Search

Lightweight magnesium alloys with good thermal conductance are in demand for structural components in portable devices. This work presents a strategy to achieve excellent thermal conductivity, room temperature (RT) formability and high strength in magnesium sheet alloys. We found that a Mg-1.6Zn-0.5Ca-0.4Zr alloy shows a substantial increase in thermal conductivity to over 130 W/(m·K) due to the reduced supersaturation of solute atoms in the matrix by the precipitation of Guinier-Preston (G.P.) zones while exhibiting excellent RT formability with a large Index Erichsen value of 8.1 mm, and a high yield strength of 227 MPa by peak aging treatment.

In order to optimize the nanogranular structure of FePt-C for heat-assisted magnetic recording media, we investigated the influence of MgO underlayers on the growth of FePt grains in the FePt-C layer. The FePt-C layer was deposited by using the alternating sputtering method, by which FePt and FePt-C layers were alternately deposited. To understand the growth mechanism of the FePt-C layer on the MgO underlayers deposited under various conditions, detailed plan-view and cross sectional transmission electron microscopy observations were made for different film thicknesses. We found that columnar FePt grains grow only when the deposition conditions of the MgO underlayer are optimal. Direct TEM observation of the growth process of the FePt-C layer revealed that the number density of nuclei is sufficient in the initial stage of the film deposition; however, coarsening of the grains after grain impingement causes a substantial decrease in the number density of the FePt grains.

Data for herbicide effects on plant flowering are needed to determine potential impacts on plant reproduction. Thus, flowering phenology was determined for up to 12 weeks after herbicide treatment for native Willamette Valley plants growing in small plots on two Oregon State University experimental farms. Six perennial species were evaluated: Camassia leichtlinii (CALE), Elymus glaucus (ELGL), Eriophyllum lanatum (ERLA), Festuca idahoensis subsp. roemeri (FEID), Iris tenax (IRTE), and Prunella vulgaris var. lanceolata (PRVU). Effects of glyphosate and dicamba, alone and in combination, were determined using simulated drift rates of 0.1 or 0.2 x field application rates (FAR) of 1119 g ha -1 active ingredient (a.i.) (830 g ha -1 acid glyphosate) for glyphosate and 560 g ha -1 a.i. for dicamba. Flowering phenology was evaluated as stage of development on a scale from no buds (converted to 0), buds (1), pre-flowering (2), flowering (3), post-flowering (4), to mature seeds (5) before herbicide treatment and for 12 weeks after treatment. Flowering response to herbicides varied by species and farm; but, in general, dicamba and glyphosate resulted in earlier flowering stages (delayed or not full flowering) for the dicot ERLA, and to a lesser extent, PRVU; and glyphosate resulted in earlier flowering stages for the monocot IRTE. Based on these data, the concentration of herbicide affecting flowering stage was 0.1 x FAR. Once flowering stage was inhibited by dicamba and glyphosate, plants generally did not recover to full flowering. This study provided evidence that common herbicides can affect flowering phenology of native plants with implications for seed production., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Chemoimmunotherapy is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, data on clinical predictive factors remain scarce., Objective: We aim to identify clinical biomarkers in patients undergoing chemoimmunotherapy., Methods: This multicenter, real-world cohort study included chemonaive patients who underwent chemoimmunotherapy between December 2018 and May 2022. Multivariate analysis was used to determine associations between survival outcomes and patient background, including baseline neutrophil-to-lymphocyte ratio (NLR) and its dynamic change (ΔNLR). To further investigate the clinical significance of NLR, patients were classified based on their peripheral immune status, defined by a combination of NLR and ΔNLR., Results: The study included 280 patients with 30.1 months of median follow-up. Multivariate analysis revealed that older individuals, poor performance status, tumor proportion score < 1%, liver metastasis, baseline NLR ≥ 5, and ΔNLR ≥ 0 independently correlated significantly with shorter progression-free and overall survival (OS). Patients with high peripheral immune status (defined as NLR <5 and ΔNLR < 0) significantly improved long-term survival (2-year OS rate of 58.3%), whereas those with low peripheral immune status (defined as NLR ≥ 5 and ΔNLR ≥ 0) had extremely poor outcomes (2-year OS rate of 5.6%). Safety profiles did not differ significantly in terms of severe adverse events and treatment-related death rates despite the patients' peripheral immune status (P = 0.46 and 0.63, respectively)., Conclusions: Our study provides real-world evidence regarding clinical prognostic factors for the efficacy of chemoimmunotherapy. The combined assessment of baseline NLR and ΔNLR could facilitate the identification of patients who are likely to achieve a durable response from chemoimmunotherapy., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future., (© 2024. The Author(s).)

