Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease Pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)-induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)-treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain-containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1ß-mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

Downregulation of dual-specificity tyrosine-regulated kinase 2 promotes tumor cell proliferation and invasion by enhancing cyclin-dependent kinase 14 expression in breast cancer.

Tumor progression is the main cause of death in patients with breast cancer. Accumulating evidence suggests that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, little is known about the mechanisms of transcriptional regulation by DYRK2 in cancer progression, particularly with respect to cancer proliferation and invasion. Here, using a comprehensive expression profiling approach, we show that cyclin-dependent kinase 14 (CDK14) is a target of DYRK2. We found that reduced DYRK2 expression increases CDK14 expression, which promotes cancer cell proliferation and invasion in vitro, in addition to tumorigenicity in vivo. CDK14 and DYRK2 expression inversely correlated in human breast cancer tissues. We further identified androgen receptor (AR) as a candidate of DYRK2-dependent transcription factors regulating CDK14. Taken together, our findings suggest a mechanism by which DYRK2 controls CDK14 expression to regulate tumor cell proliferation and invasion in breast cancer. Targeting of this pathway may be a promising therapeutic strategy for treating breast cancer.

Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis.

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

Preservation of the nipple-areola complex in skin-sparing mastectomy for early breast cancer.

PURPOSE: Skin-sparing mastectomy (SSM) enables a radical cure of breast cancer while overcoming the cosmetic issues related to surgery. We review our experience of performing SSMs and assess whether preservation of the nipple-areola complex (NAC) could have been an option for some patients who underwent SSM. METHODS: The subjects of this retrospective study were women who underwent SSM that utilized four incision types; namely, the so-called tennis racket incision, a periareolar and midaxillary incision, an areola-sparing and midaxillary incision, and a small transverse elliptical incision. We assessed whether preservation of the NAC would have been an option in SSM, based on histologic examination of three serial cut surfaces of the specimen around the nipple, ruling out the option when evidence of the malignant lesion/s was found in at least one of the following locations: in the nipple, within a 1-cm radius from the base of the nipple, or within 1 cm from the surface of the NAC. RESULTS: We performed 193 SSMs. The cumulative 10-year local disease-free survival rate was 98%, with 89% of patients reporting levels of satisfaction with the reconstructed breast, of excellent, very good, or good. We evaluated that 70 of the 193 procedures could have been performed as nipple-sparing mastectomy (NSM). CONCLUSIONS: The outcomes of SSM in this series were excellent and NSM might have been an option for about one-third of the patients.

[Pulmonary Cryptcoccosis Mimicking Malignant Tumor;Report of a Case].

Pulmonary cryptococcosis is difficult to distinguish from lung cancer clinically, and is often diagnosed by surgery. A 72-year-old woman, who underwent distal pancreatectomy and splenectomy for pancreatic carcinoma. Four months after surgery, a tumor shadow was detected in the left lung as a groundglass nodule (GGN)of 12 mm in diameter, which was found to change to 15 mm with increased density by the computed tomography(CT)scan after 2 months. The nodule showed positive accumulation of fluorodeoxyglucose(FDG)by positron emission tomography(PET), and was suspected of malignant tumor. She underwent a partial resection of the left lung under thoracoscopy.

[Elastofibroma Dorci;Report of a Case].

Elastofibroma is a relatively rare tumor that occurs commonly at the apex of scapula in elderly people. We report a case of elastofibroma of a female in her seventies. She visited our hospital with complaints of painful mass in her back, which was increasing in size. On the magnetic resonance imaging (MRI),the T1 and the T2-weighted images showed the same signal intensity as the muscle between the right scapula and the intercostal muscles. The internal fat component was cord-like, with high signal intensity. Based on the site of the tumor and characteristic findings on imaging, it was diagnosed as elastofibroma and resection was performed. Pathological findings revealed bundle-like proliferation of fibrous and spherical hyaline substances, together with collagen fibers. The hyaline substance stained in black on Elastica van Gieson staining and was confirmed to be elastic fiber. Thus, it was diagnosed as elastofibroma. The patient is on regular follow-up, with no recurrence after surgery.

