Error Bound of Mode-Based Additive Models.

Due to their flexibility and interpretability, additive models are powerful tools for high-dimensional mean regression and variable selection. However, the least-squares loss-based mean regression models suffer from sensitivity to non-Gaussian noises, and there is also a need to improve the model's robustness. This paper considers the estimation and variable selection via modal regression in reproducing kernel Hilbert spaces (RKHSs). Based on the mode-induced metric and two-fold Lasso-type regularizer, we proposed a sparse modal regression algorithm and gave the excess generalization error. The experimental results demonstrated the effectiveness of the proposed model.

A pooled analysis of primary hepatic angiosarcoma.

BACKGROUND: Angiosarcoma is an aggressive and malignant neoplasm. Primary hepatic angiosarcoma is extremely rare and accounts for only approximately 5% of all angiosarcomas. Therefore, many doctors do not know enough about this disease; this lack of knowledge motivated us to perform this study. METHODS: We carried out a systematic review of the literature published worldwide from 1990 to 2019 to study the main characteristics, demographics, treatment and prognosis of primary hepatic angiosarcoma. RESULT: A total of 219 patients were included in this study. Patients were mainly middle-aged and elderly at diagnosis, with an average age at onset of 56.7 years. The vast majority of patients (61.5%) presented with abdominal pain or distension. Of 143 patients with clear records of metastasis, 31.5% (45 patients) had distant metastasis. The median overall survival time was only 6 months, and the 1- and 2-year survival rates were 30.4 and 17.3%, respectively. Sex, age, tumor size and metastasis at diagnosis showed no correlation with survival rate. Hepatic rupture was a significant predictor of survival. Surgery is a major treatment choice, and adjuvant chemotherapy can improve the prognosis of patients. Hepatic artery embolization is mainly used in cases of tumor rupture. However, liver transplantation is not advised. CONCLUSION: We presented an overview of the demographics, tumor characteristics and treatment outcomes of the largest number of primary hepatic angiosarcoma patients investigated to date. We highlight the use of routine physical examinations and surgery combined with adjuvant chemotherapy to improve the outcomes in these cases.

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity.

BACKGROUND/AIMS: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. METHODS: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. RESULTS: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3' untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. CONCLUSIONS: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

Short linear shadows connecting pulmonary segmental arteries to oblique fissures in volumetric thin-section CT images: comparing CT, micro-CT and histopathology.

OBJECTIVES: To retrospectively evaluate short linear shadows connecting pulmonary segmental arteries to oblique fissures in thin-section CT images and determine their anatomical basis. METHODS: CT scanning was performed on 108 patients and 11 lung specimens with no lung diseases around the oblique fissures or hila. Two radiologists evaluated the imaging. The parameters included length, thickness of short linear shadows, pulmonary segmental artery variations, and traction interlobar fissures, etc. RESULTS: The short linear shadows were not related to sex, age, or smoking history. The lengths of the short linear shadows were generally within 10 mm. The thicknesses of the short linear shadows ranged from 1 to 2 mm. Of the patients, 26.9 % showed pulmonary segmental artery variations; 66.7 % of short linear shadows pulled oblique fissures. In three-dimensional images, the short linear shadows appeared as arc planes, with one side edge connected to the oblique fissure, one side edge connected to a pulmonary segmental artery. On the tissue slices, the short linear shadow exhibited a band structure composed of connective tissues, small blood vessels, and small lymphatic vessels. CONCLUSIONS: Short linear shadows are a type of normal intrapulmonary membranes and can maintain the integrity of the oblique fissures and hilar structure. KEY POINTS: • Volumetric thin-section CT scanning is commonly used to study lung anatomy. • Short linear shadows are a common intrapulmonary structure in thin-section CT. • Short linear shadows correlate with band structures on the correlative tissue slices.

Multiple techniques to evaluate the relationship between carotid artery plaque and acute stroke.

