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Purpose It is unknown whether intraoperative needle biopsy (INB) predisposes to the postoperative recurrence of lung cancer and compromises the prognosis of these patients. We conducted this study to identify the effect of INB before lobectomy on the postoperative recurrence rate and prognosis of patients with nonsmall cell lung cancer (NSCLC). Methods The subjects of this retrospective study were 953 patients with pathological stage I–III NSCLC who underwent lobectomy between 2001 and 2016. The patients were divided into two groups: the INB group (n = 94) and the non-INB group (n = 859). After propensity score matching (PSM), we compared the postoperative cumulative recurrence rate, recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) between the two groups. Results After PSM, 94 patient pairs were matched. The cumulative recurrence rate was significantly higher in the INB group than in the non-INB group (P = 0.01). The 5-year RFS rate was significantly lower in the INB group than in non-INB group (48% vs 68%), as were the 5-year DSS (76% vs 92%) and 5-year OS rates (67% vs 84%) (all P Conclusions The findings of this analysis suggest that INB before lobectomy may increase the cumulative recurrence rate and worsen the prognosis of patients with resectable NSCLC. Thus, we believe that INB should be avoided unless a lung lesion cannot be diagnosed by another type of biopsy.

As the number of lung transplantation is increasing in Japan, retransplantation is also expected to increase, especially for chronic lung allograft dysfunction (CLAD). According to international experience on lung retransplantation, the short and long-term outcomes of retransplantation is inferior to the initial lung transplantation. Thus, indication and surgical options of retransplantation should be carefully and objectively examined. Especially, patients with recognized poor prognostic factors for retransplantation should be carefully evaluated. Such factors include indications other than CLAD, restrictive allograft syndrome( RAS), and a case with short time period since the first transplantation. In addition, those with relatively old age, declined renal function, and immunological sensitization( especially formation of antibodies against human leukocyte antigen) should also be carefully evaluated. Medication adherence is one of the most important parts of assessment for retransplantation. Surgically, lung retransplantation ipsilateral to the initial transplantation needs careful dissection of hilar structures. In addition, special caution is needed for cases expected to have severe pleural adhesion including those with RAS.

BACKGROUND The number of mobile health (mHealth) apps continues to rise each year. Widespread use of the Mobile App Rating Scale (MARS) has allowed objective and multidimensional evaluation of the quality of these apps. However, no Japanese version of MARS has been made available to date. OBJECTIVE The purposes of this study were (1) to develop a Japanese version of MARS and (2) to assess the translated version’s reliability and validity in evaluating mHealth apps. METHODS To develop the Japanese version of MARS, cross-cultural adaptation was used using a universalist approach. A total of 50 mental health apps were evaluated by 2 independent raters. Internal consistency and interrater reliability were then calculated. Convergent and divergent validity were assessed using multitrait scaling analysis and concurrent validity. RESULTS After cross-cultural adaptation, all 23 items from the original MARS were included in the Japanese version. Following translation, back-translation, and review by the author of the original MARS, a Japanese version of MARS was finalized. Internal consistency was acceptable by all subscales of objective and subjective quality (Cronbach α=.78-.89). Interrater reliability was deemed acceptable, with the intraclass correlation coefficient (ICC) ranging from 0.61 to 0.79 for all subscales, except for “functionality,” which had an ICC of 0.40. Convergent/divergent validity and concurrent validity were also considered acceptable. The rate of missing responses was high in several items in the “information” subscale. CONCLUSIONS A Japanese version of MARS was developed and shown to be reliable and valid to a degree that was comparable to the original MARS. This Japanese version of MARS can be used as a standard to evaluate the quality and credibility of mHealth apps.

Glucocorticoid causes hyperglycemia, which is common in patients with or without diabetes. Prolonged hyperglycemia can be experienced even after the discontinuation of glucocorticoid use. In the present study, we examined the time course of blood glucose level in hospital patients who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance tests, level of insulin and glucagon-like peptide 1 (GLP-1), and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.

Standardized uptake values (SUVs) derived fromLTx was performed on 4 groups of rats: isograft, allograft-cyclosporineIn total, 837 radiomic features were extracted from each PET image. The SUVSUV

Background Although the number of patients who undergo extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is increasing worldwide, there are few reports on lung transplantation after long-term ECMO (more than 1 month). We report a rare case of successful bilateral lung transplantation in a Japanese patient after 5 months of veno-venous (VV)-ECMO support. Case presentation A 27-year-old man who underwent bone marrow transplantation (BMTx) with fully matched human leukocyte antigen typing was diagnosed with bronchiolitis obliterans caused by chronic graft-versus-host disease 3 years after the BMTx. One year later, his respiratory condition had exacerbated, with carbon dioxide retention that required conventional mechanical ventilation. He was then deemed a suitable candidate for lung transplantation by a multidisciplinary transplantation selection committee. While waiting for donor lungs, his hypercapnia and acidosis became barely manageable under care with mechanical ventilation and ultimately he was switched to VV-ECMO. He remained on VV-ECMO for the next 5 months, during which period the circuit was switched nine times. In addition, sophisticated intensive care was required to manage multiple episodes of sepsis and coagulopathy. A suitable donor was identified 5 months later, and bilateral lung transplantation was initiated with continuous VV-ECMO. The procedure itself was extremely challenging owing to severe adhesions resulting from previous thoracotomy, inflammation, infection, and intrapulmonary hemorrhage. The operative time for the transplantation was about 19 h. Currently, at 2 years 8 months postoperatively, the patient is alive and well. Conclusion Transplant surgery in this patient was extremely challenging because of the presence of severe pleural adhesions and stiff native lungs secondary to hemorrhagic complications due to the prolonged ECMO support. Surgeons must recognize that lung transplantation after long-term ECMO bridging can be technically more complicated and challenging than shorter-term ECMO.

