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1. The potent, functional agonist of the bile acid Takeda G-protein-coupled receptor 5 (TGR5), (S)-1-(6-fluoro- 2-methyl-3,4-dihydroquinolin-1(2H)-yl)-2-(isoquinolin-5-yloxy)ethanone (3), represents a useful tool to probe in vivo TGR5 pharmacology. Rapid degradation of 3 in both rat and mouse plasma, however, hindered the conduct of in vivo pharmacokinetic/pharmacodynamic investigations (including plasma-free fraction (fu plasma) determination) in rodent models of pharmacology. Studies were therefore initiated to understand the biochemical basis for plasma instability so that appropriate methodology could be implemented in in vivo pharmacology studies to prevent the breakdown of 3. 2. Compound 3 underwent amide bond cleavage in both rat and mouse plasma with half-lives (T1/2) of 39 ± 7 and 9.9 ± 0.1 min. bis(p-nitrophenyl) phosphate (BNPP), a specific inhibitor of carboxylesterases, was found to inhibit hydrolytic cleavage in a time- and concentration-dependent manner, which suggested the involvement of carboxylesterases in the metabolism of 3. In contrast with the findings in rodents, 3 was resistant to hydrolytic cleavage in both dog and human plasma. 3. The instability of 3 was also observed in rat and mouse liver microsomes. β-Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-dependent metabolism of 3 occurred more rapidly (T1/2 approximately 2.22-6.4 min) compared with the metabolic component observed in the absence of the co-factor (T1/2 approximately 89-130 min). Oxidative metabolism dominated the NADPH-dependent decline of 3, whereas NADPH-independent metabolism of 3 proceeded via simple amide bond hydrolysis. 4. Compound 3 was highly bound (approximately 95%) to both dog and human plasmas. Rat and mouse plasma, pre-treated with BNPP to inhibit carboxylesterases activity, were used to determine the fu plasma of 3. A BNPP concentration of 500 μM was determined to be optimal for these studies. Higher BNPP concentrations (1000 μM) appeared to displace 3 from its plasma protein-binding sites in preclinical species and human. Under the conditions of carboxylesterases-inhibited rat and mouse plasma, the level of protein binding displayed by 3 was similar to those observed in dog and human. 5. In conclusion, a novel system has been devised to measure fu plasma for a plasma-labile compound. The BNPP methodology can be potentially applied to stabilize hydrolytic cleavage of structurally diverse carboxylesterase substrates in the plasma (and other tissue), thereby allowing the characterization of pharmacology studies on plasma-labile compounds if and when they emerge as hits in exploratory drug- discovery programmes. [ABSTRACT FROM AUTHOR]

Background: Bilateral lymph node dissection is not a standard surgical treatment for non-small cell lung carcinoma. However, data from anatomical studies showing lymph flow to the contralateral mediastinal lymph nodes have prompted attempts to extend lymph node dissection to the contralateral mediastinum. Little is known about the functional effects of extended lymphadenectomy. This study aimed to determine whether bilateral mediastinal lymphadenectomy (BML) performed as part of lung cancer surgery leads to more severe impairment of respiratory function than standard systematic lymph node dissection (SLND)., Methods: Respiratory function data were derived from a randomized clinical study (BML-1), which included patients with non-small cell lung cancer (NSCLC) who underwent curative-intent lung resection with standard SLND or BML. Lung function tests were performed preoperatively and on postoperative days 1, 3-5, 7-9, and 30-32., Results: Data from 89 patients were available for the final analysis of the BML-1 study: 40 and 49 underwent BML and SLND, respectively. Complete respiratory function test data were available for 35 patients. The age, sex, Thoracoscore, revised cardiac risk index, dyspnea score, lobar location of the tumor, histology, preoperative pulmonary function test results, and type of lung resection were comparable for both groups. The vital capacities (VCs) were not different on postoperative days 1, 3-5, 7-9, and 30-32 (P=0.49, 0.66, 0.18, and 0.16, respectively). The forced expiratory volumes in 1 st second (FEV 1 ) obtained at the same time points were not different (P=0.40, 0.72, 0.81, and 0.32, respectively)., Conclusions: BML was not associated with a more severe deterioration of respiratory function than standard (unilateral) lymph node dissection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-327/coif). J.K. reports Jagiellonian University Statutory Grant. The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: This study evaluated the prevalence and quantity of lymph nodes at particular stations of the mediastinum in patients with lung cancer. These data are important to radiologists, pathologists, and thoracic surgeons because they can serve as a benchmark when assessing the completeness of lymph node dissection. However, relevant data in the literature are scarce., Methods: Data regarding the number of lymph nodes derived from two randomised trials of bilateral mediastinal lymph node dissection, the BML-1 and BML-2 study, were included in this analysis. Detectable nodes at particular stations of the mediastinum and the number of nodes at these stations were analysed., Results: The mean number of removed nodes was 28.67 (range, 4-88). Detectable lymph nodes were present at stations 2R, 4R, and 7 in 93%, 98%, and 99% of patients, respectively. Nodes were rarely present at stations 9 L (33%), and 3 (35%). The largest number of nodes was observed at stations 7 and 4R (mean, 5 nodes)., Conclusion: The number of mediastinal lymph nodes in patients with lung cancer may be greater than that in healthy individuals. Lymph nodes were observed at stations 2R, 4R, and 7 in more than 90% of patients with lung cancer. The largest number of nodes was observed at stations 4R and 7. Detectable nodes were rarely observed at stations 3 and 9 L., Trial Registration: ISRCTN 86,637,908., (© 2024. The Author(s).)