AIM: To evaluate the important characteristics of the plaque vulnerability using multimodal ultrasound imaging methods (2D, contrast-enhanced ultrasound, and elastography), and to explore the relationship between plaque and acute stroke. METHODS: A total of 244 patients with carotid plaque were enrolled, including 104 patients with acute stroke ipsilateral to the plaque as the case group and 140 patients as the control group. All patients underwent conventional carotid ultrasound, contrast-enhanced ultrasound (CEUS) and elastography (SWE). The results of each examination were compared and analyzed, and the relationship between the results and the occurrence of stroke was discussed. RESULTS: In the acute stroke group, the men, with a history of alcohol consumption the direction of contrast media diffusion was higher than that in the control group, but the plaque gray value (GSM), maximum, average and minimum Young's elastic modulus imaging values (YM) were slightly lower than those in the control group (P < 0.05). Logistic regression analysis showed that waist to body ratio (WHtR), GSM, YM, neovascularization density and contrast diffusion direction were independent risk factors for predicting acute ischemic stroke. The influence degree of each factor from strong to weak was waist to body ratio, neovascularity density, GSM and YM, respectively. The area under the curve (AUC) for the diagnosis of acute ischemic stroke by regression model was 0.746. CONCLUSION: The combination of multiple ultrasound techniques to evaluate the vulnerability of carotid plaque and predict the occurrence of acute stroke provides valuable information for clinical decision making.

Downregulation of salusins alleviates hypertrophic cardiomyopathy via attenuating oxidative stress and autophagy.

INTRODUCTION: Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM. MATERIAL AND METHODS: In vivo experiments, Sprague-Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10-6 M) for 24 h. RESULTS: After treatment with Ang II, levels of salusin-α and salusin-ß were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (ß-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-ß), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs. CONCLUSIONS: All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.

Enhancement of Tumor Perfusion and Antiangiogenic Therapy in Murine Models of Clear Cell Renal Cell Carcinoma Using Ultrasound-Stimulated Microbubbles.

OBJECTIVE: To explore the effect of ultrasound-stimulated microbubble cavitation (USMC) on enhancing antiangiogenic therapy in clear cell renal cell carcinoma. MATERIALS AND METHODS: We explored the effects of USMC with different mechanical indices (MIs) on tumor perfusion, 36 786-O tumor-bearing nude mice were randomly assigned into four groups: (i) control group, (ii) USMC0.25 group (MI = 0.25), (iii) USMC1.4 group (MI = 1.4) (iv) US1.4 group (MI = 1.4). Tumor perfusion was assessed by contrast-enhanced ultrasound (CEUS) before the USMC treatment and 30 min, 4h and 6h after the USMC treatment, respectively. Then we evaluated vascular normalization(VN) induced by low-MI (0.25) USMC treatment, 12 tumor-bearing nude mice were randomly divided into two groups: (i) control group (ii) USMC0.25 group. USMC treatment was performed, and tumor microvascular imaging and blood perfusion were analyzed by MicroFlow imaging (MFI) and CEUS 30 min after each treatment. In combination therapy, a total of 144 tumor-bearing nude mice were randomly assigned to six groups (n = 24): (i) control group, (ii) USMC1.4 group, (iii) USMC0.25 group, (iv) bevacizumab(BEV) group, (v) USMC1.4 +BEV group, (vi) USMC0.25 +BEV group. BEV was injected on the 6th, 10th, 14th, and 18th d after the tumors were inoculated, while USMC treatment was performed 24 h before and after every BEV administration. We examined the effects of the combination therapy through a series of experiments. RESULTS: Tumor blood perfusion enhanced by USMC with low MI (0.25)could last for more than 6h, inducing tumor VN and promoting drug delivery. Compared with other groups, USMC0.25+BEV combination therapy had the strongest inhibition on tumor growth, led to the longest survival time of the mice. CONCLUSION: The optimized USMC is a promising therapeutic approach that can be combined with antiangiogenic therapy to combat tumor progression.