Objectives Virtual-assisted lung mapping 2.0 is a novel preoperative bronchoscopic lung mapping technique combining the multiple dye marks of conventional virtual-assisted lung mapping with intrabronchial microcoils to navigate thoracoscopic deep lung resection. This study's purpose was to evaluate the feasibility of virtual-assisted lung mapping 2.0 in resecting deeply located pulmonary nodules with adequate margins. Methods A multicenter, prospective single-arm study was performed from 2019 to 2020 in 8 institutions. The selection criteria were barely identifiable nodules requiring sublobar lung resections, nodules requiring resection lines reaching the inner 2/3 of the pulmonary lobe on computed tomography images in wedge resection, or the nodule center located in the inner 2/3 of the pulmonary lobe in wedge resection or segmentectomy. Resection margins larger than 2 cm or the nodule diameter were considered successful resection. Bronchoscopic placement of multiple dye marks and microcoil(s) was conducted 0 to 2 days before surgery. Results We analyzed 65 lesions in 64 patients. The diameter and depth of the targeted nodules and the minimum required resection depth reported as median (interquartile range) were 9 (7-13) mm, 11 (5-15) mm, and 30 (25-35) mm, respectively. Among 60 wedge resections and 5 segmentectomies, successful resection was achieved in 64 of 65 resections (98.5%; 95% confidence interval, 91.7-100). Among 75 microcoils placed, 3 showed major displacement after bronchoscopic placement. There were no severe adverse events associated with the virtual-assisted lung mapping procedure. Conclusions This study demonstrated that virtual-assisted lung mapping 2.0 can facilitate successful resections for deep pulmonary nodules, overcoming the limitations of conventional virtual-assisted lung mapping.

Since the early 1970s, many artificial reefs (ARs) have been deployed in Japanese coastal waters to create fisheries grounds. Recently, researchers began to use environmental DNA (eDNA) methods for biodiversity monitoring of aquatic species. A metabarcoding approach using internal standard DNAs [i.e., quantitative MiSeq sequencing (qMiSeq)] makes it possible to monitor eDNA concentrations of multiple species simultaneously. This method can improve the efficiency of monitoring AR effects on fishes. Our study investigated distributions of marine fishes at ARs and surrounding stations in the open oceanographic environment of Tateyama Bay, central Japan, using qMiSeq and echo sounder survey. Using the qMiSeq with 12S primers, we found higher quantities of fish eDNAs at the ARs than at surrounding stations and different fish species compositions between them. Comparisons with echo sounder survey also showed positive correlations between fish eDNA concentration and echo intensity, which indicated a highly localized signal of eDNA at each sampling station. These results suggest that qMiSeq is a promising technique to complement conventional methods to monitor distributions of multiple fish species.

Cells adapt to applied cyclic stretch (CS) to circumvent chronic activation of proinflammatory signaling. Currently, the molecular mechanism of the selective disassembly of actin stress fibers (SFs) in the stretch direction, which occurs at the early stage of the cellular response to CS, remains controversial. Here, we suggest that the mechanosensitive behavior of myosin II, a major cross-linker of SFs, primarily contributes to the directional disassembly of the actomyosin complex SFs in bovine vascular smooth muscle cells and human U2OS osteosarcoma cells. First, we identified that CS with a shortening phase that exceeds in speed the inherent contractile rate of individual SFs leads to the disassembly. To understand the biological basis, we investigated the effect of expressing myosin regulatory light-chain mutants and found that SFs with less actomyosin activities disassemble more promptly upon CS. We consequently created a minimal mathematical model that recapitulates the salient features of the direction-selective and threshold-triggered disassembly of SFs to show that disassembly or, more specifically, unbundling of the actomyosin bundle SFs is enhanced with sufficiently fast cell shortening. We further demonstrated that similar disassembly of SFs is inducible in the presence of an active LIM-kinase-1 mutant that deactivates cofilin, suggesting that cofilin is dispensable as opposed to a previously proposed mechanism.

The challenges in video-assisted thoracic surgery for sublobar lung resection include difficulty in tumour localization by palpation and difficulty in determining appropriate resection lines. Virtual-assisted lung mapping (VAL-MAP), a bronchoscopic preoperative multispot lung dye-marking technique, allows for both tumour localization and determination of resection lines. To facilitate stapler-based resection, the AMAGAMI or ‘incomplete grasping’ stapler technique is useful to adjust the alignment of the stapler and resection lines. However, when the lung tissue to be stapled is thick, there is unavoidable uncertainty in the staple line inside the lung. We experimentally demonstrated that up to 1 cm of slippage of lung parenchyma occurs at stapling when the stapled lung tissue is >1 cm thick. VAL-MAP 2.0 is a new generation of VAL-MAP combining multispot dye markings with intrabronchial microcoil placement, allowing for 3-dimensional lung mapping and intraoperative navigation using fluoroscopy. The uncertainty of stapling in the lung parenchyma can be partly overcome by VAL-MAP 2.0.