Background: Positron-emission tomography (PET) is widely used for staging lung cancer. Although a correlation between the fluorodeoxyglucose standardized uptake value (SUV) and the histologic grade of the tumor has been shown in several studies, little is known about the impact of different clinical variables on this correlation. This study aimed to evaluate the correlation between tumor SUV and tumor grade in a large cohort of patients and to analyse the impact of clinical factors on this correlation., Methods: This retrospective cohort study including patients with non-small cell lung cancer age 18-90 years, with clinical stage I-IVA, who underwent curative-intent lung resection., Results: Data from 726 patients was included in this study. There was a strong correlation between SUV and primary tumor grade in the whole cohort (P<0.001), which was significant in both sexes (P<0.001) and in all selected age groups (P<0.001-0.03). There was a significant SUV-grade correlation for the right upper and left lower lobes, as well as for the central location in the right lung (P<0.001, P=0.005 and P=0.04, respectively). Moreover, a significant SUV-grade correlation was found for squamous cell cancer and adenocarcinoma (P<0.001 and P=0.01, respectively), and for T1-T3 factors (P<0.001, P=0.006, P=0.005 respectively)., Conclusions: In patients with resectable lung cancer, a significant correlation was observed between the SUV of the primary tumor and its grade. This correlation was maintained for both sexes, age groups, most common histological types and T factors T1-T3., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-798/coif). All authors report that this study was supported by a statutory grant of the Jagiellonian University. The authors have no other conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Objectives: This study aimed to analyze the effect of bilateral mediastinal lymphadenectomy (BML) on survival of non-small cell lung cancer (NSCLC) patients. The hypothesis was: BML offers survival benefit as compared with SLND., Methods: A randomized clinical trial including stage I-IIIA NSCLC patients was performed. All patients underwent anatomical lung resection. BML was performed during the same operation via additional cervical incision (BML group). In the control group, standard lymphadenectomy (systematic lymph node dissection, SLND) was performed., Results: In total, 102 patients were randomized. No significant difference was found in the type of lung resection, blood loss, chest tube output, air leak, pain, and complications (p = 0.188-0.959). In the BML group, the operative time was longer (318 vs 223 min, p < 0.001) with higher number of removed N2 nodes (24 vs 14, p < 0.001). The 5-year survival rate was 72 % in the BML group vs 53 % in the SLND group (OR 2.33, 95 % CI 0.95-5.69, p = 0.062). Separate comparisons for different lobar locations of the tumor have shown no significant difference in survival for the right lung tumors and left upper lobe tumors. For the left lower lobe tumors, survival time was longer in the BML group (p = 0.021), and the 5-year survival rate was 90.9 % vs 37.5 %, (OR 16.66, 95 % CI 1.36-204.04, p = 0.0277)., Conclusions: In patients with NSCLC located in the left lower lobe, bilateral lymph node dissection may be associated with better survival. The invasiveness of BML is comparable to that of SLND., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The tracheobronchomalacia is a life-threatening complication of mucopolysaccharidosis (MPS) without known effective, optimal treatment. The severe expiratory collapse of the trachea and bronchi is one of causes of the high rate of deaths in the course of airway impairment in MPSII patients., Case Presentation: Due to the adynamic tracheobronchomalacia despite of enzymatic treatment (ERT) in our MPSII patient, a life-saving tracheal bifurcated type-Y endoprosthesis (a self-expanding, metal stent for the prosthesis of tracheal and bronchial stenosis) was implanted. In the followed months, the breathing efficiency improved, but then gradual worsening, progression of bronchi occlusion at the stent border resulted in patient's death., Conclusion: The Y-stent implantation appears to be a short-term, life-saving solution without satisfactory long-term effects due to the progress of peripheral bronchomalacia and increased tissue proliferation and granulation, that arises during the illness' course.

