FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer.

Focal adhesion kinase (FAK) has been established as a promising therapeutic target for KRAS mutant non-small cell lung cancer (NSCLC). However, phase II clinical trials of a FAK inhibitor (Defactinib) have only shown modest antitumor activity. To address this challenge, here we report the use of a FAK-targeting proteolysis targeting chimera (D-PROTAC) to treat KRAS mutant NSCLC. We validated that D-PROTAC could efficiently eliminate FAK protein via the ubiquitin-proteasome pathway in KRAS mutant NSCLC A427 cells, causing over 90% degradation at 800 nM. After comparing both in vitro and in vivo therapeutic efficacies, we demonstrated that D-PRTOAC outperformed Defactinib in inhibiting tumor growth. Specifically, D-PROTAC at 800 nM reduced cell viability, migration, and invasion by ∼80%. Furthermore, a ∼85% suppression of tumor growth was elicited by D-PROTAC when intratumorally administrated at 10 mg/kg in subcutaneous A427-bearing mice. These results thus demonstrate for the first time that PROTACs may serve as promising therapeutic agents for the intractable NSCLC harboring KRAS mutations.

Overexpression of filamin c in chronic intermittent hypoxia-induced cardiomyocyte apoptosis is a potential cardioprotective target for obstructive sleep apnea.

PURPOSE: Chronic intermittent hypoxia (CIH) is key pathological mechanism of obstructive sleep apnea (OSA), which induced cardiac dysfunction. Filamin c (FLNC) is a muscle-restricted isoform and predominantly expressed in muscle tissue. In this study, we utilized a recently developed CIH rat model to mimic OSA, investigated the expression of FLNC in cardiomyocytes, and examined the correlations of FLNC with active caspase-3 to ascertain whether FLNC regulates the survival of cardiomyocytes. METHODS: Forty Sprague-Dawley rats were randomly divided into normoxia and CIH groups. All rats were exposed either to normoxia or CIH 8 h daily for 6 weeks. Echocardiogram and HE staining were used to examine cardiac pathology, structure, and function. Body weight, heart weight, and blood gas values were recorded, respectively. The FLNC, Bax, Bcl-2, BNIP 3, and active caspase-3 proteins were detected by western blot; FLNC was examined by immunohistochemistry and immunofluorescence. Association of FLNC with cardiomyocyte apoptosis was detected by immunofluorescence. RESULTS: CIH induced cardiac injuries and caused arterial blood gas disorder. FLNC significantly increased in CIH-induced cardiomyocytes than that in normoxia tissues. Pro-apoptotic BNIP 3 and Bax proteins were significantly increased in CIH, whereas anti-apoptotic member Bcl-2 was decreased. Active caspase-3, a universal marker of apoptosis, was significantly increased in CIH group. Co-localizations of FLNC and active caspase-3 were observed in CIH group. CONCLUSIONS: These results suggested FLNC is implicated in the pathogenesis of CIH-induced cardiomyocyte apoptosis, and FLNC may serve as a novel cardioprotective target for OSA patients.

Idiopathic isolated fibrotic atrial cardiomyopathy underlies unexplained scar-related atrial tachycardia in younger patients.

Aims: Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results: Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion: Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

A hybrid approach for patent ductus arteriosus closure using the Amplatzer Duct Occluder.

OBJECTIVE: We performed closure of the patent ductus arteriosus (PDA) using a hybrid approach with an Amplatzer Duct Occluder. METHODS: Six patients (two males and four females) underwent PDA closure at a mean age of 7.8 months (range 2-24 months) and a mean weight of 6.6 kg (range 4.5-13 kg). The main pulmonary artery (MPA) was exposed via a minimally invasive left parasternal second intercostal space incision. Under transesophageal echocardiography guidance, the PDA occluder was implanted via direct puncture of the MPA. RESULTS: The procedure was successful in all patients with no residual shunt. There were no hospital deaths, and the postoperative course was uneventful. All patients were discharged on the 3rd to 4th day. There was no residual shunt in any patient on midterm follow-up. CONCLUSIONS: The novel hybrid approach is a safe, minimal invasive procedure. Further experience and longer follow-up of these patients is necessary to conclude whether this technique is applicable to all the patients with a PDA.

Electroacupuncture improves cardiac function and remodeling by inhibition of sympathoexcitation in chronic heart failure rats.