[Rapidly Developing Pulmonary Cyst Complicated by Pneumothorax Occurred in the Early Post-operative Period after Lung Segmentectomy].

The patient was a 74-year-old man who had undergone surgery for rectal cancer 9 years before and had developed left lung metastasis(S3)3 years and 4 months prior to admission. He had received video assisted left lung wedge resection. He presented with a growing nodular lesion close to the remaining left lung margin and elevated serum carcinoembryonic antigen(CEA)levels, and underwent open extended segmentectomy. The chest drain tube was removed on 3rd post-operative day, but he developed left pneumothorax on 4th post-operative day and a computed tomography(CT)scan revealed a cystic lesion 5.0 cm in size at the base of his left lung. Revision surgery was performed on 8th post-operative day. A pulmonary cyst on the diaphragmatic surface of the lung(S10)was found and location of the air leak was confirmed in the same area. Following wedge resection of the cyst-containing region, the leak ceased completely. Rapid manifestation of a newly formed pulmonary cyst during the acute post-operative period is rare.

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy.

BACKGROUND: Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. METHODS: Transforming growth factor-ß (TGF-ß)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. RESULTS: We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-ß. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. CONCLUSIONS: These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

Comparison of oncological results for early- and advanced-stage thymomas: thoracoscopic thymectomy versus open thymectomy.

BACKGROUND: This study evaluated the feasibility of thoracoscopic thymectomy (TT) for the treatment of early- and advanced-stage thymoma and compared patient outcomes with those following open thymectomy (OT). METHODS: A retrospective review was conducted for 140 patients who underwent TT or OT for Masaoka stage I-IV thymoma between 1996 and 2014. RESULTS: TT was performed in 88 patients and OT in 52 patients. The postoperative hospital stay was significantly shorter in the TT group than in the OT group (4 and 13 days, respectively; P < 0.0001). WHO types B3-C were identified in Masaoka stage III-IV disease with high frequency. There was a significant relationship between Masaoka stage and WHO type (P < 0.05); the numbers of advanced-stage thymoma progressively increased in WHO type B3-C. Eight patients in each group had recurrent disease, with greater recurrence for WHO types B3-C and stage III-IV tumors. Five-year disease-free survival (DFS) was not different between groups (P = 0.3906); however, survival for patients with stage III-IV thymomas (47 %) was significantly worse than that for patients with stage I and II tumors (97.5 and 94.1 %, respectively; P < 0.0001). Based on multivariate analysis, both Masaoka stage and WHO type were significant predictors of thymoma patient survival. CONCLUSIONS: These results demonstrate the safety and substantially decreased invasiveness of TT for thymoma. The oncological results were comparable between the TT and OT groups. Furthermore, Masaoka stage III-IV and WHO B3-C were revealed as independent prognostic factors for DFS.

High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth-factor receptor cases.

A clinical implication of programmed cell death 1 ligand 1 (PD-L1) expression in lung adenocarcinoma has not been well established. We evaluated PD-L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD-L1 expression especially in terms of smoking history and epidermal growth-factor receptor (EGFR) mutation status. Patients were classified into high- and low-PD-L1 expression groups. The high-expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low-expression group (n = 189). Survival analysis showed that the prognosis of the high-expression group was worse in overall survival than that of the low-expression group (3-year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high-expression group were worse than those of the low-expression group in both strata of smokers and wild-type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD-L1 expression was a poor prognostic factor in the smokers or the patients with wild-type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology.

Metformin attenuates lung fibrosis development via NOX4 suppression.

BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-ß plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-ß-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase (AMPK), which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung fibrosis development via modulating TGF-ß signaling. METHODS: TGF-ß-induced myofibroblast differentiation in lung fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model. RESULTS: We found that TGF-ß-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-ß-induced NOX4 expression. NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-ß-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased NOX4 expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients. CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-ß.

Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence.

Cigarette smoke (CS)-induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated ß-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

Clinical comparison of four types of skin incisions for skin-sparing mastectomy and immediate breast reconstruction.

