were conducted more efficiently at Hospital A than at Hospital B, resulting in lower effective doses. Cone-beam computed tomography (CT) contributes significantly to patient effective doses because it has higher radiographic parameters. Despite their higher radiographic parameters, AFB procedures resulted in smaller skin doses than did image-guided interventional and CT fluoroscopy procedures. The effective doses differed between the two hospitals of this study due to workflow differences, with cone-beam CT playing a dominant role. No significant differences in left and right eyeHp(3) values were observed between the hospitals. For both hospitals, theHp(3) values were below the recommended limits, indicating that radiation monitoring may not be required for AFB procedures. This study provides insights into radiation exposure during AFB procedures, concerning radiation dosimetry, and safety for patients and physicians.

Precursor Induced Assembly of Si Nanoparticles Encapsulated in Graphene/Carbon Matrices and the Influence of Al2 O3 Coating on their Properties as Anode for Lithium-Ion Batteries.

The theoretical capacity of pristine silicon as anodes for lithium-ion batteries (LIBs) can reach up to 4200 mAh g-1 , however, the low electrical conductivity and the huge volume expansion limit their practical application. To address this challenge, a precursor strategy has been explored to induce the curling of graphene oxide (GO) flakes and the enclosing of Si nanoparticles by selecting protonated chitosan as both assembly inducer and carbon precursor. The Si nanoparticles are dispersed first in a slurry of GO by ball milling, then the resulting dispersion is dried by a spray drying process to achieve instantaneous solution evaporation and compact encapsulation of silicon particles with GO. An Al2 O3 layer is constructed on the surface of Si@rGO@C-SD composites by the atomic layer deposition method to modify the solid electrolyte interface. This strategy enhances obviously the electrochemical performance of the Si as anode for LIBs, including excellent long-cycle stability of 930 mAh g-1 after 1000 cycles at 1000 mA g-1 , satisfied initial Coulomb efficiency of 76.7%, and high rate ability of 806 mAh g-1 at 5000 mA g-1 . This work shows a potential solution to the shortcomings of Si-based anodes and provides meaningful insights for constructing high-energy anodes for LIBs.

Deep learning with test-time augmentation for radial endobronchial ultrasound image differentiation: a multicentre verification study.

PURPOSE: Despite the importance of radial endobronchial ultrasound (rEBUS) in transbronchial biopsy, researchers have yet to apply artificial intelligence to the analysis of rEBUS images. MATERIALS AND METHODS: This study developed a convolutional neural network (CNN) to differentiate between malignant and benign tumours in rEBUS images. This study retrospectively collected rEBUS images from medical centres in Taiwan, including 769 from National Taiwan University Hospital Hsin-Chu Branch, Hsinchu Hospital for model training (615 images) and internal validation (154 images) as well as 300 from National Taiwan University Hospital (NTUH-TPE) and 92 images were obtained from National Taiwan University Hospital Hsin-Chu Branch, Biomedical Park Hospital (NTUH-BIO) for external validation. Further assessments of the model were performed using image augmentation in the training phase and test-time augmentation (TTA). RESULTS: Using the internal validation dataset, the results were as follows: area under the curve (AUC) (0.88 (95% CI 0.83 to 0.92)), sensitivity (0.80 (95% CI 0.73 to 0.88)), specificity (0.75 (95% CI 0.66 to 0.83)). Using the NTUH-TPE external validation dataset, the results were as follows: AUC (0.76 (95% CI 0.71 to 0.80)), sensitivity (0.58 (95% CI 0.50 to 0.65)), specificity (0.92 (95% CI 0.88 to 0.97)). Using the NTUH-BIO external validation dataset, the results were as follows: AUC (0.72 (95% CI 0.64 to 0.82)), sensitivity (0.71 (95% CI 0.55 to 0.86)), specificity (0.76 (95% CI 0.64 to 0.87)). After fine-tuning, the AUC values for the external validation cohorts were as follows: NTUH-TPE (0.78) and NTUH-BIO (0.82). Our findings also demonstrated the feasibility of the model in differentiating between lung cancer subtypes, as indicated by the following AUC values: adenocarcinoma (0.70; 95% CI 0.64 to 0.76), squamous cell carcinoma (0.64; 95% CI 0.54 to 0.74) and small cell lung cancer (0.52; 95% CI 0.32 to 0.72). CONCLUSIONS: Our results demonstrate the feasibility of the proposed CNN-based algorithm in differentiating between malignant and benign lesions in rEBUS images.

