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Abstract Background Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non‐small cell lung cancer (LA‐NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases. Methods We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA‐NSCLC, isolated EVs using anti‐CD9 and anti‐CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV‐protein biomarkers were validated in an independent cohort. Results In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p

Abstract Background Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin‐mediated mitophagy, a mitochondrion‐selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD‐related sarcopenia. Methods The involvement of Parkin‐mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS‐exposure model using Parkin−/− mice, and human muscle samples from patients with COPD‐related sarcopenia. Results Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P

ObjectivesRecently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD).MethodsAll patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score.ResultsMaximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT scoreConclusionsEsophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression.

The article discusses how RNA sequencing (RNA-seq) can help detect abnormal splicing events and gene expression in primary ciliary dyskinesia (PCD). It describes a study conducted on 36 Japanese patients with suspected PCD, where genomic DNA analysis and targeted resequencing were initially performed to identify causative variants. It also highlights the importance of RNA-seq in complementing DNA sequencing for the identification and interpretation of variants of uncertain significance in PCD.

The enforcement of sphingosine-1-phosphate (S1P) signaling network protects from radiation-induced pneumonitis. We now demonstrate that, in contrast to early postirradiation period, late postirradiation sphingosine kinase-1 (SphK1) and sphingoid base-1-phosphates are associated with radiation-induced pulmonary fibrosis (RIF). Using the mouse model, we demonstrate that RIF is characterized by a marked upregulation of S1P and dihydrosphingosine-1-phosphate (DHS1P) levels in the lung tissue and in circulation accompanied by increased lung SphK1 expression and activity. Inhibition of sphingolipid de novo biosynthesis by targeting serine palmitoyltransferase (SPT) with myriocin reduced radiation-induced pulmonary inflammation and delayed the onset of RIF as evidenced by increased animal lifespan and decreased expression of markers of fibrogenesis, such as collagen and α-smooth muscle actin (α-SMA), in the lung. Long-term inhibition of SPT also decreased radiation-induced SphK activity in the lung and the levels of S1P-DHS1P in the lung tissue and in circulation. In vitro, inhibition or silencing of serine palmitoyltransferase attenuated transforming growth factor-β1 (TGF-β)-induced upregulation of α-SMA through the negative regulation of SphK1 expression in normal human lung fibroblasts. These data demonstrate a novel role for SPT in regulating TGF-β signaling and fibrogenesis that is linked to the regulation of SphK1 expression and S1P-DHS1P formation.

Background: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non‐small cell lung cancer (LA‐NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases. Methods: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA‐NSCLC, isolated EVs using anti‐CD9 and anti‐CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV‐protein biomarkers were validated in an independent cohort. Results: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF‐κB) pathway. Patients with high levels of EV‐RELA, an NF‐κB subunit, had a higher incidence of SP than those with low levels of EV‐RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV‐RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV‐RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80). Conclusions: Circulating EV‐RELA may be a predictive marker for symptomatic pneumonitis in patients with LA‐NSCLC treated with durvalumab. [ABSTRACT FROM AUTHOR]

The article focuses on vascular remodeling in pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). It explores the role of pericytes in the development of flow-induced PAH and investigates the effects of increased pulmonary blood flow on pericyte behavior and vascular remodeling using a murine model. It further suggests that pericytes contribute to PAH through activation of the Cxcl12 pathway.

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Department of Respiratory Diseases, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata, Department of Respiratory Diseases, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku Tokyo, 105-8461, Japan, Tel +81-3-3433-1111 (ext. 3271), Fax +81-3-3433-1020, Email t-numata@Jikei.ac.jpBackground: Treatment with dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody that blocks both the IL-4 and IL-13 pathways, has demonstrated efficacy for the treatment of severe asthma (SA) with type 2 inflammation. However, few studies have focused on the efficacy of this biologic for the treatment of SA in a real-world setting.Methods: From April 2019 to December 2021, 26 Japanese patients with SA received dupilumab at Jikei University Hospital. We retrospectively evaluated the number of moderate-to-severe exacerbations, pulmonary function, maintenance dose of corticosteroids, biomarkers, and adverse events.Results: During a mean follow-up period of 12.6 months, 10 patients received dupilumab as the first biologic, and 16 switched to dupilumab from other biologics. Dupilumab treatment significantly reduced the number of annual exacerbations from 3.4 ± 4.1 to 1.6 ± 2.7 (/person-year, p < 0.01) at the last follow-up regardless of previous biologic use. The Asthma Control Test score significantly improved in all patients by six months after administration but tended to worsen by 24 months in patients with previous biologic use. On the other hand, blood eosinophil counts (BECs) transiently increased and peaked three to six months after administration. The peak timing can be affected by previous biologic use. Adverse events included wheezing immediately after injection, hypereosinophilia, mild conjunctivitis, and relapse of chronic eosinophilic pneumonia in the patient switched from benralizumab.Conclusion: Dupilumab treatment was useful for patients with SA in a real-world setting. However, the BEC should be monitored carefully, especially in patients who previously received anti-IL-5/IL-5 receptor antibody.Keywords: dupilumab, severe asthma, exacerbation, transient eosinophilia, real-world

