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Sarcoidosis is a complex, polygenic, inflammatory granulomatous multi-organ disease of unknown cause. The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. Extracellular vesicles (EVs) play important roles in intercellular communication. We subjected serum EVs, isolated by size exclusion chromatography, from seven patients with sarcoidosis and five control subjects to non-targeted proteomics analysis. Non-targeted, label-free proteomics analysis detected 2292 proteins in serum EVs; 42 proteins were up-regulated in patients with sarcoidosis relative to control subjects; and 324 proteins were down-regulated. The protein signature of EVs from patients with sarcoidosis reflected disease characteristics such as antigen presentation and immunological disease. Candidate biomarkers were further verified by targeted proteomics analysis (selected reaction monitoring) in 46 patients and 10 control subjects. Notably, CD14 and lipopolysaccharide-binding protein (LBP) were validated by targeted proteomics analysis. Up-regulation of these proteins was further confirmed by immunoblotting, and their expression was strongly increased in macrophages of lung granulomatous lesions. Consistent with these findings, CD14 levels were increased in lipopolysaccharide-stimulated macrophages during multinucleation, concomitant with increased levels of CD14 and LBP in EVs. The area under the curve values of CD14 and LBP were 0.81 and 0.84, respectively, and further increased to 0.98 in combination with angiotensin-converting enzyme and soluble interleukin-2 receptor. These findings suggest that CD14 and LBP in serum EVs, which are associated with granulomatous pathogenesis, can improve the diagnostic accuracy in patients with sarcoidosis. [ABSTRACT FROM AUTHOR]

Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing is known about their involvement in lymphangiogenesis. We found here that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC). After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9-KO mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis compared with those in wildtype mice. Although mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down CD9 in human LEC also produced decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished formation of functional complexes between VEGF receptor-3 and integrins (α5 and α9). Therefore, knocking down CD9 in LEC attenuated VEGF receptor-3 signaling, as well as downstream signaling such as Erk and p38 upon VEGF-C stimulation. Finally, double deletion of CD9/CD81 in mice caused abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Tetraspanin protein CD151 on tumor cells supports invasion and metastasis. Here we show that host animal CD151 also plays a critical role. CD151-null mice showed markedly diminished experimental lung metastasis, upon injection of Lewis lung carcinoma or B16F10 melanoma cells. Diminished tumor cell residence in lung was evident 6-24 hours after injection. Consistent with an endothelial cell deficiency, isolated CD151-null mouse lung endothelial cells showed a) diminished support for B16F10 adhesion and transendothelial migration, b) diminished B16F10-induced permeability, and c) deposition of extracellular matrix deficient in support of B16F10 adhesion. However, CD151 deletion did not affect size of metastatic foci, size of subcutaneous primary B16F10 tumors, tumor aggregation, tumor clearance from the blood, or tumor-induced immune cell activation and recruitment. Hence, effects of host CD151 on metastasis do not involve altered local tumor growth or immune surveillance. VEGF-induced endothelial cell signaling through Src and Akt was diminished in CD151-null endothelial cells. However, deficient signaling was not accompanied by reduced endothelial permeability, either in vitro (monolayer permeability assay) or in vivo (VEGF-stimulated Miles assay). In summary, diminished metastasis in CD151-null host animals may be due to impaired tumor-endothelial interactions, with underlying defects in mouse lung endothelial cell ECM production. [ABSTRACT FROM AUTHOR]

CD9 and CD81 are closely related tetraspanins that regulate cell motility and signaling by facilitating the organization of multimolecular membrane complexes, including integrins. We show that CD9 and CD81 are down-regulated in smoking-related inflammatory response of a macrophage line, RAW264.7. When functions of CD9andCD81were ablated with monoclonal antibody treatment, small interfering RNA transfection, or gene knock-out, macrophages were less motile and produced larger amounts of matrix metalloproteinase(MMP)-2andMMP-9thancontrolcellsinvitro. In line with this, CD9/CD81 double-knock-out mice spontaneously developed pulmonary emphysema, a major pathological component of chronic obstructive pulmonary disease (COPD). The mutant lung contained an increased number of alveolar macrophages with elevated activities of MMP-2 and MMP-9 and progressively displayed enlarged airspace and disruption of elastic fibers in the alveoli. Secretory cell metaplasia, a finding similar to goblet cellmetaplasia in cigarette smokers,was also observed in the epithelium of terminal bronchioles. With aging, the double-knockout mice showed extrapulmonary phenotypes, including weight loss, kyphosis, and osteopenia. These results suggest that the tetraspanins CD9 and CD81 regulate cell motility and protease production of macrophages and that their dysfunction may underlie the progression of COPD. [ABSTRACT FROM AUTHOR]

Cites key research findings regarding the key role of the tetraspanins CD9 and CD81 in preventing the fusion of mononuclear phagocytes. Facilitation of the fusion between gametes, myoblasts or virus-infected cells; Analysis of pertinent topics and relevant issues; Implications on cell biology.

