Application of Acoustic Ejection MS System to High-Throughput Screening for SARS-CoV-2 3CL Protease Inhibitors.

MS is a powerful methodology for chemical screening to directly quantify substrates and products of enzymes, but its low throughput has been an issue. Recently, an acoustic liquid-handling apparatus (Echo®) used for rapid nano-dispensing has been coupled to a high-sensitivity mass spectrometer to create the Echo® MS system, and we applied this system to screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease inhibitors. Primary screening of 32033 chemical samples was completed in 12 h. Among the hits showing selective, dose-dependent 3CL-inhibitory activity, 8 compounds showed antiviral activity in cell-based assay.

Phase II study of the combination of S-1 with bevacizumab for patients with previously treated advanced non-squamous non-small-cell lung cancer.

BACKGROUND: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m2 was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed. CONCLUSION: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.

Functionalized NIR-II Semiconducting Polymer Nanoparticles for Single-cell to Whole-Organ Imaging of PSMA-Positive Prostate Cancer.

Development of molecular probes holds great promise for early diagnosis of aggressive prostate cancer. Here, 2-[3-(1,3-dicarboxypropyl) ureido] pentanedioic acid (DUPA)-conjugated ligand and bis-isoindigo-based polymer (BTII) are synthesized to formulate semiconducting polymer nanoparticles (BTII-DUPA SPN) as a prostate-specific membrane antigen (PSMA)-targeted probe for prostate cancer imaging in the NIR-II window. Insights into the interaction of the imaging probes with the biological targets from single cell to whole organ are obtained by transient absorption (TA) microscopy and photoacoustic (PA) tomography. At single-cell level, TA microscopy reveals the targeting efficiency, kinetics, and specificity of BTII-DUPA SPN to PSMA-positive prostate cancer. At organ level, PA tomographic imaging of BTII-DUPA SPN in the NIR-II window demonstrates superior imaging depth and contrast. By intravenous administration, BTII-DUPA SPN demonstrates selective accumulation and retention in the PSMA-positive tumor, allowing noninvasive PA detection of PSMA overexpressing prostate tumors in vivo. The distribution of nanoparticles inside the tumor tissue is further analyzed through TA microscopy. These results collectively demonstrate BTII-DUPA SPN as a promising probe for prostate cancer diagnosis by PA tomography.

Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors.

BACKGROUND: Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors. METHODS: This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation. In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as 'true PD'. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models. RESULTS: The present study included 62 NSCLC patients aged 27-82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17-0.94). CONCLUSIONS: Patients with DR exhibited a relatively favorable prognosis.

Benefits and Risks of Inhaled Corticosteroid Treatment in Patients with Chronic Obstructive Pulmonary Disease Classified by Blood Eosinophil Counts.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) typically includes neutrophilic airway inflammation and eosinophilic inflammation in some cases. Inhaled corticosteroid (ICS) suppresses eosinophilic inflammation of the airway and reduces acute exacerbation (AE). The present study investigated the relationship between ICS and AE in patients with COPD classified by blood eosinophil counts. METHODS: Overall, 244 patients with COPD were retrospectively evaluated between 2014 and 2017 and classified into two groups based on blood eosinophil counts (≥ 300/µL and < 300/µL). These patients were then reclassified into subgroups of those with and without ICS. Differences in the characteristics and incidence of AE and pneumonia with AE in each subgroup were evaluated retrospectively. RESULTS: All patients with ICS used 320 µg budesonide twice daily. In the group with blood eosinophil counts ≥ 300/µL, patients with ICS had a significantly lower incidence of AE than those without ICS (P = 0.023). Meanwhile, no significant differences were observed in incidence of AE in the group with blood eosinophil counts < 300/µL. In the group with blood eosinophil counts < 300/µL, patients with ICS had a higher incidence of pneumonia with AE (P = 0.009). Conversely, no significant differences were observed in the group with blood eosinophil counts ≥ 300/µL. CONCLUSIONS: ICS significantly reduced AE in COPD patients with blood eosinophil counts ≥ 300/µL. Meanwhile, ICS significantly increased pneumonia rate in patients with blood eosinophil count < 300/µL. Blood eosinophil count may be a useful indicator to identify the benefits and risks of ICS in COPD.