Background Malignant gliomas are characterized by high invasive ability. In this study, we investigated roles of layilin, a C-type lectin-homologous protein, in the invasive ability of malignant glioma cells. Methods Expression of layilin was investigated by western blotting in the malignant glioma cell lines of U251-MG, A172, and T98G and in astrocytes. The effects of layilin-knockdown on the expression and protein levels of snail family transcriptional repressor 1 (SNAI1), a transcriptional factor involved in the acquisition and enhancement of invasive ability in malignant gliomas, and on the expression of its target genes, matrix metalloproteinase 2 (MMP2), MMP9, and collagen type I alpha 1 chain (COL1A1), were investigated by qPCR and/or western blotting. Furthermore, the effects of layilin-knockdown on the expression and protein levels of metastasis associated 1 family member 3 (MTA3), a transcriptional repressor of SNAI1, were also investigated by qPCR and western blotting. Finally, the effects of layilin-knockdown on the invasive ability of the cells were investigated by a wound healing assay. Results All the tested malignant glioma cells highly expressed layilin, compared to astrocytes, one of representative glial cell types. Layilin-knockdown reduced SNAI1 both at the mRNA and protein levels in A172 cells, and consequently mRNA levels of MMP2, MMP9, and COL1A1 were also reduced. Furthermore, layilin-knockdown increased nuclear protein levels of MTA3 in A172 cells. Notably, layilin-knockdown suppressed the invasive ability of the cells. Conclusion Layilin up-regulates the expression of SNAI1 via down-regulation of MTA3. This process enhances the invasive ability of malignant glioma cells.

Introduction The prognostic implications of having patients with idiopathic pleuroparenchymal fibroelastosis (IPPFE) on lung transplantation waiting lists have been unclear. In Japan, where a severe shortage of brain-dead donors remains a major limitation for organ transplantation, it is particularly important to predict the prognoses of patients when they are listed for transplantation. The purpose of this study was to investigate the characteristics of lung transplantation candidates with IPPFE and the influence of those characteristics on prognosis. Methods This was a retrospective review of 29 consecutive adult lung transplant candidates with idiopathic interstitial pneumonia between January 2014 and April 2018. Results Eight patients with IPPFE and 21 with other types of idiopathic interstitial pneumonia were included. Body mass index (median 17.1 kg/m2 vs 23.5 kg/m2, P Conclusions Patients with IPPFE waiting for transplantation have some distinctive characteristics and should be retained on waiting lists to receive transplants.

Purpose To better determine suitable resection lines for sublobar lung resection, especially to obtain sufficient resection depth, a novel technique of virtual-assisted lung mapping (VAL-MAP) 2.0 was developed by combining multispot dye marks (conventional VAL-MAP) and a deeply placed microcoil. Description With the patient under local anesthesia and sedation, multiple dye marks were bronchoscopically made on the lung surface. Microcoils were then bronchoscopically placed centrally to the tumor to indicate deep resection margins. Postmapping computed tomography confirmed the marking locations. Evaluation Six patients underwent VAL-MAP 2.0: 5 for wedge resection and 1 for segmentectomy. The mean diameter and depth of the targeted lesions were 10.0 ± 4.1 and 12.6 ± 10.3 mm, respectively. In total, 18 dye marks and 9 microcoils were placed without major complications. The microcoils were successfully identified with intraoperative fluoroscopy, effectively assisting the surgeons' decision regarding the deep resection lines. Conclusions This study confirmed the safety and feasibility of VAL-MAP 2.0. This technique effectively assisted surgeons to obtain sufficient resection margins in sublobar lung resection, even when removing deeply located lesions.

OBJECTIVES Spread through air space (STAS) is recognized as a pattern of invasion in lung adenocarcinoma and has been reported to be a predictor of recurrence and survival in patients with early-stage lung adenocarcinoma. However, this parameter has not been studied well in stage III (N2) lung adenocarcinoma. In this study, we evaluated the association between STAS invasion patterns and recurrence and survival in stage III (N2) lung adenocarcinoma. METHODS We retrospectively reviewed data from 76 patients at University of Tokyo with stage III (N2) lung adenocarcinoma who underwent surgery from August 1998 to December 2013. Statistical analysis was performed to determine the impact of STAS invasion clinicopathological features and clarify the relationship between this pattern of invasion and survival. RESULTS Tumour STAS was observed in 46 of 76 patients (60.5%) and was significantly associated with the presence of lymphatic invasion (P CONCLUSIONS The presence of STAS invasion pattern is a significant risk factor for recurrence in stage III (N2) lung adenocarcinoma.