Takanori Numata, Jun Araya, Hanae Miyagawa, Keitaro Okuda, Yu Fujita, Hirofumi Utsumi, Daisuke Takekoshi, Mitsuo Hashimoto, Shunsuke Minagawa, Takeo Ishikawa, Hiromichi Hara, Kazuyoshi Kuwano Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Takanori Numata Tel +81-3-3433-1111 (ex 3271)Fax +81-3-3433-1020Email t-numata@jikei.ac.jpBackground: In Japan, biologic therapy was initiated for patients with severe asthma in 2009. In recent years, four biologics with different mechanisms of action have become available in the clinical setting. However, the efficacy of switching between biologics remains uncertain.Methods: To elucidate the efficacy of switching between biologics, 97 patients were enrolled who had received any biologic therapy for severe asthma at Jikei University Hospital, Tokyo, Japan, from July 2009 to December 2020. We retrospectively examined the patient characteristics, biomarkers, pulmonary function test results, selected biologics, and efficacy.Results: Thirty-one males and 66 females received any biologics. The mean age was 53.3 years at the initiation of biologic therapy. Initially, 33, 41, 15 and eight patients received omalizumab, mepolizumab, benralizumab, and dupilumab, respectively. Among three representative indicators for biologics administration, the peripheral blood eosinophil count, serum IgE levels and fractional exhaled nitric oxide, 64% of the patients had two indicators, and 28% had three indicators. Thirty-four patients (35%) switched from the initial biologic to another, and the reasons for switching included persistent asthmatic symptoms (n=22), schedule of hospital visits (n=5), and other reasons. Thus, the treatment was effective in 11 patients after switching. In addition, two patients received combination therapy with different biologics. Eighteen patients (19%) interrupted treatment for various reasons. Regardless of whether the biologic was the initial therapy, the overall efficacy of the four biologics was 60% based on the global evaluation of treatment effectiveness.Conclusion: Switching between biologics can be a promising option for severe asthma patients in whom treatment with an initial biologic is ineffective.Keywords: benralizumab, dupilumab, mepolizumab, omalizumab, switching

Objectives: Recently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD). Methods: All patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score. Results: Maximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT score<10) (18.0±7.9mm, 9.3±3.1mm, respectively, p = 0.01), and MDE was well correlated with CT score (R = 0.69, p = 0.007). MDE in high mycobacterial burden group (Gaffky score ≧5) tended to be greater than that in low mycobacterial burden group (Gaffky score <5) (16.1±6.8mm, 10.1±5.5mm, respectively, p = 0.12), and MDE was well correlated with Gaffky score (R = 0.68, p = 0.009). Lung lesions were bilateral and predominant in middle or lower lobes. Conclusions: Esophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient's respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure. [ABSTRACT FROM AUTHOR]

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPRand CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells. [ABSTRACT FROM AUTHOR]

