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Lung transplantation is widely accepted as the only viable treatment option for patients with end-stage lung disease. However, the imbalance between the number of suitable donor lungs available and the number of possible candidates often results in intensive care unit (ICU) admission for the latter. In the ICU setting, critical care is essential to keep these patients alive and to successfully bridge to lung transplantation. Proper management in the ICU is also one of the key factors supporting long-term success following transplantation. Critical care includes the provision of respiratory support such as mechanical ventilation (MV) and extracorporeal life support (ECLS). Accordingly, a working knowledge of the common critical care issues related to these unique patients and the early recognition and management of problems that arise before and after transplantation in the ICU setting are crucial for long-term success. In this review, we discuss the management and selection of candidates for lung transplantation as well as existing respiratory support strategies that involve MV and ECLS in the ICU setting. [ABSTRACT FROM AUTHOR]

Background: The development of chemo-resistance in non-small lung cancer is a major obstacle in treating patients. Hypoxia is a commonly faced microenvironment in solid tumor and suggested to be related to both autophagy and chemo-resistance. Methods: In this study, we investigated the role of hypoxia-induced autophagy in acquiring chemo-resistance in both cancer cell (A549) and human cancer tissue Results: Hypoxic exposure (1 % O2) of A549 cell stimulated autophagic induction in cancer cells, shown by increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 in Western blot, increased GFP-LC puncta in confocal microscopy, and increased number of double-membrane autophagic vacuoles in electron micrographs. Hypoxic exposure also induced resistance of cancer cells to cisplatin, and LC3B siRNA restored the sensitivity of cancer cells to chemotherapy. Furthermore, Human lung cancer tissues that experienced chemotherapy showed increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 compared with chemo-naïve cancer tissue in Western blot. Conclusion: Autophagy may play an important role in acquiring resistance to chemotherapy in lung cancer and hypoxia related pathway seems to be involved in autophagy induction. [ABSTRACT FROM AUTHOR]

Deubiquitinating enzymes (DUBs) regulate various cellular processes ranging from protein degradation to cellular signaling. USP19, the onlyDUBcontaining a carboxyl-terminal transmembrane domain, was proposed to function in endoplasmic reticulum-associated degradation (ERAD). Here we characterize the function and regulation of USP19. We identify Hsp90 as a specific partner that binds the catalytic domain of USP19 to promote substrate association. Intriguingly, although overexpressed USP19 interacts with Derlin-1 and other ERAD machinery factors in the membrane, endogenous USP19 is mostly in the cytosol where it binds Hsp90. Accordingly, we detect neither interaction of endogenous USP19 with Derlin-1 nor significant effect on ERAD by USP19 depletion. The USP19 transmembrane domain appears to be partially stabilized in the cytosol by an interaction with its own catalytic domain, resulting in autoinhibition of its deubiquitinating activity. These results clarify the role of USP19 in ERAD and suggest a novel DUB regulation that involves chaperone association and membrane integration. Moreover, our study indicates that the localization of tail-anchored membrane proteins can be subject to regulation in cells. [ABSTRACT FROM AUTHOR]

Background: Although overall survival for non-small cell lung cancer (NSCLC) has increased, survival rate for pathologically staged T2aN0M0 stage IB NSCLC remains low. Adjuvant chemotherapy is not a standard treatment for stage IB NSCLC. Our purpose was to determine the efficacy of platinum-based adjuvant chemotherapy in stage IB NSCLC. Methods: We retrospectively reviewed the medical records of 119 stage IB patients who underwent lobectomy and mediastinal lymph node dissection. Among these, 60 patients underwent platinum-based adjuvant chemotherapy (adjuvant group) and 59 did not receive chemotherapy (observation group). Results: Participants had a mean age of 62.12 ± 11.51 years and 73 (61.3%) were male. The median follow-up period was 49.04 months. Mean age was higher in the observation group whereas patients in the adjuvant group had larger tumors, more dissected lymph nodes, and better performance status. The 5-year overall survival was 64.7% in the observation group and 88.2% in the adjuvant group (p = 0.010). The 5-year disease-free survival was 51.3% in the observation group and 74.0% in the adjuvant group (p = 0.011). In multivariate analysis, only platinum-based adjuvant chemotherapy was a risk factor for overall survival [hazard ratio (HR) = 0.428, p = 0.049] and disease-free survival (HR = 0.57, p = 0.043). In subset analysis, patients with a larger tumor (greater than 3.2 cm), moderate to poor differentiation, and good performance status (Eastern Cooperative Oncology Group, 0) benefitted from platinum-based adjuvant chemotherapy. Conclusions: Platinum-based adjuvant chemotherapy for surgically treated stage IB NSCLC might offer better survival than observation alone. A large-scale randomized clinical trial is needed to validate these findings. [ABSTRACT FROM AUTHOR]