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2-adrenoceptors, with a similar potency and efficacy to that of the nonselective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit β-arrestin1/2 to the β2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

The "AMAGAMI" or "incomplete grasping" technique is used to adjust the location of the lung while gently grasping the lung tissue with a stapler. Thoracoscopic segmentectomy requires precise but complex stapling, while the surgical view and the number of available instruments are limited. In the AMAGAMI technique, instead of moving the stapler to the targeted position of the lung tissue, an unlocked stapler is used to hold the lung tissue at an easily accessible position, and the lung tissue can then be slid to the ideal resection line using forceps. To use the AMAGAMI technique effectively, "standing stitches" are very helpful in enabling visualization of the ideal resection lines. Standing stitches are placed along intersegmental lines that have been determined based on the information provided by virtual-assisted lung mapping (VAL-MAP) or other marking techniques; these stiches are usually placed at the corner of the targeted segment and in-between if necessary. Monofilament suture is used for standing stitches, and about 1 cm lengths are left to enable later visualization. As these stitches stick out of the lung surface even when viewed from a tangential angle, the direction of stapling is easily visualized in thoracoscopic surgery. These techniques are particularly useful in challenging segmentectomy requiring complex staple lines, such as S10 segmentectomy, and in surgery with limited instrumental access, such as uniportal thoracoscopic surgery.

Background: Virtual-assisted lung mapping (VAL-MAP) is a preoperative multi-spot bronchoscopic dye-marking technique. Marking failure reportedly occurs in approximately 10% of marks. The aim of the present study was to investigate whether the patient position during dye injection in VAL-MAP affected the quality of markings. Methods: This study was a retrospective review of patients with barely palpable pulmonary nodules who underwent VAL-MAP at a single institution between December 2016 and September 2017. Easily visible markings without bulla formation were defined as “appropriate”, while other markings were defined as “inappropriate”. Patients were divided in accordance with the position during dye injection into the supine position group (n=6) and the lateral position group (n=8). The two groups were compared regarding the appropriate markings rate. The Fisher exact test and logistic regression model were used for statistical analyses. Results: Fourteen patients with 17 nodules underwent VAL-MAP with a total of 48 markings (3.4±0.9 markings per patient). Of these, 21 markings were performed in supine position, whereas 27 were performed in lateral position. There were no significant differences between the two groups in lesion size, depth, and characteristics. Almost all of the performed procedures were thoracoscopic wedge resections (94%), while one procedure was thoracoscopic left upper division segmentectomy. The appropriate markings rate was significantly greater in the lateral position group than in the supine position group (88% vs . 57%, P=0.02). Among the markings located in dorsal and ventral lung segments, the appropriate markings rate in the lateral position group tended to be greater than that in the supine position group (89% vs . 59%, P=0.06). Multivariate logistic regression analysis revealed that the lateral position was independently associated with appropriate markings (P=0.014). Conclusions: The lateral position may enable the creation of better quality markings in VAL-MAP.

Development of chronic lung allograft dysfunction involves various alloimmune-independent insults including those mediated by Toll-like receptor (TLR) signaling, which is known to activate alloimmune responses. We hypothesized that TLR signaling may also contribute to the activation of fibroblasts and promoting allograft airway fibrosis. Mouse orthotopic tracheal transplants were conducted between major histocompatibility complex (MHC)-mismatched Balb/c donor and wild-type C3H or C3H-derived TLR4 mutant recipients (nonfunctional TLR4). Immunohistochemistry on day 21 showed significantly smaller alpha-smooth muscle actin (α-SMA)-positive areas in TLR4 mutant recipients than wild-type recipients (P = .01). No difference was found for CD3+ T-cell infiltration. Proliferation of alloreactive T cells derived from the recipient spleen showed no difference between TLR4 mutant and wild-type recipients in a mixed lymphocyte reaction. The effect of TLR4 signaling was examined in primary pulmonary fibroblast cultures both with lipopolysaccharide (LPS) and transforming growth factor (TGF)-β1. Stimulation with LPS significantly increased expression of α-SMA mRNA in wild-type fibroblasts cultured with TGF-β1 compared with the control without LPS (P = .001). Taken together, these findings suggest disruption of TLR signaling leads to reduced activation of fibroblasts without affecting T-cell infiltration and proliferation in this model. TLR4-mediated activation of fibroblasts may be a potentially important mechanism of allograft remodeling.

Marine populations are generally well connected through larval exchange, and juvenile and adult migration. Genetic differentiation and/or local adaptation among populations are sometimes observed at small spatial scales. The marbled flounder (Pseudopleuronectes yokohamae) is a commercially important coastal species in Tokyo Bay, Central Japan, exhibiting different spawning phenology at a small scale. Using 30 highly polymorphic microsatellite loci, including the 16 new microsatellite loci developed in the present study, we estimated the genetic structure and demographic connectivity of specimens collected along Tokyo Bay in 2012–2013 and 2015–2016. F-statistics indicated a genetic differentiation between adult populations collected within and outside Tokyo Bay during both collection periods, but almost no difference was detected between the populations from the inner and outer parts of Tokyo Bay. Assignment tests directly estimated demographic connectivity between the inner and outer bays via larval dispersal and juvenile and adult migration. The average movement distance of marbled flounder was 13.1–29.6 km, with a maximum distance of 42.8–54.0 km. This movement distance contributed to the strong demographic connectivity between the inner and outer bays. Meanwhile, an indirect method using the isolation by distance (IBD) theory underestimated the average movement distance (5.0–7.8 km) because the isolated setting of Tokyo Bay resulted in a higher IBD slope. Based on the results of F-statistics and assignment tests, we suggest that a multilayered management by local and regional organizations may benefit the fishery in Tokyo Bay.