Chronic heart failure (CHF) is responsible for significant morbidity and mortality worldwide, mainly as a result of neurohumoral activation. Acupuncture has been used to treat a wide range of diseases and conditions. In this study, we investigated the effects of electroacupuncture (EA) on the sympathetic nerve activity, heart function, and remodeling in CHF rats after ligation of the left anterior descending coronary artery. CHF rats were randomly selected to EA and control groups for acute and chronic experiments. In the acute experiment, both the renal sympathetic nerve activity and cardiac sympathetic afferent reflex elicited by epicardial application of capsaicin were recorded. In the chronic experiment, we performed EA for 30 min once a day for 1 wk to test the long-term EA effects on heart function, remodeling, as well as infarct size in CHF rats. The results show EA significantly decreased the renal sympathetic nerve activity effectively, inhibited cardiac sympathetic afferent reflex, and lowered the blood pressure of CHF rats. Treating CHF rats with EA for 1 wk dramatically increased left ventricular ejection fraction and left ventricular fraction shortening, reversed the enlargement of left ventricular end-systolic dimension and left ventricular end-diastolic dimension, and shrunk the infarct size. In this experiment, we demonstrated EA attenuates sympathetic overactivity. Additionally, long-term EA improves cardiac function and remodeling and reduces infarct size in CHF rats. EA is a novel and potentially useful therapy for treating CHF.

Increased expression of NF-AT3 and NF-AT4 in the atria correlates with procollagen I carboxyl terminal peptide and TGF-ß1 levels in serum of patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Unfortunately, the precise mechanisms and sensitive serum biomarkers of atrial remodeling in AF remain unclear. The aim of this study was to determine whether the expression of the transcription factors NF-AT3 and NF-AT4 correlate with atrial structural remodeling of atrial fibrillation and serum markers for collagen I and III synthesis. METHODS: Right and left atrial specimens were obtained from 90 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (n = 30), paroxysmal atrial fibrillation (n = 30), and persistent atrial fibrillation (n = 30) groups. NF-AT3, NF-AT4, and collagen I and III mRNA and protein expression in atria were measured. We also tested the levels of the carboxyl-terminal peptide from pro-collagen I, the N-terminal type I procollagen propeptides, the N-terminal type III procollagen propeptides, and TGF-ß1 in serum using an enzyme immunosorbent assay. RESULTS: NF-AT3 and NF-AT4 mRNA and protein expression were increased in the AF groups, especially in the left atrium. NF-AT3 and NF-AT4 expression in the right atrium was increased in the persistent atrial fibrillation group compared the sinus rhythm group with similar valvular disease. In patients with AF, the expression levels of nuclear NF-AT3 and NF-AT4 correlated with those of collagens I and III in the atria and with PICP and TGF-ß1 in blood. CONCLUSIONS: These data support the hypothesis that nuclear NF-AT3 and NF-AT4 participates in atrial structural remodeling, and that PICP and TGF-ß1 levels may be sensitive serum biomarkers to estimate atrial structural remodeling with atrial fibrillation.

Impact of 1-week preoperative auto-CPAP treatment on postoperative outcomes in patients undergoing heart valve replacement surgery: a prospective randomized controlled trial.

Background: Whether preoperative continuous positive airway pressure (CPAP) treatment improves postoperative outcomes in patients undergoing cardiac valve replacement (CVR) remains unknown. Hypothesis: This study was to evaluate the effects of 1-week perioperative auto-continuous positive airway pressure (CPAP) treatment on postoperative heart and pulmonary outcomes in patients with obstructive sleep apnea (OSA) and valvular heart disease. Methods: Thirty-two patients with OSA and valvular heart disease were randomly assigned to 1-week CPAP (n = 15) group and non-CPAP treatments (n = 17) group. After the treatment, all patients underwent CVR surgery. The length of ICU and hospital stays, postoperative cardiac and respiratory complications were assessed and compared between the 2 groups. Results: The results showed there was no significant difference in the baseline characteristics between the CPAP and non-CPAP treatment groups. The length of postoperative ICU and hospital stays, as well as the duration of mechanical ventilation were significantly reduced in the CPAP treatment group compared to the non-CPAP treatment group; however, there were no significant differences in cardiac complications (postoperative arrhythmias, pacemaker use, first dose of dopamine in the ICU, and first dose of dobutamine in the ICU), and respiratory complications (reintubation and pneumonia). Conclusion: We concluded that in patients underwent CVR, preoperative use of auto-CPAP for OSA significantly decreased the duration of mechanical ventilation, and postoperative stays in the ICU and hospital.Clinical Trial Registration: https://ClinicalTrials.gov, identifier NCT03398733.