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. [ABSTRACT FROM AUTHOR]

A supply of hormone-producing cells from stem/progenitor cells is critical to sustain the endocrine activity of the pituitary gland. In the adenohypophysis composing the anterior and intermediate lobe (AL and IL, respectively), stem/progenitor cells expressing sex-determining region Y-box 2 (SOX2) and S100β are located in the marginal cell layer (MCL) facing Rathke's cleft (primary niche) and the parenchyma of the AL (secondary niche). Our previous studies using mice and rats indicated that the tetraspanin superfamily CD9 and CD81 are expressed in S100β/SOX2-positive cells of primary and secondary niches (named CD9/CD81/S100β/SOX2-positive cell), and the cells located in the AL-side niches exhibit plasticity and multipotency. However, it is unclear whether CD9/CD81/S100β/SOX2-positive cells in the IL-side primary niche are stem/progenitor cells for the AL or IL. Here, we successfully isolated pure CD9/CD81/S100β/SOX2-positive cells from the IL-side primary niche. They had a higher level of S100β and SOX2 mRNA and a greater pituisphere forming capacity than those of CD9/CD81/S100β/SOX2-positive cells isolated from the AL. They also had capacity to differentiate into all types of adenohypophyseal hormone-producing cells, concomitantly with the loss of CD9 expression. Loss of CD9 and CD81 function in CD9/CD81/S100β/SOX2-positive cells by siRNA treatment impaired prolactin cell differentiation. Consistently, in the pituitary gland of CD9/CD81 double knockout mice, dysgenesis of the MCL and a lower population of prolactin cells were observed. These results suggest that the CD9/CD81/S100β/SOX2-positive cells in the MCL of the IL-side are potential suppliers of adult core stem cells in the AL. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by severe lung fibrosis and a poor prognosis. Although the biomolecules related to IPF have been extensively studied, molecular mechanisms of the pathogenesis and their association with serum biomarkers and clinical findings have not been fully elucidated. We constructed a Bayesian network using multimodal data consisting of a proteome dataset from serum extracellular vesicles, laboratory examinations, and clinical findings from 206 patients with IPF and 36 controls. Differential protein expression analysis was also performed by edgeR and incorporated into the constructed network. We have successfully visualized the relationship between biomolecules and clinical findings with this approach. The IPF-specific network included modules associated with TGF-β signaling (TGFB1 and LRC32), fibrosis-related (A2MG and PZP), myofibroblast and inflammation (LRP1 and ITIH4), complement-related (SAA1 and SAA2), as well as serum markers, and clinical symptoms (KL-6, SP-D and fine crackles). Notably, it identified SAA2 associated with lymphocyte counts and PSPB connected with the serum markers KL-6 and SP-D, along with fine crackles as clinical manifestations. These results contribute to the elucidation of the pathogenesis of IPF and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/μL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/μL–377.6/μL) (p = 0.023), whereas that in the control group was 47.8/μL (95% CI − 151.2/μL to 246.8/μL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = − 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability. Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020). [ABSTRACT FROM AUTHOR]

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/μL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/μL–377.6/μL) (p = 0.023), whereas that in the control group was 47.8/μL (95% CI − 151.2/μL to 246.8/μL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = − 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability. Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: A certain number of patients with coronavirus disease 2019 (COVID-19), particularly those who test positive for SARS-CoV-2 in the serum, are hospitalized. Further, some even die. We examined the effect of blood adsorption therapy using columns that can eliminate SARS-CoV-2 on the improvement of the prognosis of severe COVID-19 patients. Methods: This study enrolled seven patients receiving mechanical ventilation. The patients received viral adsorption therapy using SARS-catch column for 3 days. The SARS-catch column was developed by immobilizing a specific peptide, designed based on the sequence of human angiotensin-converting enzyme 2 (hACE2), to an endotoxin adsorption column (PMX). In total, eight types of SARS-CoV-2-catch (SCC) candidate peptides were developed. Then, a clinical study on the effects of blood adsorption therapy using the SARS-catch column in patients with severe COVID-19 was performed, and the data in the present study were compared with historical data of severe COVID-19 patients. Results: Among all SCC candidate peptides, SCC-4N had the best adsorption activity against SARS-CoV-2. The SARS-catch column using SCC-4N removed 65% more SARS-CoV-2 than PMX. Compared with historical data, the weaning time from mechanical ventilation was faster in the present study. In addition, the rate of negative blood viral load in the present study was higher than that in the historical data. Conclusion: The timely treatment with virus adsorption therapy may eliminate serum SARS-CoV-2 and improve the prognosis of patients with severe COVID-19. However, large-scale studies must be performed in the future to further assess the finding of this study (jRCTs052200134). [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic options for rare cancers are frequently limited and less effective than for common cancers. Therefore, novel therapeutic strategies to treat rare cancers are urgently required. Our clinical study on rare cancers showed that the biweekly WT1 Trio peptide vaccine comprising two WT1-cytotoxic T lymphocyte (CTL)-peptides and one WT1-helper T lymphocyte-peptide induced more robust immune responses targeting WT1 than the weekly WT1-CTL peptide (WT1-235) vaccine. In addition, the safety of WT1 Trio was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer (TC). Fifteen (33.3%) of the 45 patients with recurrent or advanced rare cancers, including malignant glioma, soft-tissue sarcoma, TC, and malignant pleural mesothelioma, achieved stable disease after 3 months of protocol treatment. Therefore, since WT1 is widely overexpressed in rare cancers, WT1-targeted immunotherapy may be a therapeutic strategy for rare cancers. No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers. [ABSTRACT FROM AUTHOR]