Incidence of and Risk Factors for Acute Kidney Injury During Antituberculosis Treatment: A Prospective Cohort Study and Literature Review.

INTRODUCTION: Acute kidney injury (AKI) is occasionally detected in patients receiving anti-tuberculosis (TB) treatment. This prospective cohort study is the first to investigate the incidence, risk factors, and renal outcomes of AKI during anti-TB treatment. METHODS: This study was conducted from January 1, 2016, to May 31, 2018. Patients with a new diagnosis of TB and on standard anti-TB treatment were enrolled, and the patients received regular laboratory monitoring. AKI was defined according to the Kidney Disease: Improving Global Outcome (KDIGO) criteria. Urinalysis, renal ultrasonography, blood erythrocyte morphology, and fractional excretion of sodium were performed at AKI onset. The TB treatment regimen was adjusted by the primary physician if necessary. Risk factors for AKI were identified through Cox regression. RESULTS: In total, 106 patients were recruited (mean age 52.6 years, 71.7% men). Eleven (10.3%) patients experienced AKI. Increased serum uric acid and hemoglobin levels were noted at AKI onset. All patients with AKI achieved renal recovery and completed anti-TB treatment containing rifampin. Age [hazard ratio (HR) 1.06 (1.02-1.11)], a higher baseline estimated glomerular filtration rate [eGFR; HR 1.04 (1.02-1.06)], and a blood eosinophil count > 350 (109/L) [HR 10.99 (2.28-53.02)] were associated with a higher risk of AKI during TB treatment. CONCLUSION: Regular pharmacovigilant monitoring revealed an incidence of renal impairment during anti-TB treatment that was higher than expected. AKI was more common in older patients with a higher eGFR and blood eosinophil count. However, the complications had no influence on TB treatment completion, and no permanent renal impairment occurred.

Effectiveness of Endobronchial Ultrasound-Guided Transbronchial Biopsy Combined With Tissue Culture for the Diagnosis of Sputum Smear-Negative Pulmonary Tuberculosis.

Background: Microorganisms of tuberculosis (TB) are frequently difficult to identify from the airway specimen; therefore, lung biopsy for further histologic and microbiologic study is required. Endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) is used for the diagnosis of pulmonary malignancy, but is rarely in the TB population. The purpose of this study was to verify the effectiveness and safety of EBUS-TBB with histologic study and tissue culture in the diagnosis of sputum smear-negative pulmonary TB. Methods: Patients who underwent EBUS-TBB with histologic study and TB tissue culture for clinically suspected, but sputum smear-negative pulmonary TB from January 2016 to December 2018, were included. The accuracy of each diagnostic modality was calculated, respectively. Factors that might influence the positive rate of TB culture (washing fluid and tissue specimen) were also evaluated. Results: One hundred sixty-one patients who underwent EBUS-TBB for clinically suspected, but sputum smear-negative pulmonary TB, were enrolled, and 43 of them were finally diagnosed as having pulmonary TB. The sensitivity of washing fluid (a combination of smear, culture, and polymerase chain reaction for TB) and tissue specimen (a combination of pathology and tissue culture) via EBUS-TBB for TB diagnosis were 48.8 and 55.8%, respectively. The sensitivity for TB diagnosis would be elevated to 67.4% when both washing fluid and tissue specimens are used. The positive TB culture rate would not statistically increase with a combination of tissue specimens and washing fluid. Univariate analysis revealed that TB microorganisms would be more easily cultivated when lesions had an abscess or cavity on the computed tomography (CT) image (presence vs. absence; 62.5 vs. 26.3%, p = 0.022), heterogeneous echogenicity on the EBUS finding (heterogeneous vs. homogeneous; 93.3 vs. 21.4%, p = 0.001), or a necrotic pattern via histologic study (presence vs. absence; 70.6 vs. 30.8%, p = 0.013). Heterogeneous echogenicity in the EBUS finding was the independent predictor according to the results of multivariate analysis. None of our patients encountered major adverse events or received further intensive care after EBUS-TBB. Conclusion: Endobronchial ultrasound-guided transbronchial biopsy is safe and effective for use in diagnosing sputum smear-negative pulmonary TB. EBUS echoic feature is also a predictor of the positive TB culture rate in pulmonary TB. However, tissue culture via EBUS-TBB has little effect in improving the positive TB culture rate.