Calcium- and integrin-binding protein-1 and calcineurin are upregulated in the right atrial myocardium of patients with atrial fibrillation.

AIMS: The aim of this study was to determine whether altered expression and distribution of calcium- and integrin-binding protein-1 (CIB1) is involved in the pathogenesis of different types of patients with atrial fibrillation (AF) associated with valvular heart disease (VHD). METHODS AND RESULTS: Right atrial specimens obtained from 65 patients undergoing valve replacement surgery were divided into three groups: sinus rhythm group (n= 24), paroxysmal atrial fibrillation group (PaAF; n= 10), and persistent atrial fibrillation group (PeAF; AF lasting >6 month; n= 31). The expression levels of mRNA and protein content for CIB1, calcineurin B, calcineurin A, and Na(+)-Ca(2+) exchanger-1 (NCX1) were measured. We also measured the combination of CIB1 with calcineurin B, L-type Ca(2+) channel, and NCX1 using immunoprecipitation. Expression of mRNA and protein content of CIB1, calcineurin B, calcineurin A, and NCX1 was increased in the AF group. Calcium- and integrin-binding protein-1 interacted with calcineurin B and L-type Ca(2+) channel. Surprisingly, CIB1 also combined with NCX1. CONCLUSIONS: The CIB1 and calcineurin expression was increased in AF atrial tissue and was related to the type of AF. This finding suggests that CIB1 may be involved in the pathogenesis of AF in VHD patients.

The influence of deep hypothermic global brain ischemia on EEG in a new rat model.

OBJECTIVES: Neurological complications following deep hypothermic circulatory arrest (DHCA) occur between t 4% ≈ 25%. However, the cerebral injury mechanisms are still not well understood due to a lack of a practical and simple animal model. We aimed to establish a rodent deep hypothermic global brain ischemia (DHGBI) model, which can be used to elucidate these mechanisms in future studies. DESIGN: 30 Sprague-Dawley rats were divided randomly into three groups: the carotid occlusion DHGBI group, the internal carotid shunt DHGBI group, and the sham operation group. We validated the model in terms of electroencephalogram (EEG) and regional cerebral blood flow (rCBF). All rats were sacrificed for analysis of brain moisture capacity after 24 hours. RESULTS: In the internal carotid shunt DHGBI group the EEG activity was suppressed to "flat-line" and the relative power of the α and θ frequency bands was decreased (p < 0.05). However, in the carotid occlusion DHGBI group we only observed the relative power of the α frequency band depressed (p < 0.05). The rCBF was significantly decreased in all groups. In the internal carotid shunt DHGBI group the rCBF was significantly reduced to 4.27 ± 2.75%, and was lower than the other two groups (p < 0.05). The result of brain moisture capacity was consistent with the EEG and rCBF observations. CONCLUSIONS: The current study presents a novel cerebral recovery model of DHCA in the rat. This experimental model may be suitable to further elucidate the mechanisms associated with adverse cerebral outcomes after DHCA and to investigate potential neuroprotective strategies.

Long noncoding RNA ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1 antisense RNA 1 recruits enhancer of zeste 2 polycomb repressive complex 2 subunit to promote the proliferation, migration and invasion of lung adenocarcinoma cells.

The detailed function of ARAP1-AS1, the antisense RNA of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 (ARAP1), in lung adenocarcinoma (LUAD) has not been clearly elucidated and required further investigation. Our study is committed to exploring the role of ARAP1-AS1 in LUAD. Gene expression in LUAD was measured by real-time quantitative polymerase-chain reaction (RT-qPCR). The influence of ARAP1-AS1 on LUAD cell malignant behaviors was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, Transwell invasion assay and wound healing assay. Subcellular fractionation assay detected the cellular localization of ARAP1-AS1 in LUAD. The protein levels were subjected to western blotting. RNA immunoprecipitation (RIP) and luciferase reporter assay were employed to verify the interaction between ARAP1-AS1, ARAP1 and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). Our investigation identified that ARAP1-AS1 was upregulated in LUAD cells and tissues. ARAP1-AS1 silencing repressed LUAD cell growth and migration. Furthermore, ARAP1-AS1 knockdown altered the expression of its sense mRNA, ARAP1. ARAP1-AS1 could recruit EZH2 to inhibit ARAP1 expression. Additionally, the downregulation of ARAP1 reversed ARAP1-AS1 downregulation-induced repression of cell growth and migration in LUAD. In conclusion, ARAP1-AS1 recruited EZH2 to silence ARAP1, facilitating cell proliferation, migration and invasion in LUAD. Our study demonstrated the possibility of ARAP1-AS1 to be a novel therapeutic target for LUAD. [Figure: see text].