This report described a rare case of subcutaneous anaerobic bacterial abscess due to Peptoniphilus olsenii and Gleimia europaea after COVID‐19. The patient received incision and drainage of the abscess and antibiotics, thereby achieving recovery. Immunodeficiency related to COVID‐19 and its treatment might contribute to secondary skin and subcutaneous bacterial infections. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients' immune responses.Methods: The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level. Secondary endpoints included safety profile, an immune response, including dynamic changes in immune cell and cytokine production, and progression-free survival (PFS). In a 3 + 3 dose-escalation design, the dosage levels for CpG ODN (K3) were 5 or 10 mg/body via subcutaneous injection and 0.2 mg/kg via intravenous administration on days 1, 8, 15, and 29.Results: Nine patients (eight non-small-cell lung cancer; one small-cell lung cancer) were enrolled. We found no DLTs at any dose level and observed no serious treatment-related adverse events. The median observation period after registration was 55 days (range: 46-181 days). Serum IFN-α2 levels, but not inflammatory cytokines, increased in six patients after the third administration of CpG ODN (K3) (mean value: from 2.67 pg/mL to 3.61 pg/mL after 24 hours). Serum IFN-γ (mean value, from 9.07 pg/mL to 12.7 pg/m after 24 hours) and CXCL10 levels (mean value, from 351 pg/mL to 676 pg/mL after 24 hours) also increased in eight patients after the third administration. During the treatment course, the percentage of T-bet-expressing CD8+ T cells gradually increased (mean, 49.8% at baseline and 59.1% at day 29, p = 0.0273). Interestingly, both T-bet-expressing effector memory (mean, 52.7% at baseline and 63.7% at day 29, p = 0.0195) and terminally differentiated effector memory (mean, 82.3% at baseline and 90.0% at day 29, p = 0.0039) CD8+ T cells significantly increased. The median PFS was 398 days.Conclusions: This is the first clinical study showing that CpG ODN (K3) activated innate immunity and elicited Th1-type adaptive immune response and cytotoxic activity in cancer patients. CpG ODN (K3) was well tolerated at the dose settings tested, although the maximum tolerated dose was not determined.Trial Registration: UMIN-CTR number 000023276. Registered 1 September 2016, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000026649. [ABSTRACT FROM AUTHOR]

Background: The impact of SARS-CoV-2 infection on the gut fungal (mycobiota) and bacterial (microbiota) communities has been elucidated individually. This study analyzed both gut mycobiota and microbiota and their correlation in the COVID-19 patients with severe and mild conditions and follow-up to monitor their alterations after recovery. Methods: We analyzed the gut mycobiota and microbiota by bacterial 16S and fungal ITS1 metagenomic sequencing of 40 severe patients, 38 mild patients, and 30 healthy individuals and reanalyzed those of 10 patients with severe COVID-19 approximately 6 months after discharge. Results: The mycobiota of the severe and mild groups showed lower diversity than the healthy group, and in some, characteristic patterns dominated by a single fungal species, Candida albicans, were detected. Lower microbial diversity in the severe group was observed, but no differences in its diversity or community structure were detected between the mild and healthy groups. The microbiota of the severe group was characterized by an increase in Enterococcus and Lactobacillus, and a decrease in Faecalibacterium and Bacteroides. The abundance of Candida was positively correlated with that of Enterococcus in patients with COVID-19. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild and healthy groups. Conclusion: In mild cases, the microbiota is stable during SARS-CoV-2 infection, but in severe cases, alterations persist for 6 months after recovery. [ABSTRACT FROM AUTHOR]