N-terminal acetylation (Nt-acetylation) refers to the acetylation of the free α-amino group at the N-terminus of a polypeptide. While the effects of Nt-acetylation are multifaceted, its most known function is in the acetylation-dependent N-end rule protein degradation pathway (Ac/N-end rule pathway), where Nt-acetylation is recognized as a degron by designated E3 ligases, eventually leading to target degradation by the ubiquitin-proteasome system. Naa10 is the catalytic subunit of the major Nt-acetylation enzyme NatA, which Nt-acetylates proteins whose second amino acid has a small side chain. In humans, NAA10 is the responsible mutated gene in Ogden syndrome and is thought to play important roles in development. However, it is unclear how the Ac/N-end rule pathway affects the differentiation ability of mouse embryonic stem cells (mESCs). We hypothesized that the balance of pluripotency factors may be maintained by the Ac/N-end rule pathway. Thus, we established Naa10 knockout mESCs to test this hypothesis. We found that Naa10 deficiency attenuated differentiation towards the epiblast lineage, deviating towards primitive endoderm. However, this was not caused by disturbing the balance of pluripotency factors, rather by augmenting FGF/MAPK signaling. [ABSTRACT FROM AUTHOR]

We previously reported protective effects of GADD45a (growth arrest and DNA damage- inducible gene 45 alpha) in murine ventilator-induced lung injury (VILI) via effects on Akt-mediated endothelial cell signaling. In the present study we investigated the role of GADD45a in separate murine models of radiation- and bleomycin-induced lung injury. Initial studies of wild-type mice subjected to single-dose thoracic radiation (10 Gy) confirmed a significant increase in lung GADD45a expression within 24 h and persistent at 6 wk. Mice deficient in/ GADD45a (GADD45a ) demonstrated increased susceptibility to radiation-induced lung injury (RILI, 10 Gy) evidenced by increased bronchoalveolar lavage (BAL) fluid total cell counts, protein and albumin levels, and levels of inflammatory cytokines compared with RILI-challenged wild-type animals at 2 and 4 wk. Furthermore,/ GADD45a mice had decreased total and phosphorylated lung Akt levels both at baseline and 6 wk after RILI challenge relative to wild-type mice while increased RILI susceptibility was observed in/ both Akt mice and mice treated with an Akt inhibitor beginning 1 wk prior to irradiation. Additionally, overexpression of a constitutively active Akt1 transgene reversed RILI-susceptibility in/ GADD45a mice. In separate studies, lung fibrotic changes 2 wk after treatment with bleomycin (0.25 U/kg IT) was significantly/ increased in GADD45a mice compared with wild-type mice assessed by lung collagen content and histology. These data implicate GADD45a as an important modulator of lung inflammatory responses across different injury models and highlight GADD45a-mediated signaling as a novel target in inflammatory lung injury clinically. [ABSTRACT FROM AUTHOR]

An abstract of the study "Rare Cresentic Shaped Radiographic Findings of Organizing Pneumonia Associated With Cutaneous T-Cell Lymphoma" by Michael Markos, Daisuke Takekoshi and Min Joo is presented.

Demetalation of chlorophyll ( Chl) a and its analogs is an important reaction in oxygenic photosynthetic organisms, which produces the primary electron acceptors in photosystem II reaction centers and is crucial in the Chl degradation. From these viewpoints, demetalation reactions of four Chl a analogs, 3,8-divinyl- Chl a ( DV- Chl a), 3-devinyl-3-ethyl- Chl a (meso Chl a), 132-demethoxycarbonyl- Chl a (pyro Chl a) and protochlorophyll a ( PChl a), were kinetically analyzed under weakly acidic conditions, and were compared with that of Chl a. DV- Chl a exhibited slower demetalation kinetics than did Chl a, whereas demetalation of meso Chl a was faster than that of Chl a. The difference in demetalation kinetics of the three chlorophyllous pigments originates from the electron-withdrawing ability of the vinyl group as the peripheral substituent compared with the ethyl group. Removal of the electron-withdrawing and homoconjugating 132-methoxycarbonyl group in Chl a ( Chl a → pyro Chl a) accelerated demetalation kinetics by two-fold. PChl a possessing the porphyrin-type skeleton exhibited slower demetalation kinetics than Chl a. The structure-dependent demetalation properties of Chl a analogs will be useful for understanding in vivo Chl demetalation reactions in oxygenic photosynthetic organisms. [ABSTRACT FROM AUTHOR]

Mycobacterium chelonae, a species of rapidly growing mycobacteria, may grow in routine blood culture media and stain as gram-positive bacilli, which may cause diagnostic confusion. A patient with native-valve endocarditis caused by M. chelonae, which was misidentified as various gram-positive bacilli, is presented. [ABSTRACT FROM AUTHOR]