A method to improve multi-node power transmission efficiency of inductively coupled mooring cable.

The inductively coupled mooring cable is an important tool for monitoring the ocean hydrological data. The mooring cable is an open-loop structure that uses a section of seawater as the transmission medium. The power transmission efficiency of this structure is very low due to the large power loss of the seawater medium, and it is rarely studied. In this paper, a contactless power transmission circuit with seawater loss is analyzed, and the theoretical model of multi-node power transmission of the inductively coupled mooring system is established. In this model, the improvement of the output power and transmission efficiency is only related to the frequency selection and the properties of the magnetic core itself, such as the magnetic core material. Moreover, the optimal scheme is selected according to the output power requirements. The experimental results show that when the input current (Irms) is 2 A, the output power of a single node is 12 W, the total output power is 120 W, and the total transmission efficiency reaches 50%.

Mathematical models for intraoperative prediction of metastasis to regional lymph nodes in patients with clinical stage I non-small cell lung cancer.

It remains challenging to determine the regions of metastasis to lymph nodes during operation for clinical stage I non-small cell lung cancer (NSCLC). This study aimed to establish intraoperative mathematical models with nomograms for predicting the hilar-intrapulmonary node metastasis (HNM) and the mediastinal node metastasis (MNM) in patients with clinical stage I NSCLC. The clinicopathological variables of 585 patients in a derivation cohort who underwent thoracoscopic lobectomy with complete lymph node dissection were retrospectively analyzed for their association with the HNM or the MNM. After analyzing the variables, we developed multivariable logistic models with nomograms to estimate the risk of lymph node metastasis in different regions. The predictive efficacy was then validated in a validation cohort of 418 patients. It was confirmed that carcinoembryonic antigen (>5.75 ng/mL), CYFRA211 (>2.85 ng/mL), the maximum diameter of tumor (>2.75 cm), tumor differentiation (grade III), bronchial mucosa and cartilage invasion, and vascular invasion were predictors of HNM, and carcinoembryonic antigen (>8.25 ng/mL), CYFRA211 (>2.95 ng/mL), the maximum diameter of tumor (>2.75 cm), tumor differentiation (grade III), bronchial mucosa and cartilage invasion, vascular invasion, and visceral pleural invasion were predictors of MNM. The validation of the prediction models based on the above results demonstrated good discriminatory power. Our predictive models are helpful in the decision-making process of specific therapeutic strategies for the regional lymph node metastasis in patients with clinical stage I NSCLC.

Perirenal adipose afferent nerves sustain pathological high blood pressure in rats.

Hypertension is a pathological condition of persistent high blood pressure (BP) of which the underlying neural mechanisms remain obscure. Here, we show that the afferent nerves in perirenal adipose tissue (PRAT) contribute to maintain pathological high BP, without affecting physiological BP. Bilateral PRAT ablation or denervation leads to a long-term reduction of high BP in spontaneous hypertensive rats (SHR), but has no effect on normal BP in control rats. Further, gain- and loss-of-function and neuron transcriptomics studies show that augmented activities and remodeling of L1-L2 dorsal root ganglia neurons are responsible for hypertension in SHR. Moreover, we went on to show that calcitonin gene-related peptide (CGRP) is a key endogenous suppressor of hypertension that is sequestered by pro-hypertensive PRAT in SHRs. Taken together, we identify PRAT afferent nerves as a pro-hypertensive node that sustains high BP via suppressing CGRP, thereby providing a therapeutic target to tackle primary hypertension.

[Proteomic analysis of the effect of noradrenalin on human pulmonary arterial smooth muscle cells].