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small-cell lung cancer (NSCLC) might depend on the presence of emphysema, but this association is not established. We aimed to investigate if quantitively and automatically measuring emphysema can predict the effect of ICIs. We retrospectively analyzed 56 patients with NSCLC who underwent immunotherapy at our hospital. We used the Goddard scoring system (GS) to evaluate the severity of emphysema on baseline CT scans using three-dimensional image analysis software. The emphysema group (GS ≥ 1) showed better progression-free survival (PFS) than the non-emphysema group (GS = 0) (6.5 vs. 2.3 months, respectively, p < 0.01). Multivariate analyses revealed that good performance status, GS of ≥ 1, and high expression of PD-L1 were independently associated with better PFS, while smoking status was not. In conclusion, quantitative evaluation of emphysema can be an objective parameter for predicting the therapeutic effects of ICIs in patients with NSCLC. Our findings can be used to generate hypotheses for future studies. [ABSTRACT FROM AUTHOR]

This is the first report of COVID‐19 in a human T‐cell lymphotropic virus type‐1 (HTLV‐1) carrier. HTLV‐1 infection can cause immune dysfunction even in asymptomatic carriers. This case highlights the need for guidance on management of COVID‐19‐HTLV‐1 coinfection, specifically on the appropriate use of corticosteroid treatment while considering secondary infection. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • We assessed the relationship between spliceosome abnormality and cancer. • A mutational hotspot was observed at G96V of the SNRPD3 gene in various cancers. • The SNRPD3 G96V substitution led to hypoxia resistance. • G96V impacted the splicing of DNM1L , which encodes DRP1, a mitochondrial regulator. • DRP1 inhibition weakened the hypoxia resistance of SNRPD3 G96V. [ABSTRACT FROM AUTHOR]

• Clinical effects of ICI and AA therapy are evaluated in comparison with either monotherapy for advanced non-small cell lung cancer. • ICI and AA therapy showed a higher objective response rate than either monotherapy. • AA administered concomitantly or immediately after ICI can provide favorable survival benefits compared to either monotherapy. • ICI administered immediately after AA may show no survival benefits compared to ICI monotherapy. Several studies have demonstrated that anti-angiogenic agents (AAs) have the ability to regulate immune-related cells in the tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). Therefore, we investigated the drug interaction between ICI and AA for advanced non-small cell lung cancer (NSCLC). We systematically searched PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science before August 23, 2021. ICI and AA therapy included the concomitant and sequential use of ICIs and AAs. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients who received ICI and AA therapy were evaluated and compared to those of patients who received either monotherapy. Subgroup analyses were performed to clarify the cause of heterogeneity; the timing and sequence of ICI and AA administration were predefined as the subgroups. Thirteen studies involving 2414 patients were included in the meta-analysis. ICI and AA therapy had significantly higher ORR than either monotherapy (OR [95% CI]: 0.61 [0.50–0.74]; p < 0.001; I2 = 29%). PFS and OS were favorable benefits in ICI and AA therapy; however, significant heterogeneity was identified in these analyses (I2 = 80% and 59%, respectively). According to the administration timing and sequence, ICI immediately after AA showed no PFS and OS benefits compared to ICI monotherapy (HR [95 % CI]: 1.54 [1.14–2.08] and 1.50 [1.04–2.15], respectively), whereas favorable PFS and OS were demonstrated when AA was concomitantly administered with ICI (HR [95 % CI]: 0.57 [0.43–0.76] and 0.80 [0.61–1.05], respectively) or when AA was administered immediately after ICI (HR [95 % CI]: 0.58 [0.34–1.00] and 0.56 [0.40–0.80], respectively). ICI and AA therapy can provide favorable clinical effects compared to either monotherapy; however, ICI administered immediately after AA may not show survival benefits. [ABSTRACT FROM AUTHOR]