Effect and mechanism of circHMGA2 on ferroptosis and pyroptosis in myocardial ischemia-reperfusion model CircHMGA2 exacerbates MI/R injury.

Myocardial ischemia-reperfusion (MI/R) injury is a common and serious complication following reperfusion treatment for myocardial infarction (MI). Increasing evidence has verified the crucial role of circular RNAs (circRNAs) in the MI/R injury processes. The objective of this study was to investigate the effects and potential regulatory mechanisms of circHMGA2 on MI/R injury. Hypoxia/reoxygenation (H/R) models were established using human cardiac myocytes (HCMs) and mice models were induced by MI/R. The level of circHMGA2 was detected by RT-qPCR. Myocardial function was evaluated by the hemodynamic parameters, the activity of serum myocardial enzymes, HE staining and TUNEL assays. Cell proliferation was measured by CCK-8 assay. The ferrous ion (Fe2+) level was determined with an iron assay kit. Ferroptosis- and pyroptosis-related proteins were determined using western blotting. The levels of oxidative stress and inflammatory factors were analyzed using DCFH-DA staining or ELISA assays. CircHMGA2 was upregulated in H/R-induced HCMs and myocardial tissues of MI/R mice. In vitro, circHMGA2 knockdown attenuated the proliferation inhibition, restrained the ferroptosis and pyroptosis in H/R-induced HCMs. This regulatory mechanism may be associated with the suppression of NLRP3 pathway. In vivo, circHMGA2 depletion attenuated myocardial tissue damage of MI/R mice through inhibiting the oxidative stress and pyroptosis. Taken together, CircHMGA2 enhanced MI/R injury via promoting ferroptosis and pyroptosis, providing new insights into the treatment of MI/R injury.

Dissecting the effect of ileal faecal diversion on the intestine using single-cell sequencing.

BACKGROUND: Although ileal faecal diversion is commonly used in clinical settings, complications accompany it. Elucidating the intestinal changes caused by ileal faecal diversion will help resolve postoperative complications and elucidate the pathogenic mechanisms of associated intestinal disorders, such as Crohn's disease (CD). Therefore, our study aimed to provide new insights into the effects of ileal faecal diversion on the intestine and the potential mechanisms. METHODS: Single-cell RNA sequencing was performed on proximal functional and paired distal defunctioned intestinal mucosae from three patients with ileal faecal diversion. We also performed in vitro cellular and animal experiments, tissue staining and analysed public datasets to validate our findings. RESULTS: We found that the epithelium in the defunctioned intestine tended to be immature, with defective mechanical and mucous barriers. However, the innate immune barrier in the defunctioned intestine was enhanced. Focusing on the changes in goblet cells, we demonstrated that mechanical stimulation promotes the differentiation and maturation of goblet cells through the TRPA1-ERK pathway, indicating that the absence of mechanical stimulation may be the main cause of defects in the goblet cells of the defunctioned intestine. Furthermore, we found obvious fibrosis with a pro-fibrotic microenvironment in the defunctioned intestine and identified that monocytes may be important targets for faecal diversion to alleviate CD. CONCLUSIONS: This study revealed the different transcription landscapes of various cell subsets and the potential underlying mechanisms within the defunctioned intestine, when compared to the functional intestine, based on the background of ileal faecal diversion. These findings provide novel insights for understanding the physiological and pathological roles of the faecal stream in the intestine.

Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE(-/-) mice.