Functional Status After Pulmonary Rehabilitation as a Predictor of Weaning Success and Survival in Patients Requiring Prolonged Mechanical Ventilation.

Background: Comprehensive rehabilitation programs are recommended for patients with prolonged mechanical ventilation (PMV) to facilitate functional recovery and ventilator weaning, but whether the functional status after rehabilitation influences outcome has not been clearly evaluated. This study aimed to investigate the association between post-rehabilitation functional status and weaning and survival outcome in PMV patients. Methods: We retrospectively enrolled PMV patients admitted to the respiratory care center (RCC), a post-ICU weaning facility with protocolized rehabilitation program, from January 2016 through December 2017. Functional status was measured by the de Morton Mobility Index (DEMMI), with a cut-off value set at 20 points. The primary outcomes were the weaning status at RCC discharge and hospital survival. The secondary outcomes were overall survival and survival at 3 months after RCC discharge. We followed patients until 3 months after RCC discharge or death. Logistic and Cox regressions were performed to identify significant parameters associated with weaning success and survival. Results: In total, 320 patients were enrolled. The weaning success rate was 71.6%. The survival rate at RCC discharge, hospital discharge, and 3 months after RCC discharge was 89.1, 77.5, and 66.6%, respectively. Post-rehabilitation DEMMI ≥ 20 (odds ratio [OR], 3.514; 95% confidence interval [CI], 1.436-8.598; P = 0.006) was the most significantly associated with weaning success. The weaning success and higher post-rehabilitation DEMMI were the two most significant independent factors associated with both hospital survival (weaning success, OR, 12.272; 95% CI, 5.281-28.517; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 6.298; 95% CI, 1.302-30.477; P = 0.022) and survival at 3 months after RCC discharge (weaning success, OR, 38.788; 95% CI, 11.505-130.762; P < 0.001; post-rehabilitation DEMMI ≥ 20, OR, 4.830; 95% CI, 1.072-21.756; P = 0.040). Post-rehabilitation DEMMI ≥ 20 remained significantly association with overall survival at 3 months after RCC discharge (hazard ratio, 0.237; 95% CI, 0.072-0.785; P = 0.018). Conclusions: Post-rehabilitation functional status of PMV patients was independently associated with weaning success, as well as hospital and 3-month overall survival after RCC discharge. Post-rehabilitation, but not pre-rehabilitation, functional status was a significant parameter associated with weaning success and survival in patients requiring PMV.

Efficacy and Safety of Cone-Beam Computed Tomography-Derived Augmented Fluoroscopy Combined with Endobronchial Ultrasound in Peripheral Pulmonary Lesions.

BACKGROUND: The diagnostic yield of peripheral pulmonary lesions (PPLs) using radial endobronchial ultrasound (EBUS) remains challenging without navigation systems. Cone-beam computed tomography-derived augmented fluoroscopy (CBCT-AF) represents a recently developed technique, and its clinical utility remains to be investigated. OBJECTIVES: The aim of this study was to investigate the diagnostic yield of transbronchial biopsy (TBB) using a combination of CBCT-AF and radial EBUS. METHODS: We recruited consecutive patients with PPLs who underwent radial EBUS-guided TBB, with or without AF, between October 2018 and July 2019. Following propensity score 1:1 matching, we recorded the procedure-related data and measured their efficacy and safety. RESULTS: While 72 patients received EBUS-plus-AF, 235 patients received EBUS only. We included 53 paired patients following propensity score matching. The median size of lesions was 2.8 and 2.9 cm in the EBUS-plus-AF group and EBUS-only group, respectively. Diagnostic yield was higher in the former group (75.5 vs. 52.8%; p = 0.015). The diagnostic yield for the EBUS-plus-AF group was significantly higher for lesions ≤30 mm (73.5 vs. 36.1%; p = 0.002). Moreover, there was no significant difference in the complication rates (3.8 vs. 5.7%; p = 1.000). Twenty-four nodules (45.3%) were invisible by fluoroscopy in the EBUS-plus-AF group. All of them were identifiable on CBCT images and successfully annotated for AF. The mean radiation dose of total procedure, CBCT, and fluoroscopy was 19.59, 16.4, and 3.17 Gy cm2, respectively. CONCLUSIONS: TBB using a combination of CBCT-AF and EBUS resulted in a satisfactory diagnostic yield and safety.

Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer.

(1) Background: Lung cancer is silent in its early stages and fatal in its advanced stages. The current examinations for lung cancer are usually based on imaging. Conventional chest X-rays lack accuracy, and chest computed tomography (CT) is associated with radiation exposure and cost, limiting screening effectiveness. Breathomics, a noninvasive strategy, has recently been studied extensively. Volatile organic compounds (VOCs) derived from human breath can reflect metabolic changes caused by diseases and possibly serve as biomarkers of lung cancer. (2) Methods: The selected ion flow tube mass spectrometry (SIFT-MS) technique was used to quantitatively analyze 116 VOCs in breath samples from 148 patients with histologically confirmed lung cancers and 168 healthy volunteers. We used eXtreme Gradient Boosting (XGBoost), a machine learning method, to build a model for predicting lung cancer occurrence based on quantitative VOC measurements. (3) Results: The proposed prediction model achieved better performance than other previous approaches, with an accuracy, sensitivity, specificity, and area under the curve (AUC) of 0.89, 0.82, 0.94, and 0.95, respectively. When we further adjusted the confounding effect of environmental VOCs on the relationship between participants' exhaled VOCs and lung cancer occurrence, our model was improved to reach 0.92 accuracy, 0.96 sensitivity, 0.88 specificity, and 0.98 AUC. (4) Conclusion: A quantitative VOCs databank integrated with the application of an XGBoost classifier provides a persuasive platform for lung cancer prediction.

Multigenerational and transgenerational effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure on ovarian reserve and follicular development through AMH/AMHR2 pathway in adult female rats.

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), one of the key endocrine disruptors, has been shown to cause reproductive and developmental disorders. Our previous studies have primarily focused on TCDD induced impairment of ovarian follicular development in female F1 rats. It is unknown whether TCDD exposure will interfere with follicular development by altering mRNA expression of anti-Müllerian hormone (AMH) and AMH receptor type II (AMHR2) in the ovary. In the present study, pregnant Sprague Dawley rats were treated with TCDD (100 or 500 ng/kg body weight) dissolved in a corn oil vehicle by gavage from gavage from gestational days (GD) 8-14, while the control group received solely corn oil. The F1 rats were mated with unexposed males for the F2 generation, while another portion of the female offspring (F2) were mated for the F3 generation. Serum AMH levels and ovarian AMH/AMHR2 mRNA expression in the adult female offspring (F1, F2 and F3 generations) were measured. Follicle count and granulosa cell apoptosis were evaluated in the F2 and F3 generations. The results showed that in the F2 generation, TCDD exposure affected the number of primordial follicles, secondary follicles, and corpora lutea. It also increased serum AMH concentration and the apoptosis rate of granulosa cells. These results might be associated with the upregulation of AMH/AMHR2 mRNA expression in the ovary. In conclusion, TCDD exposure reduced the ovarian reserve in rats and inhibited follicular development in adult female offspring, an effect that persisted for multiple generations. The altered AMH and AMHR2 mRNA expression may contribute to the observed adverse effects.

Localization of Small Pulmonary Nodules Using Augmented Fluoroscopic Bronchoscopy: Experience from 100 Consecutive Cases.

BACKGROUND: We developed augmented fluoroscopic bronchoscopy (AFB) for the localization of small pulmonary nodules. Here, we review the results of 100 consecutive cases of AFB localization performed in our institute in order to evaluate its efficacy, safety, and procedural details. METHODS: This study was a retrospective analysis of prospectively collected data. Between July 2018 and September 2019, a total of 100 patients with 124 small lung nodules underwent AFB localization with dye marking and/or microcoil placement. All localizations were performed in a cone-beam computed tomography examination room followed by thoracoscopic resection within 3 days. RESULTS: The mean nodule size was 9.7 mm, and the mean distance from the pleural space was 18.6 mm. Sixty-three patients received dye marking only, and 37 patients received microcoil placement with/without additional dye marking. The mean bronchoscopy duration was 10.4 min, and the mean fluoroscopy duration was 3.4 min. The mean radiation exposure (expressed as the dose-area product) was 3140.8 µGy × m2. The AFB procedures were successful in 94 patients [augmented fluoroscopy discrepancy (n = 2), incomplete C-arm confirmation (n = 3), microcoil unlooping (n = 1)]; of those, 91 received successful marker-guided resection [invisible dye (n = 2), failed nodule resection with first wedge (n = 1)]. The mean length of postoperative stay and chest drainage was 4.2 and 2.9 days, respectively. CONCLUSIONS: The AFB technique is a safe and reproducible alternative for localizing small pulmonary nodules, and various localization strategies can be implemented for different nodule locations and resection plans.