In this article, we describe the discovery of an aryl ether series of potent and selective Na v 1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Na v channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Na v 1.3 as a target for pain.

INTRODUCTION    There are no widely accepted standards for the diagnosis of sarcoidosis. OBJECTIVES    The aim of this study was to assess the relative diagnostic yield of endobronchial ultrasound fine-needle aspiration (EBUS -FNA) and endoscopic ultrasound fine needle aspiration (EUS -FNA), and to compare them with standard diagnostic techniques such as endobronchial biopsy (EBB), transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA), and mediastinoscopy. PATIENTS AND METHODS    This was a prospective randomized study including consecutive patients with clinical diagnosis of stage I or II sarcoidosis. EBB, TBLB, and TBNA were performed at baseline in all patients. Subsequently, patients were randomized to group A (EBUS -FNA) or group B (EUS -FNA). Next, a crossover control test was performed: all patients with negative results in group A underwent EUS -FNA and all patients with negative results in group B underwent EBUS -FNA. If sarcoidosis was not confirmed, mediastinoscopy was performed. RESULTS    We enrolled 106 patients, of whom 100 were available for the final analysis. The overall sensitivity and accuracy of standard endoscopic methods were 64% each. When analyzing each of the standard endoscopic methods separately, the diagnosis was confirmed with EBB in 12 patients (12%), with TBLB in 42 patients (42%), and with TBNA in 44 patients (44%). The sensitivity and accuracy of each endosonographic technique were significantly higher than those of EBB+TBLB+TBNA (P = 0.0112 vs P = 0.0134). CONCLUSIONS    The sensitivity and accuracy of EBUS -FNA and EUS -FNA are significantly higher than those of standard endoscopic methods. Moreover, the sensitivity and accuracy of EUS -FNA tend to be higher than those of EBUS -FNA.

Background: Sufficiently large, prospective randomized trials comparing suction drainage and nonsuction drainage are lacking. The aim of the present study was to compare the effects of suction drainage and nonsuction drainage on the postoperative course in patients who have undergone lung resection., Methods: This prospective, randomized trial included patients undergoing different types of lung resections. On the day of surgery, suction drainage at -20 cm H2O was used. On the morning of the first postoperative day, patients, in whom the pulmonary parenchyma was fully reexpanded, were randomized in the ratio of 1:1. Patients assigned to group A continued with suction drainage, while those assigned to group B underwent nonsuction drainage., Results: The study included 254 patients, with 127 patients in each group. The drainage volumes were 1098.8 mL and 814.4 mL in groups A and B, respectively (p = 0.0014). The times to chest tube removal were 5.61 days and 4.49 days in groups A and B, respectively (p = 0.0014). Prolonged air leakage occurred in 5.55% of patients in group A and in 0.7% of patients in group B (p = 0.032), and asymptomatic residual air spaces were noted in 0.8% of patients in group A and 9.4% of patients in group B (p = 0.0018)., Conclusions: Nonsuction drainage is more effective than suction drainage with regard to drainage volume, drainage duration, and incidence of persistent air leakage. However, it is associated with a higher incidence of asymptomatic residual air spaces., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Iatrogenic tracheobronchial injuries are rare., Aim: To analyse the mechanism of injury, symptoms and treatment of these patients., Material and Methods: Retrospective analysis of hospital records of all patients treated for main airway injuries between 1990 and 2012 was performed., Results: There were 24 patients, including 21 women and 3 men. Mean time between injury and initiation of treatment was 12 hours (range: 2-48). In 16 patients the injury occurred during tracheal intubation, in 1 during rigid bronchoscopy, in 1 during rigid oesophagoscopy, in 1 during mediastinoscopy and in 5 during open surgery. Mean length of airway tear was 3.8 cm (range: 1.5-8). In 1 patient there was an injury to the cervical trachea and in the remaining 23 in the thoracic part of the airway. The treatment included repair of the membranous part of the trachea performed via right thoracotomy in 10 patients (in 1 patient additionally coverage with a pedicled intercostal muscle flap was used), a self-expanding metallic stent in 1 patient, suture of the right main bronchus and the oesophagus in 1, left upper sleeve lobectomy in 1, right upper lobectomy in 1, implantation of a silicone Y stent in 3, mini-tracheostomy in 1, and conservative treatment in 5 patients., Conclusions: Intubation is the most frequent cause of iatrogenic main airway injuries. Patients with these life-threatening complications require an individualised approach and treatment in a reference centre.