AIM: The severity of atherosclerosis is primarily determined by overall lipid metabolism and the degree of inflammation present within the vessel wall. We evaluated the effects of T-0901317, a liver X receptor agonist, on the atherosclerosis process, and especially on the endothelial function in ApoE(-/-) mice. METHODS AND RESULTS: ApoE(-/-) mice were treated with LXR agonist T-0901317 (1 µmol/L) for 6 weeks. ApoE(-/-) mice receiving T-0901317 were found to have markedly improved overall serum lipid profiles, albeit increased serum triglycerides. MRI imaging demonstrated that T-0901317 attenuated the atherosclerotic plaque burden in the aorta of ApoE(-/-) mice. Transmission electron microscopy and immunohistochemistry revealed attenuated ultrastructural changes as well as enhanced expression of the ATP-binding cassette transporter ABCA1. In addition, treatment with the LXR agonist improved the vasomotor function of atherosclerotic arteries, as assessed by KCl/norepinephrine-induced vasoconstrictive and acetylcholine-induced vasorelaxation functional assays. In vitro studies showed increased ABCG1, phospho-Akt and phospho-eNOS expression in ApoE(-/-) mice aorta endothelial cells (ECs) after T0901317 treatment. CONCLUSION: The present study suggest that LXR agonists protect the endothelium against atherosclerotic insults by increasing ABCA1 and ABCG1 expression, and improve the endothelial-dependent vasomotor function probably by promoting Akt and eNOS phosphorylation.

The Elevated Circ_0067835 Could Accelerate Cell Proliferation and Metastasis via miR-1236-3p/Twist2 Axis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignant cancer with leading mortality worldwide. Circ_0067835 is a circRNA which plays an important role in various kinds of tumor, while the potential functions of circ_0067835 in HCC remains unclear. In this study, our results of microarray and real-time PCR (RT-PCR) showed that it was obviously elevated in human HCC tumor tissues and HCC cell lines. Inhibition of circ_0067835 restrained cell proliferation and migration in vitro. Furthermore, miR-1236-3p was decreased in tumor samples, and it was indicated to be a target of circ_0067835. Moreover, Twist2 was established to be elevated in HCC tissues, and we identified it as the direct target of miR-1236-3p. Finally, we found that knockdown of miR-1236-3p could reverse the circ_0067835 inhibition effects in HCC cells. In conclusion, our study demonstrated that circ_0067835 contributed to promoting hepatocellular carcinoma cell proliferation and metastasis through downregulating miR-1236-3p expression and then elevating Twist2 expression, which might provide a new vision for HCC patients.

Quantitative evaluation of diaphragmatic motion during forced breathing in chronic obstructive pulmonary disease patients using dynamic chest radiography.

Objective: To quantitatively evaluate the bilateral diaphragmatic motion difference during forced breathing between chronic obstructive pulmonary disease (COPD) patients and healthy individuals using dynamic chest radiography technique. Methods: This prospective study included the COPD patients (n: 96, f/m: 17/79, age: 66 ± 8 years old) and healthy individuals (n: 50, f/m: 42/8, age: 53 ± 5 years old) that underwent dynamic chest radiography with a flat panel X-ray detector system during forced breathing in a standing position. After analyzing the excursions, duration and velocity of diaphragmatic motion were automatically calculated using the postprocessing software. The parameters of diaphragmatic motion including excursion, duration, velocity, inhalation/exhalation times were assessed in all subjects for both diaphragms. The correlation between lung function parameters and diaphragmatic motion excursions were further evaluated. Results: The excursions of diaphragmatic motion in COPD patients were significantly decreased in COPD patients compared with healthy individuals during forced breathing (P < 0.05). The excursion in COPD patients was 35.93 ± 13.07 mm vs. 41.49 ± 12.07 mm in healthy individuals in the left diaphragm, and 32.05 ± 12.29 mm in COPD patients vs. 36.88 ± 10.96 mm in healthy individuals in the right diaphragm. The duration of diaphragmatic motion significantly decreased in COPD patients, compared with the healthy individuals (P < 0.05). The inhalation time in COPD patients was 2.03 ± 1.19 s vs. 2.53 ± 0.83 s in healthy individuals in the left diaphragm and 1.94 ± 1.32 s in COPD patients vs. 2.23 ± 1.21 s in healthy individuals in the right diaphragm. The exhalation time was 4.77 ± 1.32 s in COPD patients vs. 6.40 ± 2.73 s in healthy individuals in the left diaphragm and 4.94 ± 3.30 s in COPD patients vs. 6.72 ± 2.58 s in healthy individuals in the right diaphragm. The peak velocity of diaphragmatic motion showed no significant difference between COPD and healthy groups. The excursions of bilateral diaphragmatic motion showed moderate correlation with FEV1/FVC (r = 0.44, P < 0.001). Multi-linear regression analysis showed that the excursions of bilateral diaphragm are significantly associated with COPD occurrence (P < 0.05). Conclusion: The excursions and duration of diaphragmatic motion during forced breathing are significantly decreased in COPD patients, compared with healthy individuals. Our study showed that precise bilateral diaphragmatic motion activity can be evaluated by dynamic chest radiography.