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Background: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes., Objective: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs)., Methods: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps., Results: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo., Conclusion: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

RNA splicing is a fundamental cellular mechanism performed by spliceosomes that synthesise multiple mature RNA isoforms from a single gene. The association between spliceosome abnormality and solid cancers remains largely unknown. Here, we demonstrated that Sm proteins, which are common components of the spliceosomes and constitute the Sm ring, were overexpressed in multiple cancers and their expression levels were correlated with clinical prognosis. In a pan-cancer mutational hotspot in the Sm ring at SNRPD3 G96V, we found that the G96V substitution confers resistance to hypoxia. RNA-seq detected numerous differentially spliced events between the wild-type and mutation-carrying cells cultured under hypoxia, wherein skipping exons and mutually exclusive exons were frequently observed. This was observed in DNM1L mRNA, which encodes the DRP1 protein that regulates mitochondrial fission. The mitochondria of cells carrying this mutation were excessively fragmented compared with those of wild-type cells. Furthermore, treatment with a DRP1 inhibitor (Mdivi-1) recovered the over-fragmented mitochondria, leading to the attenuation of hypoxia resistance in the mutant cells. These results propose a novel correlation between the cancer-related spliceosome abnormality and mitochondrial fission. Thus, targeting SNRPD3 G96V with a DRP1 inhibitor is a potential treatment strategy for cancers with spliceosome abnormalities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort., Experimental Design: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers., Results: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed., Conclusions: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy., Significance: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: Nivolumab plus ipilimumab with chemotherapy (NICT) and pembrolizumab with chemotherapy (PCT) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). Compared with immune checkpoint inhibitor (ICI) monotherapy, ICI combination therapy can increase immune-related toxicity instead of prolonging survival. This study aimed to compare the efficacy and safety of NICT and PCT to decide on the favorable treatment., Methods: We conducted a multi-center retrospective cohort study on patients who underwent NICT or PCT between December 2018 and May 2022. Propensity score matching (PSM) was performed with the variables age, sex, smoking status, performance status, stage, histology, and programmed cell death ligand-1 (PD-L1). The Kaplan-Meier method was used to compare survival for the matched patients., Results: Six hundred consecutive patients were included. After PSM, 81 and 162 patients were enrolled in the NICT and PCT groups, respectively. The baseline characteristics were well-balanced. The median progression-free survival was equivalent (11.6 vs. 7.4 months; P = 0.582); however, the median overall survival (OS) was significantly longer in the NICT group than in the PCT group (26.0 vs. 16.8 months; P = 0.005). Furthermore, OS was better in PD-L1-negative patients who underwent NICT than in those who underwent PCT (26.0 vs. 16.8 months; P = 0.045). Safety profiles did not differ significantly in terms of severe adverse event and treatment-related death rates (P = 0.560, and 0.722, respectively)., Conclusions: Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up is needed to determine the long-term prognostic benefit., (© 2023. The Author(s).)