Rapid on-site cytologic evaluation by pulmonologist improved diagnostic accuracy of endobronchial ultrasound-guided transbronchial biopsy.

BACKGROUND/PURPOSE: Rapid on-site cytologic evaluation (ROSE) has been shown to improve the diagnostic accuracy of endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB). However, ROSE by a cytopathologist or cytotechnologist is not always available during the procedure. The purposes of this study were to verify that a pulmonologist, after receiving training in cytology, could accurately assess an EBUS-TBB specimen on-site, and to evaluate the contribution of ROSE to EBUS-TBB. METHODS: A retrospective chart review of patients who underwent EBUS-TBB for diagnosis of peripheral pulmonary lesions (PPLs) from January 2014 to June 2017 was performed. PPLs without a malignant diagnosis were excluded. The ROSE result determined by a pulmonologist was compared to the formal imprint cytologic report and pathologic report. The diagnostic accuracy of EBUS-TBB was also compared between those with and without ROSE. RESULTS: Two hundred ninety-three patients who underwent 336 EBUS-TBB procedures for PPL diagnosis and were found to have proven malignancy were enrolled. Eighty-six procedures were performed with ROSE. With the formal imprint cytologic diagnosis as the standard, ROSE had 96.9% sensitivity, 68.2% specificity, 89.9% positive predictive value (PPV), 88.2% negative predictive value (NPV), and 89.5% diagnostic accuracy. With the formal pathologic result as the standard, ROSE had 88.2% sensitivity, 80% specificity, 97.1% PPV, 47.1% NPV, and 87.2% diagnostic accuracy, respectively. The diagnostic accuracy was significantly higher when ROSE was performed during EBUS-TBB (88.4% vs 68.0%, P < 0.001). CONCLUSION: A trained pulmonologist can interpret adequately cytologic smears on-site and effectively improve the accuracy of EBUS-TBB in the diagnosis of PPLs.

Augmented fluoroscopic bronchoscopy (AFB) versus percutaneous computed tomography-guided dye localization for thoracoscopic resection of small lung nodules: a propensity-matched study.

BACKGROUND: Dye localization is a useful method for the resection of unidentifiable small pulmonary lesions. This study compares the transbronchial route with augmented fluoroscopic bronchoscopy (AFB) and conventional transthoracic CT-guided methods for preoperative dye localization in thoracoscopic surgery. METHODS: Between April 2015 and March 2019, a total of 231 patients with small pulmonary lesions who received preoperative dye localization via AFB or percutaneous CT-guided technique were enrolled in the study. A propensity-matched analysis, incorporating preoperative variables, was used to compare localization and surgical outcomes between the two groups. RESULTS: After matching, a total of 90 patients in the AFB group (N = 30) and CT-guided group (N = 60) were selected for analysis. No significant difference was noted in the demographic data between both the groups. Dye localization was successfully performed in 29 patients (96.7%) and 57 patients (95%) with AFB and CT-guided method, respectively. The localization duration (24.1 ± 8.3 vs. 21.4 ± 12.5 min, p = 0.297) and equivalent dose of radiation exposure (3.1 ± 1.5 vs. 2.5 ± 2.0 mSv, p = 0.130) were comparable in both the groups. No major procedure-related complications occurred in either group; however, a higher rate of pneumothorax (0 vs. 16.7%, p = 0.029) and focal intrapulmonary hemorrhage (3.3 vs. 26.7%, p = 0.008) was noted in the CT-guided group. CONCLUSION: AFB dye marking is an effective alternative for the preoperative localization of small pulmonary lesions, with a lower risk of procedure-related complications than the conventional CT-guided method.

Real-time augmented fluoroscopy-guided lung marking for thoracoscopic resection of small pulmonary nodules.