Resveratrol Attenuate Myocardial Injury by Inhibiting Ferroptosis Via Inducing KAT5/GPX4 in Myocardial Infarction.

Myocardial infarction (MI) is a coronary artery-related disease and ranks as the leading cause of sudden death globally. Resveratrol (Res) is a bioactive component and has presented antioxidant, anti-inflammatory and anti-microbial properties. However, the effect of Res on ferroptosis during MI progression remains elusive. Here, we aimed to explore the function of Res in the regulation of ferroptosis and myocardial injury in MI. We observed that the treatment of Res attenuated the MI-related myocardium injury and fibrosis in the rats. The expression of collagen 1 and α-SMA was induced in MI rats, in which the treatment of Res could decrease the expression. Treatment of Res suppressed the levels of IL-6 and IL-1ß in MI rats. The GSH levels were inhibited and MDA, lipid ROS, and Fe2+ levels were induced in MI rats, in which the treatment of Res could reverse the phenotypes. Meanwhile, the expression of GPX4 and SLC7A11 was reduced in MI rats, while the treatment of Res could rescue the expression in the model. Meanwhile, Res relieved oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury. Importantly, Res repressed OGD-induced cardiomyocyte ferroptosis in vitro. Mechanically, we identified that Res was able to enhance GPX4 expression by inducing KAT5 expression. We confirmed that KAT5 alleviated OGD-induced cardiomyocyte injury and ferroptosis. The depletion of KAT5 or GPX4 could reverse the effect of Res on OGD-induced cardiomyocyte injury. Thus, we concluded that Res attenuated myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Our finding provides new evidence of the potential therapeutic effect of Res on MI by targeting ferroptosis.

Identification of prognostic factors for predicting survival of patients with malignant adrenal tumors: A population-based study.

Background: This study aimed to identify the prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with malignant adrenal tumors and establish a predictive nomogram for patient survival. Methods: The clinical characteristics of patients diagnosed with malignant adrenal tumors between 1988 and 2015 were retrieved from the Surveillance, Epidemiology and End Results (SEER) database. As the external validation set, we included 110 real-world patients from our medical centers. Univariate and multivariate Cox regressions were implemented to determine the prognostic factors of patients. The results from Cox regression were applied to establish the nomogram. Results: A total of 2,206 eligible patients were included in our study. Patients were randomly assigned to the training set (1,544; 70%) and the validation set (662; 30%). It was determined that gender, age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy were prognostic factors that affected patient survival. The OS prediction nomogram contained all the risk factors, while gender was excluded in the CSS prediction nomogram. The receiver operating characteristic (ROC) curve and decision curve analysis (DCA) indicated that the nomogram had a better predictive performance than SEER stage. Moreover, the clinical impact curve (CIC) showed that the nomograms functioned as effective predictive models in clinical application. The C-index of nomogram for OS and CSS prediction was 0.773 (95% confidence interval [CI]: 0.761-0.785) and 0.689 (95% CI: 0.675-0.703) in the training set. The calibration curves exhibited significant agreement between the nomogram and actual observation. Additionally, the results from the external validation set also presented that established nomograms functioned well in predicting the survival of patients with malignant adrenal tumors. Conclusions: The following clinical variables were identified as prognostic factors: age, marital status, histological type, tumor size, SEER stage, surgery, and chemotherapy. The nomogram for patients with malignant adrenal tumors contained the accurate predictive performance of OS and CSS, contributing to optimizing individualized clinical treatments.