Introduction: In transbronchial biopsy of peripheral pulmonary lesions, the bronchoscope can reach only a limited depth due to the progressive narrowing of bronchi, which may reduce the diagnostic rate. This study examined the balloon dilatation for bronchoscope delivery (BDBD) technique, employing a novel balloon device to enhance bronchoscopy into the peripheral lung areas., Methods: Anaesthetised swine served as our primary model. Using computed tomography (CT) scans, we positioned virtual targets characterised by a positive bronchus sign and a diameter of 20 mm beneath the pleura. The bronchoscope was navigated along the pathways determined from the CT images. We performed balloon dilatation when bronchial narrowing obstructed progress to assess whether balloon dilatation would enable the bronchoscope to enter further into the periphery., Results: We established 21 virtual targets on the CT scans. An average of 12.1 branches were identified along the pathways on the CT scans; however, bronchoscopy without BDBD only allowed access to an average of 6.7 branches. Based on 72 balloon dilatations with 3.0-mm or 4.0-mm ultra-thin bronchoscopes, there was an average increased access of 3.43 and 5.14 branches per route, respectively, with no significant BDBD complications. The bronchoscope was able to reach the planned location along all pathways, and the mean final bronchoscopic endpoints were at an average distance of 14.7 mm from the pleura. Post-procedure CT confirmed biopsy accuracy., Conclusion: The BDBD technique can enhance access of a flexible bronchoscope into the peripheral lung fields, which could potentially allow more accurate transbronchial interventions for peripheral targets., (© 2024 S. Karger AG, Basel.)

Background: The Japanese Government programme 'General Principles of Suicide Prevention Policy' (GPSPP) contributed to decreasing suicide mortality rates (SMRs) before the COVID-19 pandemic, but they increased after the pandemic., Aims: To identify risk factors for youth suicide and the impact of GPSPP on youth suicide., Method: Annual suicide numbers during 2007-2022 were obtained from government databases. SMRs of student and non-student youths were analysed with a linear mixed-effects model. Interrupted time-series analysis was conducted to investigate temporal relations between three GPSPP periods and SMRs with 52 suicide motives among high school, special vocational school and university students. Multiple regression analysis was conducted to investigate the influence of grade repetition on university student SMRs., Results: Non-student youth SMRs were higher than student SMRs. School-related (worrying about the future/underachievement), health-related (mainly mental illness) and family-related (conflict with parent and severe verbal reprimands) motives were major motives for student SMRs. During the first GPSPP period (2007-2012), no student SMRs decreased. During the second period (2012-2017), university and special vocational school student SMRs increased, but high school student SMRs were unchanged. In contrast, during the third period (2017-2022), with the exception of male special vocational school students, all SMRs increased. Unexpectedly, long-term grade repetition was negatively associated with health-related SMRs., Conclusions: These findings suggest that GPSPP-supported programmes in schools partially contributed to student suicide prevention. To suppress increasing student SMRs, social/life support specialists should participate in in-school support services to bolster the social standing and lives of students who repeat grades or experience setbacks.

Introduction: Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC., Methods: We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias., Results: Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85-7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29-5.42; p  = 0.008) were independently associated with worse overall survival., Conclusions: After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT., (© 2023 The Authors.)

To provide recommendations for establishment of plants on low-pH Formosa Mine tailings, two greenhouse experiments were conducted to evaluate the use of remedial amendments to improve the survival and growth of Douglas fir ( Pseudotsuga menziesii ) seedlings. A preliminary experiment indicated that 1% lime (by weight) raised tailings pH, permitting seedling survival. However, high rates of biosolid application (BS; 2% by weight) added to supply nutrients were phytotoxic when added with lime. A gasified conifer biochar (BC) added to tailings at 1%, 2.5%, or 5% (by weight), along with lime and BS, caused an additional increase in pH, decreased electrical conductivity (EC), and tended to increase the survival of Douglas fir. The addition of a locally sourced microbial inoculum (LSM) did not affect survival. A subsequent experiment expanded our experimental design by testing multiple levels of amendments that included lime (0.5% and 1% by weight), three application rates (0.2%, 0.5%, and 2%) of two nutrient sources (BS or mineral fertilizer), BC (0% and 2.5%), and with or without LSM. There were many interactions among amendments. In general, Douglas fir survival was enhanced when lime and BC were added. These experiments suggest that amending with lime, a nutrient source, and BC would enhance revegetation on low-pH, metal-contaminated mine tailings., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.