Introduction: The exclusion of mediastinal involvement in patients with non-small cell lung cancer is essential for choosing an appropriate therapy., Objectives: The aim of the study was to analyze the ability of a new minimally invasive strategy combining positron emission tomography (PET), endobronchial ultrasound needle aspiration (EBUS-NA), and endoscopic ultrasound needle aspiration (EUS-NA) to exclude mediastinal nodal metastases of non-small cell lung cancer., Patients and Methods: In a group of consecutive patients with primary non-small cell lung cancer, the preoperative assessment of medisastinal lymph nodes using PET, EBUS-NA, and EUS-NA. Patients in whom this minimally invasive staging protocol did not confirm mediastinal nodal metastases underwent pulmonary resection with systematic lymph node dissection. The negative predictive values of the combined EBUS-NA/EUS-NA as well as PET/EBUS -NA/EUS-NA were calculated., Results: We analyzed data of 532 patients (367 men and 165 women; mean age, 65 years [range, 30-84 years]). Squamous carcinoma were diagnosed in 276 patients; adenocarcinoma, in 150; large cell carcinoma, in 22; adenosquamous carcinoma, in 40; small cell carcinoma, in 4; carcinoids, in 21; and other histological types, in 19. We performed 421 lobectomies, 55 pneumonectomies, 51 bilobectomies, and 5 sublobar resections. In all patients, systematic lymph node dissection was performed. The mean number of removed lymph nodes was 22. The negative predictive value of EBUS-NA/EUS-NA was 89.8% and of PET/EBUS-NA/EUS-NA-93.2%., Conclusions: Patients with lung cancer with negative results of PET, EBUS-NA, and EUS-NA are at low risk of mediastinal nodal metastasis. In these patients, invasive mediastinal staging may not be necessary.

Objectives: The aim of this review is to present the current role of two techniques of extensive mediastinal dissection, in the staging of lung cancer., Materials and Methods: The authors performed a search for original papers published in English language, peer-reviewed journals., Results: According to the published evidence, definitions of VAMLA and TEMLA are given and the main elements of the operative technique are briefly presented. Extensiveness and completeness of mediastinal lymph node dissection using these techniques, their diagnostic yield as well as complications and use of hospital resources are discussed. The role of VAMLA and TEMLA in the contemporary staging of lung cancer is presented in context of other staging techniques and the current clinical practice guidelines., Conclusion: On the basis of the evidence currently available, it may be concluded that VAMLA and TEMLA have no contemporarily use in the routine mediastinal staging of lung cancer. This is because of their invasiveness and - at least for TEMLA - high risk of complications and mortality, which renders it unacceptable as a diagnostic procedure, and also due to the development of equally accurate, but far less invasive techniques, i.e. EBUS-NA and EUS-NA., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE., (Copyright 2010 Elsevier Ltd. All rights reserved.)

MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.

HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains an important goal. Using an HIV-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affinity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).