Background Thymic large cell neuroendocrine carcinoma (LCNEC) is extremely rare. The detailed clinical features of thymic LNCECs remain unknown. Case presentation A 90-year-old man with a history of diabetes mellitus, chronic renal failure, and an abdominal aortic aneurysm underwent computed tomography for follow-up, which showed an anterior mediastinal tumor, measuring 31 mm × 28 mm in diameter. Magnetic resonance imaging showed an iso-intensity mass on T1-weighted images and high intensity on T2-weighted images. 18F-Fluorodeoxyglucose-positron emission tomography showed marked uptake in the mass, which was diagnosed as invasive thymoma or thymic carcinoma. Video-assisted thoracic surgery through the left thoracic cavity was converted to median sternotomy due to severe adhesions between the left lung and the chest wall. Partial thymectomy and combined partial resection of left upper lobectomy and the first and the second costal cartilages were performed. The pathologic diagnosis was thymic LCNEC, Masaoka stage III. The patient developed pleural dissemination and left lung metastases in 5 months and died 12 months after surgery. Conclusions Thymic LCNEC has high malignant potential. More cases need to be studied.

Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged

Recently, activities of daily living (ADL) were identified as a prognostic factor among elderly patients with heart disease; however, a specific association between ADL and prognosis after cardiac and aortic surgery is not well established. We aimed to clarify the impact of ADL capacity at discharge on prognosis in elderly patients after cardiac and aortic surgery. This retrospective cohort study included 171 elderly patients who underwent open operation for cardiovascular disease in a single center (median age: 74 years; men: 70%). We used the Barthel Index (BI) as an indicator for ADL. Patients were classified into 2 groups according to the BI at discharge, indicating a high (BI ≥ 85) or low (BI

Object Functions of layilin, a type 1 transmembrane protein with a C-type lectin motif, remain to be clarified. We here investigated precise intracellular localization of layilin and the location-related functions. Methods We used HEK293T cells to assess the co-localization of layilin with different individual organelle markers by double immunostaining. We then investigated mitochondrial morphology in layilin-knockdown (KD) conditions, also with immunostaining. Next, we measured amounts of proteins involved in regulation of mitochondrial dynamics, DRP1, pS616-DRP1, mitofusin1, mitofusin2, CDK1, pY15-CDK1, and cyclin B1, in layilin-KD cells versus control cells by Western blot. Furthermore, by using layilin-knockout (KO) cells, amounts of CDK1 and pY15-CDK1 as well as mitochondrial morphology were investigated. Result We found that layilin localized to mitochondria rather than the other organelles. Small round-shape mitochondria were observed in control cells, whereas elongated and highly connected mitochondria were observed in layilin-KD cells. Amounts of active DRP1 (pS616-DRP1) and total DRP1 were significantly smaller in layilin-KD cells than in controls. Amounts of inactive CDK1 (pY15-CDK1) were significantly larger in layilin-KD cells than in controls. No other tested molecules were significantly altered in layilin-KD cells. Amounts of inactive CDK1 were significantly larger in layilin-KO cells than in wild type (WT) cells. Small round-shape mitochondria were observed in WT cells, whereas elongated and highly connected mitochondria were observed in layilin-KO cells. Conclusion We here demonstrated that layilin played a role in the maintenance of fragmented mitochondria in mitochondrial dynamics and that this function needed CDK1 and DRP1 activation. Our data unveiled a novel function for layilin, regulation of mitochondrial dynamics.

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis., This work was supported by grants from MICINN (RTI2018-098581-B-I00 to L.M.P.), Fundación Tatiana Pérez de Guzman el Bueno, and the SynCogDis Network (SAF2014-52624-REDT and SAF2017- 90664-REDT to L.M.P. and A. Bayes). Collaboration between L.M.d.l.P. and Y.H. was supported by Human Frontiers Science Program (HFSP) grant RGP0022/2013. J.P.L.-A. was supported by grants from MICIU co-financed by ERDF (RYC-2015-18056 and RTI2018-102260-B-I00) and Severo Ochoa grant SEV-2017-0723. R.R.-V. and A. Bayes were supported by MINECO BFU2015-69717-P and RTI2018-097037-B-100 and a Marie Curie career integration grant (ref. 304111). A.V.M. was supported by MICINN (SAF2017- 85717-R) and Fundación Alicia Koplowitz. A. Barco was supported by grants SAF2017-87928-R from MICINN co-financed by ERDF and RGP0039/2017 from the Human Frontiers Science Program Organization. The Instituto de Neurociencias is a ‘‘Centre of Excellence Severo Ochoa.’’ D.G.-D. and C.M.N. hold PhD fellowships from MICINN (BES-2013-064171 and BES2016-076281, respectively).