Development and future perspectives of natural orifice specimen extraction surgery for gastric cancer.

In recent years, natural orifice specimen extraction surgery (NOSES), a novel minimally invasive surgical technique, has become a focus in the surgical field, and has been initially applied in gastric surgery in many national medical centers worldwide. In addition, this new surgical technique was launched in major hospitals in China. With an increasing number of patients who have accepted this new surgical technique, NOSES has provided new prospects for the treatment of gastric cancer (GC), which may achieve a better outcome for both patients and surgeons. More and more experts and scholars from different countries and regions are currently paying close attention to NOSES for the treatment of GC. However, there are only a few reports of its use in GC. This review focuses on the research progress in NOSES for radical gastrectomy in recent years. We also discuss the challenges and prospects of NOSES in clinical practice.

Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers.

TNFα is a key mediator of immune and radiotherapy-induced cytotoxicity, but many cancers, including head and neck squamous cell carcinomas (HNSCC), display TNF resistance due to activation of the canonical IKK-NF-κB/RELA pro-survival pathway. However, toxicities associated with direct targeting of the canonical pathway point to the need to identify mechanism(s) contributing to TNFα resistance and synthetic lethal targets to overcome such resistance in cancer cells. Here, RNAi screening for modulators of TNFα-NF-κB reporter activity and cell survival unexpectedly implicated the WEE1 and CDC2 G2-M checkpoint kinases. The IKKα/ß-RELA and WEE1-CDC2 signaling pathways are activated by TNFα and form a complex in cell lines derived from both human papillomavirus (-) and (+) subtypes of HNSCC. WEE1 inhibitor AZD1775 reduced IKK/RELA phosphorylation and the expression of NF-κB-dependent pro-survival proteins Cyclin D1 and BCL2. Combination of TNFα and AZD1775 enhanced caspase-mediated apoptosis in vitro, and combination treatment with radiotherapy and AZD1775 potentiated inhibition of HNSCC tumor xenograft growth in vivo, which could be significantly attenuated by TNFα depletion. These data offer new insight into the interplay between NF-κB signaling and WEE1-mediated regulation of the G2-M cell-cycle checkpoint in HNSCC. IMPLICATIONS: Inhibiting WEE1 and IKK-RELA crosstalk could potentially enhance the effects of therapies mediated by TNFα with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-κB/RELA signaling.

Beta3-Adrenergic Receptor Activation Alleviates Cardiac Dysfunction in Cardiac Hypertrophy by Regulating Oxidative Stress.

BACKGROUND: Excessive myocardial oxidative stress could lead to the congestive heart failure. NADPH oxidase is involved in the pathological process of left ventricular (LV) remodeling and dysfunction. ß3-Adrenergic receptor (AR) could regulate cardiac dysfunction proved by recent researches. The molecular mechanism of ß3-AR regulating oxidative stress, especially NADPH oxidase, remains to be determined. METHODS: Cardiac hypertrophy was constructed by the transverse aortic constriction (TAC) model. ROS and NADPH oxidase subunits expression were assessed after ß3-AR agonist (BRL) or inhibitor (SR) administration in cardiac hypertrophy. Moreover, the cardiac function, fibrosis, heart size, oxidative stress, and cardiomyocytes apoptosis were also detected. RESULTS: ß3-AR activation significantly alleviated cardiac hypertrophy and remodeling in pressure-overloaded mice. ß3-AR stimulation also improved heart function and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis. Meanwhile, ß3-AR stimulation inhibited superoxide anion production and decreased NADPH oxidase activity. Furthermore, BRL treatment increased the neuronal NOS (nNOS) expression in cardiac hypertrophy. CONCLUSION: ß3-AR stimulation alleviated cardiac dysfunction and reduced cardiomyocytes apoptosis, oxidative stress, and fibrosis by inhibiting NADPH oxidases. In addition, the protective effect of ß3-AR is largely attributed to nNOS activation in cardiac hypertrophy.