This study examined the hypothesis that the control of NADPH oxidase-2 (Nox2)-mediated reactive oxygen species (ROS) regulates the expression of matrix metalloproteinases (MMPs) and the migration of macrophages. Lipopolysaccharide (LPS) stimulation of Raw264.7 cells and mice peritoneal macrophages increased the expression of MMP-9, 10, 12 and 13 mRNA, and also increased Raw264.7 cell migration. Treatment with an antioxidant (N-acetyl cysteine) or Nox inhibitors strongly inhibited the expression of MMPs by LPS and inhibited cell migration. LPS caused ROS production in macrophages and increased the mRNA expression of Nox isoforms Nox1 and Nox2 by 20-fold and two-fold, respectively. While Nox1 small interfering RNA (siRNA) did not inhibit LPS-mediated expression of MMPs, Nox2 siRNA inhibited the expressions of MMP-9, 10 and 12. Neither Nox1 nor Nox2 siRNA influenced the LPS-mediated expression of MMP-13. In addition, NAC or apocynin attenuated LPS-induced ROS production and MMP-9 expression. MMP-9 expression and cell migration were controlled by ERK1/2–ROS signaling. Collectively, these results suggest that LPS stimulates ROS production via ERK and induce various types of MMPs expression and cell migration. [ABSTRACT FROM AUTHOR]

The article reports on long-term survival after pneumonectomy for non-small cell lung cancer (NSCLC) patients. Ninety-four NSCLC survivors who underwent pneumonectomy were evaluated and compared with 147 long-term survivors who underwent lobectomy. Results indicate that late cancer relapse or second primary malignancies were rare in long-term survivors following pneumonectomy but overall mortality remained high.

Since the first successful lung transplantation in 1983, there have been many advances in the field. Nevertheless, the latest data from the International Society for Heart and Lung Transplantation revealed that the risk of death from transplantation is 9%. Various aspects of postoperative management, including mechanical ventilation, could affect intensive care unit stay, hospital stay, and immediate postoperative morbidity and mortality. Complications such as reperfusion injury, graft rejection, infection, and dehiscence of anastomosis increase fatal adverse side effects immediately after surgery. In this article, we review the possible immediate complications after lung transplantation and summarize current knowledge on prevention and treatment. [ABSTRACT FROM AUTHOR]

(1) Background: Lung transplant recipients (LTRs) are at substantial risk of invasive fungal disease (IFD), although no consensus has been reached on the use of antifungal agents (AFAs) after lung transplantation (LTx). This study aimed to assess the risk factors and prognosis of fungal infection after LTx in a single tertiary center in South Korea. (2) Methods: The study population included all patients who underwent LTx between January 2012 and July 2019 at a tertiary hospital. It was a retrospective cohort study. Culture, bronchoscopy, and laboratory findings were reviewed during episodes of infection. (3) Results: Fungus-positive respiratory samples were predominant in the first 90 days and the overall cumulative incidence of Candida spp. was approximately three times higher than that of Aspergillus spp. In the setting of itraconazole administration for 6 months post-LTx, C. glabrata accounted for 36.5% of all Candida-positive respiratory samples. Underlying connective tissue disease-associated interstitial lung disease, use of AFAs before LTx, a longer length of hospital stay after LTx, and old age were associated with developing a fungal infection after LTx. IFD and fungal infection treatment failure significantly increased overall mortality. Host factors, antifungal drug resistance, and misdiagnosis of non-Aspergillus molds could attribute to the breakthrough fungal infections. (4) Conclusions: Careful bronchoscopy, prompt fungus culture, and appropriate use of antifungal therapies are recommended during the first year after LTx. [ABSTRACT FROM AUTHOR]

Background: This study aimed to introduce the authors' surgical technique of bilateral video-assisted thoracoscopic thymectomy (BVT) and to compare their early surgical results between BVT and transsternal extended thymectomy (T3-b thymectomy) for patients with myasthenia gravis (MG). Methods: The records of 114 patients who underwent either BVT ( n = 55) or T3-b thymectomy ( n = 59) for MG were reviewed retrospectively between January 2006 and November 2009. Results: No surgical mortality or major morbidity occurred in either group. There was no conversion to open thymectomy, and no statistical difference was found in operation time between the two groups (112.2 ± 26.2 min for BVT vs. 130.7 ± 27.3 min for T-3b; p = 0.908). The duration of the chest tube, the length of the intensive care unit (ICU) or hospital stay, and the duration of opioid use for pain control were shorter in BVT group. The estimated blood loss and the total amount of drainage were greater in the T3-b thymectomy group. The specimen weights retrieved by BVT (72.5 ± 61.6 g) were similar to those retrieved by T3-b thymectomy (74.1 ± 38.2 g, p = 0.63) in nonthymomatous MG. Conclusions: The BVT was a safe procedure with a surgical extent and amount similar to those of T-3b thymectomy and less invasive for patients with MG. Long-term follow-up assessment and more extensive data are mandatory to verify the early surgical outcomes. [ABSTRACT FROM AUTHOR]

Background: Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib. Methodology and Principal Findings: Here we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI. Conclusions and Significance: Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics. [ABSTRACT FROM AUTHOR]