Emerging evidence suggests that G protein coupled receptor 55 (GPR55) may influence adrenoceptor function/activity in the cardiovascular system. Whether this reflects direct interaction (dimerization) between receptors or signalling crosstalk has not been investigated. This study explored the interaction between GPR55 and the alpha 1A-adrenoceptor (α

Background Virtual-assisted lung mapping (VAL-MAP) is a preoperative bronchoscopic multi-spot dye-marking technique, which can be combined with bronchoscopic placement of a microcoil (VAL-MAP 2.0). VAL-MAP can identify unpalpable pulmonary lesions; however, the markings are occasionally deemed invisible intraoperatively. We investigated preoperative risk factors for invisible markings after VAL-MAP. Methods We prospectively performed preoperative VAL-MAP in patients at the University of Tokyo between January 2014 and June 2020. Data of 219 patients (257 lesions) and 857 markings were retrospectively reviewed. Dye markings were categorized as Grade 0 (invisible) or 1–5 (visible). The risk factors for Grade 0 markings were assessed using multiple logistic regression analysis. Subsegments of the bronchus showing Grade 0 markings were also evaluated for 133 lesions and 504 markings without missing data for the target segment. Results Sixty-one of the 257 lesions (24%) displayed > 1 Grade 0 markings. Seventy-six (8.9%) of the 857 markings were Grade 0 intraoperatively. VAL-MAP 1.0 was performed for 202 (79%) and 25 lesions (10%) without and with electromagnetic navigation bronchoscopy, and VAL-MAP 2.0 with a microcoil was performed for 30 lesions (11%). Upper lobe markings were associated with a significantly increased risk of invisible markings. There was no significant difference in the frequency of Grade 0 markings among the VAL-MAP methods. Among all bronchi subsegments, left B1+2c exhibited the highest rate of Grade 0 markings. Conclusions Markings placed using VAL-MAP are more likely to be invisible for upper lobe pulmonary lesions. Injecting markings for lesions in the left S1+2c thus require caution.

Background: Antagonistic tasks are cognitive-motor task trainings. Intervention programs involving antagonistic exercise tasks are being employed to help prevent falls and reduce the need for nursing care in older populations. Meanwhile, the effects of such tasks on blood flow in the brain remain obscure. This study aimed to clarify the effects of antagonistic tasks on prefrontal cortical cerebral hemodynamics. Materials and Methods: We assessed 13 healthy adults (two men, 11 women; mean age, 21.4 ± 1.0 years). Participants imitated each of the antagonistic tasks presented on a PC monitor placed at a 120-mm viewing distance. All participants performed six tasks, consisting of upper-limb tasks (non-antagonism, simple antagonism, and complex antagonism) and upper- and lower-limb tasks (tasks combining lower-limb opening and closing movements with each upper-limb task). We used near-infrared spectroscopy (NIRS) to measure cerebral blood flow dynamics, with oxygenated hemoglobin (Oxy-Hb) concentration changes as the main outcome. A 10-channel probe was placed on the participants’ forehead, focusing on the prefrontal cortex. We first obtained a baseline NIRS measurement for 10 s; the participants then imitated the task presented on the PC monitor for 90 s. We measured the number of errors and the subjective difficulty of each task. Results: The increase in prefrontal cortex Oxy-Hb concentration was significantly higher in the complex antagonist conditions than in the non-antagonistic and simple antagonistic conditions. There were no significant prefrontal cortex Oxy-Hb differences between the upper limb and upper- and lower-limb conditions (increasing number of motor limbs). Conclusions: The study findings support that an increase in finger-shaped complexity has a greater effect on cerebral blood flow dynamics in the prefrontal cortex than does an increase in the number of motor limbs involved in the task.

Background Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare lung disease that manifests as parenchymal fibrosis of the upper lung lobe and pleura. There have been no reports of IPPFE complicating pregnancy. Here, we report a case of IPPFE that deteriorated rapidly during pregnancy. Case presentation A 29-year-old woman presented with dyspnea and dry cough at 19 weeks of gestation. IPPFE with acute exacerbation was suspected on chest computed tomography (CT). Despite steroid treatment, her condition progressed. A cesarean section was performed at 28 weeks of gestation. On postoperative day 26, she underwent living-donor lung transplantation. She was discharged a year after transplantation. Conclusion Our experience suggested that when pregnancy is complicated by PPFE, the disease may deteriorate rapidly. In this case, even though IPPFE with acute exacerbation was diagnosed during pregnancy, live birth was achieved, and the mother survived after lung transplantation. Lung transplantation should be considered in these patients because, once advanced, pulmonary lesions may be irreversible.

This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF).We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018.There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/mDespite extrapulmonary problems such as a flat chest, low BMI, and associated restrictive impairment persisting in patients with IPPFE, patient survival after LT for IPPFE or IPF was equivalent.