To evaluate tumor blood flow using 15O-water positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) before and after chemotherapy with bevacizumab, and to investigate the effects of bevacizumab on tumor blood flow changes and progression-free survival (PFS). Twelve patients with NSCLC were enrolled. Six patients underwent chemotherapy with bevacizumab and the other six without bevacizumab. 15O-water dynamic PET scans were performed within 1 week before the start of chemotherapy and within 1 week after the first day of chemotherapy. Tumor blood flow was analyzed quantitatively using a single one-tissue compartment model with the correction of pulmonary circulation blood volume and arterial blood volume via an image-derived input function. In the bevacizumab group, mean tumor blood flow was statistically significantly reduced post-chemotherapy (pre-chemotherapy 0.27 ± 0.14 mL/cm3/min, post-chemotherapy 0.18 ± 0.12 mL/cm3/min). In the no bevacizumab group, there was no significant difference between mean tumor perfusion pre-chemotherapy (0.42 ± 0.42 mL/cm3/min) and post-chemotherapy (0.40 ± 0.27 mL/cm3/min). In the bevacizumab group, there was a positive correlation between the blood flow ratio (tumor blood flow post-chemotherapy/tumor blood flow pre-chemotherapy) and PFS (correlation coefficient 0.94). Mean tumor blood flow decreases after bevacizumab administration and was positively correlated with longer PFS. [ABSTRACT FROM AUTHOR]

• Messenger RNA COVID-19 vaccine may cause acute exacerbation of interstitial pneumonia. • Clinicians should recognize the risk and carefully monitor patients. • Immunologic mechanism may be involved in the etiology of the exacerbation. Messenger RNA (mRNA) vaccines that protect against COVID-19 are widely used in many countries owing to their high efficacy and safety profiles. Recently, few severe adverse events, such as anaphylaxis and myocarditis, were reported in healthy individuals. The safety of mRNA COVID-19 vaccines has not been adequately studied in patients with interstitial lung disease. We report 2 cases of acute exacerbation of preexisting interstitial pneumonia associated with mRNA COVID-19 vaccination. In both cases, lung disease was stable before the vaccination. Initial responses to steroid therapy were unfavorable, and intravenous cyclophosphamide was administered in both cases. Both patients were diagnosed with vaccine-related exacerbation of interstitial pneumonia based on laboratory results, radiologic features, and the observed clinical course, which lacked other causative events. We suggest that clinicians should note the possibility of acute exacerbation of pneumonia after mRNA COVID-19 vaccination and carefully monitor patients with interstitial lung disease. [ABSTRACT FROM AUTHOR]

Combined small cell lung cancer (c‐SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non‐small cell carcinoma (NSCLC). Standard chemotherapy for patients with c‐SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c‐SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c‐SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK‐positive c‐SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR‐ or ALK‐positive c‐SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component. Key points: Significant findings of the study: • This is the first report describing the treatment course comprising immunochemotherapy and ALK‐TKI in a patient with c‐SCLC harboring ALK rearrangement. What this study adds: • Our case and literature review suggest that although ALK mutation is rare in patients with c‐SCLC, its identification and treatment with ALK‐TKIs may contribute to clinical benefits. [ABSTRACT FROM AUTHOR]

Recent clinical trials have demonstrated that anti‐PD‐1 blocking antibodies showed remarkable clinical efficacy in a subset of non‐small cell lung cancer (NSCLC) patients. Clinical trials usually exclude patients with renal dysfunction who are receiving hemodialysis (HD). Therefore, it is unclear whether these patients can be safely and effectively treated with pembrolizumab. Here, we present a non‐small cell lung cancer patient on HD who achieved complete remission after one dose of pembrolizumab without severe adverse events. We assessed pembrolizumab binding to peripheral blood T cells in this patient using a method that we recently developed. This is the first report to visualize pembrolizumab binding to T cells in a patient on HD during and after pembrolizumab treatment. The pharmacokinetics of pembrolizumab in this case were similar to those in patients with normal renal function, suggesting that severe renal dysfunction has little influence on the metabolism of pembrolizumab, and is not a contraindication for anti‐PD‐1 treatment. Immune checkpoint inhibitors, including pembrolizumab, may be a vital therapeutic option for lung cancer patients on HD. [ABSTRACT FROM AUTHOR]