PURPOSE: Skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) has become popular as an effective procedure for patients with early breast cancer. We herein report an overview of the four types of skin incisions used for SSM. METHODS: The records of 111 consecutive breast cancer patients, who received SSM and IBR from 2003 to 2012, were reviewed retrospectively. Four types of skin incisions were used. Type A was the so-called tennis racquet incision, type B was a periareolar incision and mid-axillary incision, type C was the so-called areola-sparing with mid-axillary incision and type D was a small transverse elliptical incision and transverse axillary incision. RESULTS: Twenty-six type A, 59 type B, 20 type C and six type D incisions were made. The average blood loss and average length of the operation during SSM were not significantly different between the four approaches. The average areolar diameter was 35 mm for type A, B and D incisions, and 45 mm for type C. There was a need for postoperative nipple-areolar complex plasty (NAC-P) in 75 % of the cases following type A, B and D incisions, and 35 % of the cases treated using type C incisions. CONCLUSION: The type C incision is superior with regard to the cost and cosmetic outcomes, because fewer of these patients request postoperative NAC-P.

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence.

Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated ß-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

Insufficient autophagy in idiopathic pulmonary fibrosis.

Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.

Bronchiolar epithelial catalase is diminished in smokers with mild COPD.

This study aimed to investigate bronchiolar catalase expression and its relationship with smoking and/or chronic obstructive pulmonary disease (COPD) in humans and to determine the dynamic change of bronchiolar catalase expression in response to cigarette smoke in mice. Lung tissue was obtained from 36 subjects undergoing surgery for peripheral tumours, consisting of life-long nonsmokers and smokers with or without COPD. Male C57BL/6 mice were subjected to cigarette smoke exposure for up to 3 months followed by a 28-day cessation period. We quantified bronchiolar catalase mRNA using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction. C22 club cells (Clara cells) in culture were exposed to cigarette smoke extract and monitored for viability when catalase expression was decreased by siRNA. Catalase was decreased at mRNA and protein levels in bronchiolar epithelium in smokers with COPD. In mice, bronchiolar catalase is temporarily upregulated at 1 day after cigarette smoke exposure but is downregulated by repeated cigarette smoke exposure, and is not restored long after withdrawal once emphysema is developed. Decreasing catalase expression in C22 cells resulted in greater cigarette smoke extract-induced cell death. Bronchiolar catalase reduction is associated with COPD. Regulation of catalase depends on the duration of cigarette smoke exposure, and plays a critical role for protection against cigarette smoke-induced cell damage.

Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD.

BACKGROUND: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. METHODS: Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. RESULTS: The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. CONCLUSIONS: These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.

Insulin-dependent phosphatidylinositol 3-kinase/Akt and ERK signaling pathways inhibit TLR3-mediated human bronchial epithelial cell apoptosis.

TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.

Thoracoscopic lung segmentectomy simulated by a tailor-made virtual lung: computed bronchography and angiography.

We describe the benefits of simulating an anatomical lung segmentectomy using multidetector computed tomography bronchography and angiography (tailor-made virtual lung). Preoperative determination of the anatomical intersegmental plane is possible by visualizing the segmental bronchi and pulmonary vein branches. This advanced technique could be useful during thoracoscopic anatomical segmentectomy for lung cancer.

Polarized Neutrons Observed Nanometer-Thick Crystalline Ice Plates in Frozen Glucose Solution.

Spin-contrast-variation (SCV) small-angle neutron scattering (SANS) is a technique to determine the nanostructure of composite materials from the scattering of polarized neutrons that changes with proton polarization of samples. The SCV-SANS enabled us to determine structure of nanoice crystals that were generated in rapidly frozen sugar solutions by separating the overlapped signals from the nanoice crystals and frozen amorphous solutions. In the frozen glucose solution, we found that the nanoice crystals formed a planar structure with a radius larger than several tens of nanometers and a thickness of 2.5 ± 0.5 nm, which was close to the critical nucleation size of ice crystals in supercooled water. This result suggests that the glucose molecules were preferentially bound to a specific face of nanoice crystals and then blocked the crystal growth perpendicular to that face.