BACKGROUND: Small pulmonary nodule localization via an endobronchial route is safe and has fewer complications than that with the transthoracic needle approach, but accurate marking without a navigation system remains challenging. We aimed to evaluate the safety and efficacy of endobronchial dye marking using conventional bronchoscopy guided by cone-beam computed tomography-derived augmented fluoroscopy (CBCT-AF) for small pulmonary nodules. METHODS: We retrospectively reviewed the clinical records of 61 nodules in 51 patients who underwent preoperative CBCT-AF-guided bronchoscopic dye marking, followed by thoracoscopic resection, between July 2018 and March 2019. RESULTS: The median nodule size was 8.6 mm [interquartile range (IQR) 7.0-11.8 mm], and the median distance from the pleural space was 15.4 mm (IQR 10.6-23.1 mm). All nodules were identifiable on CBCT images and annotated for AF. The median bronchoscopy duration was 8.0 min (IQR 6.0-11.0 min), and the median fluoroscopy duration was 2.2 min (IQR 1.2-4.0 min). The median radiation exposure (expressed as the dose area product) was 2337.2 µGym2 (IQR 1673.8-4468.8 µGym2). All nodules were successfully marked and resected, and the median duration from localization to surgery was 16.4 h (IQR 4.2-20.7 h). There were no localization-related complications or operative mortality, and the median length of the postoperative stay was 4 days (IQR 3-4 days). CONCLUSIONS: Bronchoscopic dye marking under CBCT-AF guidance before thoracoscopic surgery was safely conducted with satisfactory outcomes in our initial experience.

TCDD inhibited the osteogenic differentiation of human fetal palatal mesenchymal cells through AhR and BMP-2/TGF-ß/Smad signaling.

Exposure to environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes cleft palate at high rates, but little is known about the underlying biological mechanisms. In the present study, we cultured osteoblasts from human fetal palate mesenchymal cells (hFPMCs) to explore the effects of TCDD on osteogenic differentiation. The results showed that TCDD significantly decreased cell proliferation, alkaline phosphatase (ALP) activity and calcium deposition. RNA analyses and protein detection demonstrated that TCDD downregulated a wide array of pro-osteogenic biomarkers. Further investigation of the underlying molecular mechanisms revealed that exposure to TCDD activated aryl hydrocarbon receptor (AhR) signaling and inhibited BMP-2/TGF-ß1/Smad pathway molecules. The inactivation of AhR signaling using CRISPR/Cas9-mediated AhR deletion or by genetic siRNA knockdown significantly blocked the effects induced by TCDD, suggesting a critical role of AhR activation in the TCDD-mediated inhibition of hFPMC osteogenic differentiation. The cotreatment with TGF-ß1 or BMP-2 and TCDD significantly relieved the activation of AhR and rescued the impairment of osteogenesis caused by TCDD. Taken together, our findings indicated that TCDD inhibited the osteogenic differentiation of hFPMCs via crosstalk between AhR and BMP-2/TGF-ß1/Smad signaling pathway.

Transgenerational impairment of ovarian induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) associated with Igf2 and H19 in adult female rat.

2,3,7,8-Tetrachlorobenze-p-dioxin (TCDD), one of representive Endocrine Disrupting Chemicals (EDCs), has potential adverse effects on human health. Direct exposure to TCDD has been implicated in ovarian follicles development and functions deficits in adulthood. However, it is rarely reported whether indirect exposure to TCDD can cause similar negative impact on F3. The aim of our study was to evaluate the effect of ancestral TCDD exposure on ovarian toxicity in offspring rats (F3), focusing on the Igf2/H19 pathway which was important for follicular development. Pregnant Sprague-Dawley female rats (F0) were given with either vehicle or TCDD (100 or 500 ng/kg BW/day) by gavages during days 8-14 of gestation. Ovarian development and functions of F3 generation was assessed using the ovary coefficient, the vaginal opening time, and regularity of estrous cycle, ovarian pathology, follicles counts and apoptosis of granular cells. The level of E2, FSH and LH in the serum was also detected. Results showed that in the F3 generation 500 ng/kg BW/day TCDD group, ovarian coefficient, LH concentration in serum and number of primary follicles were decreased, and the apoptosis of granular cells was significantly increased. The abnormal rate of estrous cycle and advance rate of vaginal opening time displayed a significantly increase in TCDD-treated groups. RT-PCR analysis showed that the expression level of H19 mRNA in ovary of TCDD treated F3 female rats was increased, compared to the control. Our data showed that ancestral TCDD exposure may impair transgenerational adult ovary development and functions, which may be related to an inhibition of the Igf2/H19 pathway in the ovarian.