Background: Mycobacterium obuense (M. obuense) is a rapidly growing mycobacterium (RGM) which has been considered nonpathogenic. Here, we report a case of disseminated non-tuberculous mycobacterial (NTM) infection caused by M. obuense in an immunocompromised patient., Case Presentation: A 16-year-old boy was referred to our hospital due to acute myeloid leukemia. During the treatment of leukemia, the patient exhibited continuous fever, and diffuse miliary nodules with random distribution were found on chest computed tomography. Repeated examinations of bacterial culture tests revealed sputum and urine samples to be smear-positive for acid-fast bacillus, and blood culture from a peripherally inserted central catheter line showed the growth of NTM. The NTM species was identified as M. obuense by mass spectrometry and confirmed by genome sequencing. Combination therapy with amikacin, rifampicin, azithromycin, and moxifloxacin significantly improved the patient's symptoms and radiological findings., Conclusion: We report a case of disseminated NTM infection caused by M. obuense for which combination anti-microbial therapy was effective. An immunocompromised host indwelling catheter is at risk of RGM bloodstream infections. Although relatively rare, M. obuense may be considered as a potential pathogen causing infectious diseases, especially in high-risk patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Importance: The suicide mortality rate per 100 000 population (SMRP) consistently decreased before the COVID-19 pandemic outbreak in Japan and then unexpectedly increased during the pandemic. However, the underlying mechanisms remain poorly understood., Objective: To identify trends in and factors associated with suicidal mortality and motives among students in Japan from 2007 to 2022., Design, Setting, and Participants: In this cross-sectional study, data on SMRPs among Japanese middle-school, high-school, and university students were obtained from the government suicide database Suicide Statistics of the National Police Agency., Main Outcomes and Measures: Age-dependent and temporal fluctuations in annual SMRPs, disaggregated by suicidal motive (7 categories and 52 subcategories), sex, and school, were analyzed using linear mixed-effect and joinpoint regression models, respectively., Results: Total suicide numbers from 2007 to 2022 were as follows: 760 male middle-school students, 635 female middle-school students, 2376 male high-school students, 1566 female high-school students, 5179 male university students, and 1880 female university students. The mean (SD) student populations from 2007 to 2022 were as follows: 1 752 737 (81 334) male middle-school students, 1 675 572 (78 824) female middle-school students, 1 648 274 (67 520) male high-school students, 1 614 828 (60 032) female high-school students, 1 652 689 (32 724) male university students, and 1 229 142 (57 484) female university students. Among male students, the leading motives were school-related factors (underachievement and worrying about the future), followed by family-related and health-related motives. Among female students, school-related and family-related motives decreased, but health-related motives showed an age-dependent increase. The SMRPs of middle-school male students and female students were almost equal (mean [SD], 2.7 [1.0] vs 2.4 [1.4]), but the age-dependent increase in SMRPs among male students was pronounced (mean [SD], high-school vs university male students, 9.1 [2.4] vs 19.6 [3.0]; high-school vs university female students, 6.1 [2.4] vs 9.6 [1.8]). However, the incidence of suicide among high-school students associated with health-related motives was greater in female students. The majority of suicides associated with major impactable suicidal motives (school-related, health-related, and family-related motives) began increasing before the pandemic. Changes in SMRP associated with interpersonal relationships, such as conflict with classmates or parents, were not significant, but the rates increased greatly during the pandemic., Conclusions and Relevance: School-related, health-related, and family-related problems were major motives, whereas the impacts of health-related and family-related motives increased and decreased with age, respectively. Notably, most SMRPs associated with major impactable motives (underachievement, conflict with a parent or classmate, and mental illnesses) had already begun increasing in the late 2010s, indicating that recent increasing SMRPs among school-aged individuals were associated with pandemic-related factors and other factors affecting this generation before the pandemic. It may be inappropriate to uniformly apply research findings based on school-aged individuals to school-based suicide prevention programs for students in middle school, high school, and university.

Minocycline is often administered prophylactically or therapeutically to non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for skin rash as an adverse event. We examined the effects of minocycline on the outcomes of EGFR-mutant NSCLC treated with first-line EGFR-TKIs based on a single-center retrospective analysis. In this retrospective cohort study, data were collected on NSCLC patients treated with first-line EGFR-TKIs between January 2010 and June 2021. The treatment efficacy of first-line EGFR-TKIs was compared between patients who received minocycline and those who did not. Median progression-free survival (PFS) with first-line EGFR-TKIs was significantly longer in the minocycline group (N = 32) than in the control group (N = 106); 714 (95% confidence interval CI 411-1247) days vs. 420 (95% CI 343-626) days, p = 0.019. A multivariate analysis including skin rash as a variable confirmed that the administration of minocycline for 30 days or longer correlated with good PFS and overall survival (OS) with first-line EGFR-TKIs (HR 0.44 [95% CI 0.27-0.73], p = 0.0014 and HR 0.50 [95% CI 0.27-0.92], p = 0.027, respectively). The administration of minocycline influenced good treatment efficacy with first-line EGFR-TKIs independently of skin rash., (© 2023. The Author(s).)