Background: Physical function may influence perioperative outcomes of lung transplantation. We investigated the feasibility of a pulmonary rehabilitation program initiated in the immediate postoperative period at an intensive care unit (ICU) for patients who underwent lung transplantation. Methods: We retrospectively evaluated 22 patients who received pulmonary rehabilitation initiated in the ICU within 2 weeks after lung transplantation at our institution from March 2015 to February 2016. Levels of physical function were graded at the start of pulmonary rehabilitation and then weekly throughout rehabilitation according to criteria from our institutional pulmonary rehabilitation program: grade 1, bedside (G1); grade 2, dangling (G2); grade 3, standing (G3); and grade IV, gait (G4). Results: The median age of patients was 53 years (range, 25 to 73 years). Fourteen patients (64%) were males. The initial level of physical function was G1 in nine patients, G2 in seven patients, G3 in four patients, and G4 in two patients. Patients started pulmonary rehabilitation at a median of 7.5 days (range, 1 to 29 days) after lung transplantation. We did not observe any rehabilitation-related complications during follow-up. The final level of physical function was G1 in six patients, G3 in two patients, and G4 in 14 patients. Fourteen of the 22 patients were able to walk with or without assistance, and 13 of them maintained G4 until discharge; the eight remaining patients never achieved G4. Conclusions: Our results suggest the feasibility of early pulmonary rehabilitation initiated in the ICU within a few days after lung transplantation. [ABSTRACT FROM AUTHOR]

Background: The role of tumor matrix metalloproteinase-9 (MMP-9) expression in non-small cell lung cancer (NSCLC) remains controversial. In this study, we investigated the prognostic value of tumor MMP-9 expression and other clinicopathologic factors in patients with completely resected NSCLC. Methods: This retrospective study included patients who underwent complete resection of pathological stage I-IIIA NSCLC at Severance Hospital, Seoul, Korea, between 1998 and 2009. Tumor samples of 417 patients were stained by immunohistochemistry, and the expression of MMP-9 in tumor cells was evaluated, using the median immunohistochemical score of 10 (range, 0-300) as the cut-off. Results: Tumor MMP-9 expression was observed in 161 (38.6%) of 417 patients. Log-rank analysis showed a significant association of tumor MMP-9 expression with shortened disease-free survival (p = 0.01) but not with overall survival (p = 0.109). Multivariate analysis demonstrated that tumor MMP-9 expression was not an independent prognostic factor of recurrence (p = 0.142) or survival (p = 0.807). However, among patients with adenocarcinoma, tumor MMP-9 expression was associated with relapse (p = 0.003) and poor survival (p = 0.033). Furthermore, tumor MMP-9 expression was an independent prognostic indicator of relapse in patients with adenocarcinoma (p = 0.035). Conclusions: Among patients with NSCLC, tumor MMP-9 expression was associated with poor outcomes in those with adenocarcinoma, but not in those with squamous cell carcinoma. In addition, MMP-9 expression was identified as an independent predictor of relapse of completely resected lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALKnegative lung adenocarcinoma in never-smokers has not been conducted. Methods We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis (IPA). Results We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P < 0.001) and cAMPdependent protein kinase signaling (P < 0.001). Conclusions The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background This study was designed to analyze the predictive factors for survival in second primary lung cancer patients following operation. Methods A total of 1852 patients who underwent resection for primary lung cancer between January 1990 and December 2008 were reviewed, retrospectively. Results Nineteen patients were treated for synchronous second primary lung cancer and 23 patients were treated for metachronous cancer. The overall 5-year survival rate for patients with synchronous second primary lung cancer was comparable to that of patients with single-lung cancer (51.4 vs. 48.7%, p = 0.755). The overall 5-year survival rate after the first tumor resection in patients with metachronous second primary lung cancer was significantly better than that of patients with single-lung cancer (85.4 vs. 48.7%, p = 0.003), but was not significantly different after the second tumor resection (77.0 vs. 48.7%, p = 0.057). Conclusion Surgically resected second primary lung cancer had a survival comparable with single-lung cancer. Histologic concordance between the first and second tumors. [ABSTRACT FROM AUTHOR]

The mechanism by which misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol for proteasomal degradation is still poorly understood. Here, we show that importin β, a well established nucleocytoplasmic transport protein, interacts with components of the retrotranslocation complex and promotes ER-associated degradation (ERAD). Knockdown of importin β specifically inhibited the degradation of misfolded ERAD substrates but did not affect turnover of non-ERAD proteasome substrates. Genetic studies and in vitro reconstitution assays demonstrate that importin β is critically required for ubiquitination of mutant α1-antitrypsin, a luminal ERAD substrate. Furthermore, we show that importin β cooperates with Ran GTPase to promote ubiquitination and proteasomal degradation of mutant α1-antitrypsin. These results establish an unanticipated role for importin β in ER protein quality control. [ABSTRACT FROM AUTHOR]