• It is unclear whether T cell immunity in ILD is appropriate for immunotherapy of NSCLC patients. • CD4+ and CD8+ T cell subsets were high in the lung tissues of NSCLC patients with ILD. • TNFα production by CD4+ T cells, which was negatively correlated with the ratio of Treg cells, was low in ILD. • These results highlight the key role of Treg cells and TNFα in the lung tissues of NSCLC patients with ILD. Limited treatment options are available for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). The rationale for immunotherapy and its adverse events for NSCLC with ILD remains unclear. In this study, we examined T cell profiles and functions in the lung tissues of NSCLC patients with or without ILD to provide evidence for the potential mechanism of immune checkpoint inhibitor (ICI)-related pneumonitis in NSCLC patients with ILD. We investigated T cell immunity in the lung tissues of NSCLC patients with ILD to support the application of immunotherapy for these patients. We analyzed T cell profiles and functions in surgically resected lung tissues from NSCLC patients with and without ILD. The T cell profiles of infiltrating cells in lung tissues were analyzed by flow cytometry. T cell functions were measured based on cytokine production by T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin. The percentages of CD4+ T cells expressing immune checkpoint molecules (Tim-3, ICOS, and 4-1BB), CD103+CD8+ T cells, and regulatory T (Treg) cells were higher in NSCLC patients with than in those without ILD. A functional analysis of T cells in lung tissues indicated that CD103+CD8+ T cells positively correlated with IFNγ production, whereas Treg cells negatively correlated with IFNγ and TNFα production. Cytokine production by CD4+ and CD8+ T cells did not significantly differ between NSCLC patients with and without ILD, except for TNFα production by CD4+ T cells being lower in the former than in the latter. In NSCLC patients with ILD stable for surgery, T cells were active participants and balanced in part by Treg cells in lung tissues, suggesting the potential development of ICI-related pneumonitis in NSCLC patients with ILD. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) can cause severe lymphopenia and respiratory failure requiring prolonged invasive mechanical ventilation (MV). COVID‐19 patients with severe lymphopenia or respiratory failure are at risk of developing secondary infections. Here, we present the needle autopsy findings of a critically ill patient with COVID‐19 who required reintubation and prolonged MV, and eventually died of secondary cytomegalovirus (CMV) pneumonia. This case highlights the potential risk of long‐term steroid use and the need for routine monitoring for CMV infection in critically ill patients with COVID‐19. [ABSTRACT FROM AUTHOR]

Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts in mice compared with trastuzumab ( P < 0.05). Histological analysis of xenografts was performed to evaluate the therapeutic effect on apoptosis, proliferation and tumor vasculature. T-DM1 monotherapy induced apoptosis in SBC-3/SN-38 xenografts to a greater extent than trastuzumab monotherapy with the apoptotic index of 3.71 ± 1.56% vs. 0.60 ± 0.32% ( P < 0.05), and also inhibited the proliferation of tumor cells compared with trastuzumab with the proliferative index of 74.30 ± 5.54% vs. 80.12 ± 4.81% ( P < 0.05). On the other hand, no significant difference in micro vessel density was observed between the treatment groups. In vivo imaging using fluorescence-labeled T-DM1 showed that intravenously administered T-DM1 was rapidly delivered to xenografts and continued to accumulate for several days in a HER2-selective fashion. From these findings, delivery of the cytotoxic agent DM1 into cells via HER2-mediated internalization is expected to exert antitumor effect in such ADCC-lacking SCLC cells. Collectively, T-DM1 will be a promising option for overcoming trastuzumab-resistance in HER2-upregulated SCLC. [ABSTRACT FROM AUTHOR]

We identified CHK2 K373E as a recurrent mutation in The Cancer Genome Atlas ( TCGA) database. In this study, we demonstrate that the K373E mutation disrupts CHK2 autophosphorylation as well as kinase activity, thus leading to impairment of CHK2 functions in suppressing cell proliferation and promoting cell survival after ionizing radiation. We propose that K373E impairs p53-independent induction of p21 WAF1/ CIP1 by CHK2. Our data implicate the K373E mutation of CHK2 in tumorigenesis. [ABSTRACT FROM AUTHOR]

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m 2 , days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC. [ABSTRACT FROM AUTHOR]

Purpose: We retrospectively analyzed patients with clinically diagnosed interstitial pneumonia to investigate the factors which contribute to the difference in prognosis from the initiation of long-term oxygen therapy (LTOT) among subtypes. Methods: Seventy-six patients with clinically diagnosed idiopathic interstitial pneumonia (IIP; n = 49) or interstitial pneumonia associated with collagen vascular disease (CVD-IP; n = 27) in whom LTOT was initiated in our facility from January 1999 to December 2012 were analyzed. Results: Patients with CVD-IP had significantly longer survival time from the initiation of LTOT than those with IIP with the median survival of 51.7 months versus 18.8 months, respectively. The 1-year survival rate was 92.4 % for patients with CVD-IP versus 76.5 % for those with IIP, and 2-year survival was 88.6 versus 36.0 %, respectively. The patterns classified with high-resolution computed tomography (HRCT) were not associated with prognosis. The association between pulmonary hypertension and prognosis was unclear. In results of the multivariate Cox analysis which included factors demonstrating p < 0.1 in the univariate Cox analysis, male gender, low body mass index, and the absence of collagen vascular disease (CVD) were significantly associated with poor prognosis. Conclusions: After the initiation of LTOT, patients with IIP had poor prognosis regardless of the patterns classified with HRCT, while those with CVD-IP survived longer. Male gender, low body mass index, and the absence of CVD were the independent negative prognostic factors in patients with interstitial pneumonia receiving LTOT. [ABSTRACT FROM AUTHOR]

Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages. [ABSTRACT FROM AUTHOR]

Abstract: CXCL12 is a chemokine essential for the organ-specific spread of a variety of cancers including small cell lung cancer (SCLC). Here, we examined the anti-metastatic efficacy of TF14016, a small peptidic inhibitor of CXCL12 receptor CXCR4, in SCLC. Treatment of mice with TF14016 significantly suppressed pulmonary metastases of CXCR4-expressing SCLC in size and number. Furthermore, histological examination revealed that the expression of vascular endothelial cell growth factor and the density of CD31-positive microvessels in metastatic foci were both significantly reduced in TF14016-treated mice. Collectively, CXCR4 could be an attractive target for anti-metastatic and anti-angiogenic therapy in SCLC. [Copyright &y& Elsevier]

We present two patients with leptomeningeal metastases (LM) from lung adenocarcinoma that progressed or newly developed, respectively, during gefitinib therapy which had exhibited substantial antitumor effects on widespread lesions. In both cases, a switch to erlotinib therapy brought about long-lasting dramatic symptomatic improvement and markedly prolonged survival. The first patient is a 46-year-old female who presented with progressive headache and vomiting. Multiple pulmonary, hepatic and bone metastases immediately shrank in response to gefitinib. However, 1 month after completion of concurrent whole brain radiation, dizziness and urinary retention newly emerged, worsening the symptoms observed at presentation. Magnetic resonance imaging (MRI) demonstrated enlargement of ventricles and new gadolinium (Gd)-enhanced disseminated nodules on the surface of the cerebral cortex, suggesting the existence of uncontrollable LM. Sequential erlotinib therapy resulted in symptomatic improvement with a finding of regression of Gd-enhancement on MRI. The beneficial effect lasted for 10 months, though a follow-up brain MRI showed further enlarged ventricles. She finally died due to LM after surviving for 11 months under erlotinib treatment. The other patient is a 55-year-old female in whom headache and vomiting occurred while gefitinib therapy had maintained shrinkage of all pre-existing tumors in the thorax and bones. Brain MRI strongly suggested occurrence of LM with a finding of Gd-enhanced sulci. A switch to erlotinib therapy relieved the symptoms with disappearance of Gd-enhancement. However, the symptoms recurred with a finding of further enlargement of ventricles on brain MRI after 11 months. Finally, she died due to LM after surviving for 12 months under erlotinib treatment. [ABSTRACT FROM AUTHOR]

Abstract: The α,β-unsaturated aldehyde 4-hydroxy-2-nonenal (4-HNE) is an endogenous product of oxidative stress that is found at increased levels in the lungs of patients with chronic obstructive pulmonary disease (COPD) and animal models of this lung disorder. In the present study, levels of 4-HNE adducts were increased in two different mouse models of COPD. Challenging lungs with 4-HNE enlarged the airspace and induced goblet cell metaplasia of the airways in mice, two characteristics of COPD. 4-HNE induced the accumulation of inflammatory cells expressing high levels of MMP-2 and MMP-9. Our results indicate that 4-HNE production during oxidative stress is a key pathway in the pathogenesis of COPD. [Copyright &y& Elsevier]

Gefitinib-sensitive nonsmall cell lung cancers (NSCLC) are characterized by somatic mutations in the kinase domain of epidermal growth factor receptor (EGFR). The mutant EGFR forms are reported to mediate characteristic signal transduction pathways that are different from those mediated by the wild-type EGFR and are involved in transformation in vivo. We have examined signal transduction pathways initiated from a frequently identified gefitinib-sensitizing mutant EGFR lacking residues 746–750 by employing a mouse fibroblast cell line that is free of endogenous EGFR and transiently transfected COS-7 cells. Upon EGF stimulation, the deletion-mutant EGFR mediated prolonged downstream signals. The analysis of the phosphotyrosine patterns of the receptor revealed that the deletion-mutant EGFR lacked phosphorylation at tyrosine residue 1045, which is the major binding site of Cbl. The EGF-induced endocytosis of the deletion-mutant EGFR was impaired. The ubiquitination and downregulation of the deletion-mutant EGFR were also reduced. On the other hand, another mutant, EGFR, possessing a L858R substitution, exhibited phosphorylation at 1045 and its downstream signalings were not prolonged. These data suggest that the signal transduction pathways initiated from these mutant forms are different, and that impaired endocytosis might be responsible for the prolonged signals mediated by the deletion-mutant EGFR. [ABSTRACT FROM AUTHOR]