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8 + T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Introduction: Durvalumab maintenance therapy after definitive concurrent chemoradiotherapy (CRT) is the standard treatment modality for stage III NSCLC. Although severe treatment-related lymphopenia (TRL) during CRT may impair the efficacy of subsequent durvalumab therapy, data on the effect of TRL recovery on consolidation durvalumab therapy are lacking., Methods: This retrospective study evaluated patients with unresectable stage III NSCLC treated with durvalumab after concurrent CRT. The patients were enrolled across nine institutes throughout Japan between August 2018 and March 2020. The effect of TRL recovery on survival was evaluated. The patients were divided into two groups on the basis of their lymphocyte recovery status: the recovery group involved patients who did not experience severe TRL or experienced TRL but exhibited lymphocyte count recovery at durvalumab initiation, and the nonrecovery group involved patients who experienced severe TRL and did not exhibit lymphocyte count recovery on durvalumab initiation., Results: Among the 151 patients evaluated, 41 (27%) and 110 (73%) patients were classified into the recovery and the nonrecovery groups, respectively. The nonrecovery group had significantly worse progression-free survival than the recovery group (21.9 mo versus not reached, p  = 0.018). Recovery from TRL ( p  = 0.027) and high pre-CRT lymphocyte count ( p  = 0.028) independently influenced progression-free survival., Conclusions: Baseline lymphocyte count and recovery from TRL at the start of durvalumab therapy were predictive factors for survival outcomes in patients with NSCLC treated with durvalumab consolidation after concurrent CRT., (© 2023 The Authors.)

Background: Bronchoscopes cannot reach the periphery of the lung because the bronchi are tapered. Therefore, selectively advancing a device-e.g., an endobronchial ultrasonography (EBUS) probe-to the targets can be challenging. Virtual fluoroscopic preprocedural planning (VFPP) is a method in which the route to the target is superimposed on an X-ray fluoroscopy-like image reconstructed from CT images, facilitating the advancement of the EBUS probe to the target. The VFPP method was integrated into the Ziostation2 bronchoscopic navigation system (Ziosoft, Inc., Tokyo, Japan) in 2018. Here, we prospectively examined the feasibility of the VFPP method using Ziostation2 (Zio-VFPP)., Methods: Thirty-six patients who had pulmonary lesions with long axes ≤30 mm and who underwent thin-slice CT with ≤0.625-mm thickness were enrolled. We initiated bronchoscopy using EBUS with a guide sheath (EBUS-GS) while referring to Ziostation2 bronchoscopic navigation. When the probe was not "within" a lesion, we attempted to correct its position based on Zio-VFPP. EBUS findings before and after Zio-VFPP were compared., Results: Zio-VFPP was performed in 24 patients, and EBUS findings improved in nine patients. Before Zio-VFPP, 18 patients were "outside," but after Zio-VFPP, the number decreased to ten. Statistically, this difference was significant (p = 0.0392). There were no cases in which EBUS findings worsened with Zio-VFPP., Conclusion: Zio-VPFPP improves EBUS findings and significantly reduces "outside" cases. However, further investigation is necessary to verify its effectiveness., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective: No studies have demonstrated the real-world efficacy of antifibrotics for progressive fibrosing interstitial lung disease (PF-ILD). Therefore, we evaluated the efficacy of antifibrotics in patients with PF-ILD., Methods: We retrospectively reviewed the medical records of patients with ILD from January 2012 to July 2021. Patients were diagnosed with PF-ILD if they had ≥10% fibrosis on high-resolution CT (HRCT) and a relative forced vital capacity (FVC) decline of either ≥10% or >5% to <10% with clinical deterioration or progression of fibrosis on HRCT during overlapping windows of 2 years and with a %FVC of ≥45%. We compared FVC changes and overall survival (OS) between patients with and without antifibrotics. FVC changes were analysed using generalised estimating equations. We used inverse probability weighting (IPW) and statistical matching to adjust for covariates., Results: Of the 574 patients, 167 were diagnosed with PF-ILD (idiopathic pulmonary fibrosis (IPF), n=64; non-IPF, n=103). Antifibrotics improved the FVC decline in both IPF (p=0.002) and non-IPF (p=0.05) (IPW: IPF, p=0.015; non-IPF, p=0.031). Among patients with IPF, OS was longer in the antifibrotic group (log-rank p=0.001). However, among patients with non-IPF, OS was not longer in the antifibrotic group (p=0.3263) (IPW and statistical matching: IPF, p=0.0534 and p=0.0018; non-IPF, p=0.5663 and p=0.5618)., Conclusion: This is the first real-world study to show that antifibrotics improve the FVC decline in PF-ILD. However, among patients with non-IPF, we found no significant difference in mortality between those with and without antifibrotics. Future studies must clarify whether antifibrotics improve the prognosis of non-IPF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration., Methods: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed., Results: Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as "estrogen signaling pathway," "p160 steroid receptor coactivator (SRC) signaling pathway," and "transcriptional regulation by STAT" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics., Conclusions: Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes., (© 2022. The Author(s).)