OBJECTIVE: To observe the effect of noradrenalin (NE) on human pulmonary arterial smooth muscle cells (PASMC) by using a proteomic approach. METHODS: Human PASMC were cultured primarily in vitro. Experiments were performed in the 3(rd) to 5(th) passages of the cells. The human PASMC were cultured in serum-free medium for 24 h prior to treatment with either NE (10(-5) mol/L, the test group) or completed-serum culture medium (the control group) for 24 h. And then analysis via 2-DE gel electrophoresis and MALDI-TOF-MS was performed to display the different protein profiles of whole cell protein from cultures of the control and the NE-treatment group. Real-time RT-PCR and Western blot analysis were used to confirm the proteomic analysis. RESULTS: The purity of the primary culture cells was about 99%. When the human PASMC were treated by NE, the expression of different groups of cellular proteins was changed, including cell cytoskeleton-associated proteins, cell signal-associated proteins, and glycolytic and metabolism-associated proteins. The results were confirmed using real-time RT-PCR and Western blot. NE enhanced the proliferation of human PASMC partly by affecting the expression of α-enolase. CONCLUSION: The data suggest that a wide range of signaling pathways may be involved in NE-induced proliferation of human PASMC, and α-enolase associated pathway may be an important one.

Prognosis of early stage pulmonary mucinous adenocarcinoma with different treatments.

BACKGROUND: The effects of surgical approach and adjuvant chemotherapy (AC) of early stage pulmonary mucinous adenocarcinoma (MAD) have not been thoroughly studied yet. This study intends to clarify whether AC provides clinical benefit to the early stage MAD patients and the survival difference between surgical approaches. METHODS: All cases of stage I MAD were identified from the SEER database during the period of 2009-2014. The primary cohort was divided into AC and surgery (S) groups. Meanwhile, the patients with tumor ≤1 cm were divided into lobectomy and sublobar resection group. Clinical characteristics, treatments and survival data including overall survival (OS) and cancer-specific survival (CSS) were analyzed. RESULTS: A total of 1,816 patients were included in the final cohort. Referring to surgical procedure, 140 patients received lobectomy and 75 patients received sublobar resection. AC showed worse survival outcomes than surgery alone (OS: 71.2 vs. 93.4 months; CSS: 74.9 vs. 101.1 months). No significant difference was observed between lobectomy group and sublobar resection group (OS: 97.3 vs. 93.1 months; CSS: 103.7 vs. 101.3 months). Consistent results were also shown after the propensity score matching analysis (PSM) was applied. CONCLUSIONS: Early stage of MAD has an ideal prognosis. AC may bring adverse effects which would lower OS and CSS of stage I MAD patients. No significant difference is observed in the comparison of prognosis between lobectomy and sublobar resection in tumor size ≤1 cm MAD patients.

Proteomic analysis of the effect of iptakalim on human pulmonary arterial smooth muscle cell proliferation.

AIM: To investigate the anti-proliferative effect of iptakalim (Ipt), a newly selective K(ATP) channel opener, in endothelin-1 (ET-1)-induced human pulmonary arterial smooth muscle cells (PASMCs) using proteomic analysis. METHODS: Human PASMCs were incubated with ET-1 (10(-8) mol/L) and ET-1 (10(-8) mol/L) plus iptaklim (10(-5) mol/L) for 24 h. Analysis via 2-DE gel electrophoresis and MALDI-TOF-MS was employed to display the different protein profiles of whole-cell protein from cultures of control, ET-1 treatment alone, and treatment with ET-1 and iptaklim combined. Real time RT-PCR and Western blot analysis were used to confirm the proteomic analysis. RESULTS: When iptakalim inhibited the proliferative effect of ET-1 in human PASMCs by opening the K(ATP) channels, the expression of different groups of cellular proteins was changed, including cytoskeleton-associated proteins, plasma membrane proteins and receptors, chaperone proteins, ion transport-associated proteins, and glycolytic and metabolism-associated proteins. We found that iptakalim could inhibit the proliferation of human PASMCs partly by affecting the expression of Hsp60, vimentin, nucleoporin P54 (NUP54) and Bcl-X(L) by opening the K(ATP) channel. CONCLUSION: The data suggest that a wide range of signaling pathways may be involved in abolishing ET-1-induced proliferation of human PASMCs following iptakalim treatment.

Cardiac Sympathetic Denervation Suppresses Atrial Fibrillation and Blood Pressure in a Chronic Intermittent Hypoxia Rat Model of Obstructive Sleep Apnea.