Background Systemic scleroderma (SSc) involves multiple organs including the skin, the lung, the kidney, and the esophagus. Nowadays, patient life prognosis has substantially improved due to more appropriate management of lung complications, including lung transplantation. However, the extension of their survival may increase SSc patients with chronic kidney diseases and requiring renal replacement therapy (RRT). Case presentation A 51-year-old female with SSc who underwent unilateral deceased-donor lung transplantation was referred because of progressive renal dysfunction. Despite no episodes of scleroderma renal crisis, her renal function gradually deteriorated for 2 years with her serum creatinine level increasing from 0.5 mg/dL at transplantation to 4.3 mg/dL. Although we reinforced antihypertensive treatment and reduced calcineurin inhibitor dose, she thereafter developed symptomatic uremia. Due to impaired manual dexterity with contracture of the interphalangeal joints, no caregivers at home, and kidney transplantation donor unavailability, maintenance hemodialysis was chosen as RRT modality. Further, due to the narrowing of superficial vessels in the sclerotic forearm skin and post-transplant immunocompromised status, the native left brachiocephalic arteriovenous fistula was created. Post-operative course was uneventful while any sign of cutaneous infection and pulmonary hypertension was closely monitored. Our literature review also indicates several difficulties with initiating and maintaining RRT in patients with SSc although case reports of kidney failure after lung transplanation in SSc were not accumulated. Conclusions With respect to initiating RRT for post-lung transplant patients with SSc, the clinical course of our case exemplifies recent complex trends of renal management. The optimal modality with secured initiation of RRT should be carefully determined based on the severity and risk for the cardiopulmonary, peripheral vascular, cutaneous, and systemic or local infectious complications.

Physical biomarkers to stratify patients with lung cancer into subtypes predictive of outcome beyond tumor-related characteristics are underexplored. This study was designed to investigate the clinical utility of preoperative sarcopenia based on respiratory strength and pectoralis muscle mass to predict the risk of death.This retrospective study included 346 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. Respiratory strength and muscle mass were assessed by peak expiratory flow rate and pectoralis muscle index (pectoralis muscle area/body mass index) using preoperative spirometry and chest axial images, respectively. Sarcopenia cutoff points were defined by gender-specific medians of peak expiratory flow rates and pectoralis muscle indices. Survival was compared between patients with sarcopenia and patients without.Sarcopenia was present in 98 patients (28.3%) and was significantly associated with advancing age (P .001). Patients with sarcopenia exhibited worse 5-year overall survival compared with patients without sarcopenia (69.9% vs 87.2%, P .001). Multivariate analysis revealed that sarcopenia was an independent adverse prognostic factor (hazard ratio, 1.88; 95% confidence interval, 1.09-3.24; P = .023) after adjustment for gender, age, smoking status, coronary heart disease, diffusing capacity for carbon monoxide, neutrophil-to-lymphocyte ratio, albumin, histologic type, and pathologic stage.Preoperative sarcopenia as identified by the criteria of low respiratory strength and reduced pectoralis muscle mass is significantly associated with poor overall survival. This may help to develop more individualized management strategies and optimize longitudinal care for patients.

Purpose The 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has the potential of a noninvasive method for lung allograft rejection (AR) detection, but the accuracy is unsatisfied. Radiomics has been shown to improve the accuracy of diagnosis and treatment response assessment in other fields. Using a rat model of lung transplantation (LTx), we aim to assess the correlation between 18F-FDG PET-based radiomics and lung AR, and compare the predictive power to standardized uptake values (SUVs). Methods Twenty-eight rats were included in three groups at week 3 (Syngeneic, Immunosuppression and AR) and four groups (Syngeneic, Immunosuppression, Hybrid and AR) at week 6. The PyRadiomics package was used to extract the radiomic features from the PET images. The least absolute shrinkage and selection operator (LASSO) algorithm was used to establish the AR-related radiomics signature. A radiomics signature-based nomogram was created to visualize the outcome prediction. We compared the predictive performance of the radiomics signature and SUVs using the area under the receiver operator characteristic curve (AUC). Histopathology results served as a reference. Results From the PET images, a total of 110 radiomic features were extracted, and most of the radiomic features had an acceptable correlation with the histopathological results (P Conclusion The 18F-FDG PET-based radiomics is a potential noninvasive and accurate method to predict lung AR in a rat model of an orthotopic LTx. The radiomics signature showed a better predictive power than SUVs.

Living-donor lobar lung transplantation is often indicated for acute exacerbation of idiopathic interstitial pneumonia because of the long waiting time for cadaveric lung transplantation in Japan. Donors without major underlying diseases are selected after medical screening. A 44-year-old man donated his right lower lobe to his sibling with idiopathic interstitial pneumonia. Although he was free of any major medical problems before transplantation, fibrotic changes appeared in both the donated lung and the donor's remaining lungs in a case of familial interstitial pneumonia. For living-donor lobar lung transplantation for idiopathic interstitial pneumonia, donor candidates should be informed of the potential issue of a familial disease.

BackgroundNot all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.MethodsNSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.ResultsTwenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.ConclusionsAlthough autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration numberUMIN000006128

The β3 -adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at β-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [3 H]-2-deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at β3 -adrenoceptors as they were largely absent in adipocytes derived from β3 -adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the β3 -adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the β3 -adrenoceptor.