EGFR is involved in the density-dependent inhibition of cell growth, while coexpression of EGFR with erbB2 can render normal cells transformed. In this study, we have examined the effect of a species of p185 that contains the transmembrane domain and the extracellular domain of p185c-neu, on growth properties of a human malignant mesothelioma cell line that coexpresses EGFR and erbB2. The ectodomain form of p185c-neu enhanced density-dependent inhibition of cell growth and we found that p21 induction appeared to be responsible for this inhibitory effect. Previously, the extracellular domain species was shown to suppress the transforming abilities of EGFR and p185c-neu/erbB2 in a dominant-negative manner. The ability of this subdomain to affect tumor growth is significant, as it reduced in vivo tumor growth. Unexpectedly, we found that the domain did not abrogate all of EGFR functions. We noted that EGFR-induced density-dependent inhibition of cell growth was retained. Tyrosine kinase inhibitors of EGFR did not cause density-dependent inhibition of cell growth of malignant mesothelioma cells. Therefore, simultaneously inhibiting the malignant phenotype and inducing density-dependent inhibition of cell growth in malignant mesothelioma cells by the extracellular domain of p185c-neu may represent an important therapeutic advance. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) invades locally and metastasizes distantly extremely early when compared with nonsmall cell lung cancer (NSCLC). The underlying molecular mechanisms, however, have not been elucidated. Accumulating evidence suggests that downregulation of several members of tetraspanins is associated with progression of solid tumors, thus indicating poor prognosis. Here we screened 30 lung cancer cell lines for expression of tetraspanins, CD9, CD63, CD81, CD82, CD151, and NAG-2. Flow cytometry revealed that, among these proteins, CD9 is broadly expressed in NSCLC lines, but is absent or highly reduced in most SCLC lines (P<0.0001). Using the Boyden chamber and videomicroscopic cell motility assays, we showed that stable transfection of CD9 into an SCLC line, OS3-R5, reduced cell motility on fibronectin. Furthermore, by transient transfection of green fluorescent protein (GFP)-tagged CD9 into three other SCLC lines, we observed that SCLC cells expressing GFP-CD9 were uniformly less motile than untransfected cells. CD9 or GFP-CD9 was associated with β1 integrins and distributed at the tumor cell periphery and cell–cell contacts, suggesting that CD9 modifies β1 integrin function to reduce motility. These findings suggest that low expression of CD9 may contribute to the highly invasive and metastatic phenotype of SCLC.Oncogene (2003) 22, 674–687. doi:10.1038/sj.onc.1206106 [ABSTRACT FROM AUTHOR]

Background: In Japan and other countries, the number of patients with syphilis is increasing year by year. Recently, the cases of the pulmonary involvement in patients with secondary syphilis have been reported. However, it is still undetermined how to obtain a desirable specimen for a diagnosis of the pulmonary involvement, and how to treat it if not cured.Case Presentation: A 34-year-old man presented with cough and swelling of the right inguinal nodes. A physical examination revealed erythematous papular rash over the palms, soles and abdomen. A 4 cm mass in the right lower lobe of the lung was detected on computed tomography. He was diagnosed as having secondary syphilis, because he was tested positive for the rapid plasma reagin and Treponema pallidum hemagglutination assay. Amoxycillin and probenecid were orally administered for 2 weeks. Subsequently, rash and serological markers were improved, however, the lung mass remained unchanged in size. Transbronchial biopsy (TBB) confirmed the pulmonary involvement of syphilis using polymerase chain reaction techniques (tpp47- and polA-PCR). Furthermore, following surgical resection revealed the lung mass to be an abscess.Conclusions: To our knowledge, this is the first surgically treated case of a lung abscess caused by syphilis, which was diagnosed by PCR techniques in TBB. This report could propose a useful diagnostic method for the pulmonary involvement of syphilis. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the clinical impact of sarcopenia on the efficacy of programmed death (PD)-1 inhibitors. We retrospectively reviewed the medical records of all patients treated with nivolumab or pembrolizumab between January 2016 and September 2018 for previously treated advanced non-small cell lung cancer (NSCLC). The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). A total of 42 patients were analysed. The prevalence of sarcopenia was 52.4%. Sarcopenia was significantly associated with poorer progression-free survival (PFS) (median, 2.1 vs. 6.8 months, p = 0.004). Compared to patients with sarcopenia, those without sarcopenia had a higher overall response rate (40.0% vs. 9.1%, p = 0.025) and 1-year PFS rate (38.1% vs. 10.1%). In conclusion, sarcopenia at baseline as determined using computed tomography is a significant predictor of worse outcome in patients with advanced NSCLC receiving PD-1 blockade. Screening for sarcopenia may help identify patients more likely to achieve a long-term response in routine clinical practice. [ABSTRACT FROM AUTHOR]