Next-generation sequencing (NGS) has become increasingly more important for lung cancer management. We now expect biopsies to be sensitive, safe, and yielding sufficient samples for NGS. In this study, we propose ultraselective biopsy (USB) with sample volume adjustment (SVA) as a novel method that integrates an ultrathin bronchoscope, radial probe endobronchial ultrasound, and the direct oblique method for ultraselective navigation, and adjustment of sample volume for NGS. Our purpose was to estimate the diagnostic potential and the applicability of USB-SVA for amplicon-based NGS analysis. The diagnostic yield of bronchoscopy in forty-nine patients with malignant peripheral pulmonary lesions (PPLs) was retrospectively analyzed, and amplicon-based NGS analysis was performed on samples from some patients using USB. The diagnostic yields of distal PPLs in the USB group were significantly higher than those in the non-USB group (90.5% vs. 50%, respectively, p = 0.015). The extracted amounts of nucleic acids were at least five times the minimum requirement and the sequence quality met the criteria for the Oncomine™ Target Test. Only the tumor cell content of some samples was insufficient. The feasibility of the pipeline for USB, SVA, and amplicon-based NGS in distal PPLs was demonstrated., (© 2022. The Author(s).)

Anti-programmed cell death-1 (PD-1) therapy exerts beneficial effects in a limited population of cancer patients. Therefore, more accurate diagnostics to predict the efficacy of anti-PD-1 therapy are desired. The present study investigated whether peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer (NSCLC) patients. Advanced NSCLC patients treated with anti-PD-1 monotherapy (nivolumab or pembrolizumab) were consecutively enrolled in the present study. Peripheral blood samples were subjected to an analysis of peripheral T cell cytotoxicity and flow cytometry prior to the initiation of anti-PD-1 therapy. Peripheral T cell cytotoxicity was assessed using bispecific T-cell engager (BiTE) technology. We found that progression-free survival was significantly longer in patients with high peripheral T cell cytotoxicity (p = 0.0094). In the multivariate analysis, treatment line and peripheral T cell cytotoxicity were independent prognostic factors for progression-free survival. The analysis of T cell profiles revealed that peripheral T cell cytotoxicity correlated with the ratio of the effector memory population in CD4+ or CD8+ T cells. Furthermore, the results of flow cytometry showed that the peripheral CD45RA+CD25+/CD4+ T cell ratio was higher in patients with than in those without severe adverse events (p = 0.0076). These results indicated that the peripheral T cell cytotoxicity predicted the efficacy of anti-PD-1 therapy for advanced NSCLC patients., (© 2022. The Author(s).)

Competing Interests: Disclosure: There is no conflict of interest or other disclosures.