In the hippocampus, locations associated with salient features are represented by a disproportionately large number of neurons, but the cellular and molecular mechanisms underlying this over-representation remain elusive. Using longitudinal calcium imaging in mice learning to navigate in virtual reality, we find that the over-representation of reward and landmark locations are mediated by persistent and separable subsets of neurons, with distinct time courses of emergence and differing underlying molecular mechanisms. Strikingly, we find that in mice lacking Shank2, an autism spectrum disorder (ASD)-linked gene encoding an excitatory postsynaptic scaffold protein, the learning-induced over-representation of landmarks was absent whereas the over-representation of rewards was substantially increased, as was goal-directed behavior. These findings demonstrate that multiple hippocampal coding processes for unique types of salient features are distinguished by a Shank2-dependent mechanism and suggest that abnormally distorted hippocampal salience mapping may underlie cognitive and behavioral abnormalities in a subset of ASDs.Using longitudinal two-photon calcium imaging in mice during virtual navigation, Sato et al. demonstrate that persistent and separable neuronal subsets mediate the hippocampal over-representation of reward and landmark locations. Learning-induced over-representation of landmarks is absent while rapid over-representation of rewards is enhanced, in a mouse model of autism lacking Shank2., This work was supported by Precursory Research for Embryonic Science and Technology (PRESTO) JPMJPR12A1 from the Japan Science and Technology Agency (JST), KAKENHI grants 24700403, 25116528, 26115530,17H05985, 19H04942, and 20H03550 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS), and a grant from the Senshin Medical Research Foundation to M.S.; RIKEN, NIH grant R01DA17310, KAKENHI grants 22110006, 16H01292, and 18H05434, a Human Frontier Science Programme grant, and Fujitsu Laboratories to Y.H.; KAKENHI grants 25830023, 15H01571, 17H05695, and 19K16293 to K.M.; KAKENHI grant 26870577 to T.T.; KAKENHI grant 15H04265 to T.F; KAKENHI grants 26115504, 15H05723, and 16H06536, and the program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from MEXT and the Japan Agency for Medical Research and Development (AMED) to J.N.; Regional Innovation Cluster Program grant (City Area Type, Central Saitama Area) from MEXT to J.N. and M.O.; and grants from the VW Foundation (ZN2632), BCCN (01GQ1005A and 01GQ1005B), DFG (CRC 1286, 889), the Ministry for Science and Culture of Lower Saxony, and the Max Planck Society to F.W. D.G.-D. is a recipient of the PhD fellowship BES-2013-064171 and a grant from the shortterm visit program EEBB-I-15-09552.

The β3‐adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity‐related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at β‐adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron‐mediated effects were examined on cyclic AMP, UCP1 mRNA, [3H]‐2‐deoxyglucose uptake, cellular glycolysis, and O2 consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1‐mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at β3‐adrenoceptors as they were largely absent in adipocytes derived from β3‐adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the β3‐adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the β3‐adrenoceptor.

Background Although the cuff technique in rat lung transplantation (LTx) has a long history, it remains technically challenging. We have developed key tricks and modifications in the devices and the cuff technique that optimize the rat LTx model to achieve successful operations during a short learning period. Methods Altogether, 180 consecutive rats underwent orthotopic left LTx performed by a single surgeon using our modified devices and procedures. Allogeneic and syngeneic transplantation were performed using Lewis rats as recipients and Brown Norway and Lewis rats as donors. Allogeneic recipients were treated with cyclosporine during the first week. Recipients were sacrificed at various time points after ≥2 weeks. Results A special cuff-preparation plate was created using a petri dish and two foam blocks. This modified plate stabilizes the preparation and prevents donor lung compression. A "┴"-shaped incision was carved into the front wall of the pulmonary artery (PA) using micro-scissors. "V"-shaped incisions were made from the inferior-to-superior branches of the pulmonary vein (PV) and bronchus. A "pendulum model" was applied at implantation to make the hilar anastomosis tension-free and technically easier to perform. There were no intraoperative complications. Ten rats (5.6%) experienced partial or full pulmonary atelectasis. Five deaths (2.8%) due to pleural effusion occurred during the follow-up period. The operative times for heart-lung block retrieval, cuff preparation, cold ischemia, warm ischemia, and total procedure time were 8.4±0.8, 11.6±1.5, 25.1±2.2, 8.1±1.2, and 46.7±2.8 min, respectively. Conclusions The key tricks and improvements we made in the cuff technique for rat LTx provided the advantages of expeditiousness, a low complication rate, and a high success rate.

Bronchiolitis obliterans syndrome (BOS) had been considered to be the representative form of chronic rejection or chronic lung allograft dysfunction (CLAD) after lung transplantation. In BOS, small airways are affected by chronic inflammation and obliterative fibrosis, whereas peripheral lung tissue remains relatively intact. However, recognition of another form of CLAD involving multiple tissue compartments in the lung, termed restrictive allograft syndrome (RAS), raised a fundamental question: why there are two phenotypes of CLAD? Increasing clinical and experimental data suggest that RAS may be a prototype of chronic rejection after lung transplantation involving both cellular and antibody-mediated alloimmune responses. Some cases of RAS are also induced by fulminant general inflammation in lung allografts. However, BOS involves alloimmune responses and the airway-centered disease process can be explained by multiple mechanisms such as external alloimmune-independent stimuli (such as infection, aspiration and air pollution), exposure of airway-specific autoantigens and airway ischemia. Localization of immune responses in different anatomical compartments in different phenotypes of CLAD might be associated with lymphoid neogenesis or the de novo formation of lymphoid tissue in lung allografts. Better understanding of distinct mechanisms of BOS and RAS will facilitate the development of effective preventive and therapeutic strategies of CLAD.