MiR-223/NFAT5 signaling suppresses arterial smooth muscle cell proliferation and motility in vitro.

Aberrant proliferation and migration of vascular smooth muscle cells contributes to cardiovascular diseases (CVDs), including atherosclerosis. MicroRNA-223 (miR-223) protects against atherosclerotic CVDs. We investigated the contribution of miR-223 to platelet-derived growth factor-BB (PDGF-BB)-induced proliferation and migration of human aortic smooth muscle cells (HASMCs). We found that miR-223 was downregulated in PDGF-BB-treated HASMCs in a dose- and time-dependent manner, while nuclear factor of activated T cells 5 (NFAT5) was upregulated. Gain- and loss-of-function studies demonstrated that miR-223 treatment reduced PDGF-BB-induced HASMC proliferation and motility, whereas miR-223 inhibitor enhanced these processes. Moreover, NFAT5 was identified as a direct target of miR-223 in HASMC. The inhibitory effects of miR-223 on HASMC proliferation and migration were partly rescued by NFAT5 restoration. Overall, these findings suggest that miR-223 inhibits the PDGF-BB-induced proliferation and motility of HASMCs by targeting NFAT5 and that miR-223 and NFAT5 may be potential therapeutic targets for atherosclerosis.

Laparoscopic extralevator abdominoperineal excision for the treatment of perianal Paget's disease: A case report.

RATIONAL: Perianal Paget's disease (PPD) is a very rare intraepithelial adenocarcinoma. Very few cases of PPD have been reported till date, so the treatment remains controversial and more experience is needed. PATIENT CONCERNS: A 73-year-old female was admitted to several hospitals with diagnosed as "perianal eczema" in perianal lesion. After a variety of treatments, the patient's condition did not improve. DIAGNOSES: Abdominopelvic computed tomography and rectal magnetic resonance imaging showed thickening of the soft tissue around the anus, with significant enhancement. Histologic examination revealed the state of Paget's cells. INTERVENTIONS: Laparoscopic Extralevator Abdominoperineal Excision (ELAPE) surgery was performed at our department. OUTCOMES: The patient recovered well. After 10 months, a check-up revealed that her perianal area was disease-free. LESSONS: The aim of this report was to present the characteristics of PPD in order to improve its diagnosis and treatment. Laparoscopic ELAPE is a successful therapy.

[Prospective clinical study on serum immunity in IgG-antibodies positive patients convalescent from severe acute respiratory syndrome].

OBJECTIVE: To investigate the serum immunological characteristics in patients convalescent from severe acute respiratory syndrome (SARS). METHODS: In the 1 st, 3 rd, 6 th month after their discharge, eg. SARS-IgG, T cell subsets, blood routine, and the blood biochemistry were systemically determined in SARS convalescent patients. RESULTS: The SARS-antibodies could be used as the diagnostic evidence. During the 6 months after discharge, the titers of SARS-antibodies were high, but they lowered along with passage of time. At the first recheck, the CD4(+) lymphocyte count was lower than normal level in 55.9% of patients, the CD3(+) lymphocyte count was lower than normal level in 31.2% of patients, and the CD8(+) lymphocyte count was lower than normal level in 14.0% of patients. At the second recheck, the levels of T cell subsets recovered to normal level in the most patients. CONCLUSION: T cell subsets, and the number of leukocyte are abnormal in some patients convalescent from SARS. All the indexes examined recover to normal levels half year after discharge. Therefore, it is necessary to follow up the changes in the levels of SARS-antibodies.