Background Chronic intermittent hypoxia ( CIH ) is a distinct pathological mechanism of obstructive sleep apnea ( OSA ), which is recognized as an independent risk factor for cardiovascular diseases. The aims of this study were to ascertain whether CIH induces atrial fibrillation ( AF ), to determine whether cardiac sympathetic denervation ( CSD ) can prevent it and suppress blood pressure, and to explore the potential molecular mechanisms involved. Methods and Results Sixty Sprague-Dawley male rats were randomly divided into 4 groups: sham, CSD , CIH , CIH + CSD . The rats were exposed either to CIH 8 hours daily or normoxia for 6 weeks. Cardiac pathology and structure were analyzed by hematoxylin and eosin staining and echocardiogram. ECG, blood pressure, body weight, and blood gas were recorded. Connexin 43 and tyrosine hydroxylase were detected by western blot, immunohistochemistry, and immunofluorescence. CIH induced atrial remodeling, and increased AF inducibility. CSD treatment reduced postapneic blood pressure rises and AF susceptibility, which could attenuate CIH -associated structural atrial arrhythmogenic remodeling. In addition, CIH -induced sympathetic nerve hyperinnervation and CSD treatment reduced sympathetic innervation, which may affect CIH -induced AF -associated sympathovagal imbalance. Connexin 43 was specifically downregulated in CIH , whereas CSD treatment increased its expression. Conclusions These results suggested CIH induces atrial remodeling, increases AF inducibility, results in sympathetic nerve hyperinnervation, and decreases connexin 43 expression, but CSD treatment reduces AF susceptibility, postapneic blood pressure increase, sympathetic innervation, and the alteration of Cx43, which may be a key point in the genesis of CIH -induced AF .

Prediction of lymph node metastatic status in superficial esophageal squamous cell carcinoma using an assessment model combining clinical characteristics and pathologic results: A retrospective cohort study.

BACKGROUND: It is important to identify the risk of lymph node metastasis (LNM) in patients with superficial esophageal squamous carcinoma (SESC) who have received endoscopic resection (ER). We aimed to develop a risk-predicting model for metastasis of SESC to lymph nodes using clinicopathological features and pathological results. METHODS: Clinical data on 539 consecutive patients who underwent esophagectomy for SESC in our hospital were collected. Their post-surgical pathological results were assessed and analyzed. Multivariate logistic regression was used to identify all independent risk factors associated with LNM that then were incorporated into the prediction model. RESULTS: LNM was identified in 53 of 366 patients and 30 of 173 patients by positive histopathological results in the training and validation cohorts. The risk factors associated with LNM were large tumor size, poor tumor grade, deep invasion, and presence of angiolymphatic invasion. The model achieved good discriminatory ability of 0.80 (95%CI, 0.74-0.86) and 0.81 (95%CI, 0.75-0.86) in predicting LNM in the training and validation cohorts respectively. A LNM-predicting nomogram was formed with an area under curve of 0.80 (95% CI, 0.74-0.86), which had well-fitted calibration curves. CONCLUSIONS: A prediction model was constructed to generates 3 categories for estimated LNM risk in SESC patients. It provides a practical way of estimation of LNM risk in SESC patients who had received ER.

Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of K(ATP) channel.

To determine whether iptakalim inhibited endothelin-1(ET-1)-induced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) through the activation of ATP-sensitive potassium (K(ATP)) channel, the effect of iptakalim on the ET-1-induced proliferation of human PASMCs was examined by [3H]thymidine incorporation, staining with propidium iodide and flow cytometry analyses, measurement of cytosolic free Ca2+ concentration ([Ca2+]cyt) and Western blot for the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in vitro. The results showed that iptakalim inhibited the ET-1-induced proliferation of human PASMCs, including [3H]thymidine incorporation and the transition of cell cycle phase, and blocked the ET-1-induced transient raise of [Ca2+]cyt, and the ET-1-induced phosphorylation of ERK1/2 in the human PASMCs. Iptakalim exerted a similar role as pinacidil did in human PASMCs and both inhibited the [3H] thymidine incorporation and the transition of cell cycle phase induced by ET-1 in the human PASMCs. Furthermore, we found that the inhibition of iptakalim and pinacidil on the ET-1-induced proliferation of human PASMCs was blocked by glyburide, a selective K(ATP) channel antagonist. These findings provide a strong evidence to support that iptakalim acts as a specific K(ATP) channel opener to antagonize the proliferating effect of ET-1 in the human PASMCs. This study provides further evidence that iptakalim may serve as another candidate drug to treat pulmonary hypertension.