Efficacy of anti-PD-1 therapy for recurrence after chemoradiotherapy in locally advanced NSC LC.

PURPOSE: Chemoradiotherapy (CRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Recently, anti-PD-1 antibody therapy became a key treatment for stage IV NSCLC as the combination of immune checkpoint inhibitors (ICIs) and platinum doublet chemotherapy. However, the efficacy and toxicity of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC are not well examined. METHODS: Patients who received anti-PD-1 therapy for recurrence after CRT were identified in our clinical database. The safety and efficacy of anti-PD-1 therapy were retrospectively analyzed. RESULTS: From March 1, 2013 to April 30, 2018, there were 20 patients who received anti-PD-1 therapy for recurrence after CRT. The median duration from CRT to initial anti-PD-1 therapy was 9.3 months. 12 patients (60%) were alive and 7 patients (35%) were still receiving anti-PD-1 therapy at the data cutoff point (median follow-up, 13.5 months). The ORR for anti-PD-1 therapy was 45.0%. Median progression-free survival (PFS) and overall survival (OS) from initiation of anti-PD-1 therapy was 8.4 months and 26.2 months, respectively. PFS in patients who had a short interval from last CRT to initial anti-PD-1 therapy seemed to have better outcomes (duration from last CRT to initial anti-PD-1 therapy < 9.3 months vs. ≥ 9.3 months; median PFS, 17.0 months vs. 4.9 months). Grade 3 or 4 immune-related adverse events occurred in 5% of patients. Only grade 1 pneumonitis was observed. CONCLUSION: The efficacy of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC might better than in stage IV NSCLC. The duration from CRT to initial anti-PD-1 therapy might be related to efficacy.

Significant Improvement of Unipolar n-Type Transistor Performances by Manipulating the Coplanar Backbone Conformation of Electron-Deficient Polymers via Hydrogen Bonding.

The development of high-performance unipolar n-type semiconducting polymers still remains a significant challenge. Only a few examples exhibit a unipolar electron mobility over 5 cm2 V-1 s-1. In this study, a series of new poly(benzothiadiazole-naphthalenediimide) derivatives with a high unipolar electron mobility (µe) up to 7.16 cm2 V-1 s-1 in thin-film transistors are reported. The dramatically increased µe is achieved by finely optimizing the coplanar backbone conformation through the introduction of vinylene bridges, which can form intramolecular hydrogen bonds with the neighboring fluorine and oxygen atoms. The hydrogen-bonding functionalities are fused to the backbone to ensure a much more planar conformation of the conjugated π-system, as demonstrated by the density functional theory (DFT)-based calculations. The theoretical prediction is in good agreement with the experimental results. As the coplanarity is promoted by the hydrogen bonding, the thin-film crystallinity and molecular packing strength are also improved, which is evidenced by the synchrotron two-dimensional grazing-incidence wide-angle X-ray scattering (GIWAXS) and atomic force microscopy (AFM) measurements. Notably, the GIWAXS measurements reveal an extremely short π-π stacking distance of 3.40 Å. Overall, this study marks a significant advance in the unipolar n-type semiconducting polymers and offers a general approach for further increasing the electron mobility of semiconducting polymers in organic electronics.

Predictive factors for relapse of cryptogenic organizing pneumonia.

BACKGROUND: Relapse of cryptogenic organizing pneumonia (COP) may lead to poor long-term prognosis and necessitates multiple rounds of steroid treatment with potential adverse effects. The objective of this study is to identify predictive factors of COP relapse by comparing demographic and clinical variables between relapse and non-relapse groups. METHODS: During 2008-2013, 33 COP patients were treated, of which 23 (69.7%) and 10 patients (30.3%) were assigned to the non-relapse and relapse group, respectively. From medical records, we compared the following variables at initial episode: clinical characteristics, serum parameters, chest CT scan findings, and steroid treatment. RESULTS: Clinical characteristics, cumulative prednisone dose, and steroid treatment duration were similar between groups. In univariate analysis, alternatively, the proportion of patients with bilateral shadow pattern, traction bronchiectasis, and partial remission after steroid treatment was significantly higher in the relapse group. These differences were not significant by multivariate Cox regression analysis. CONCLUSIONS: We identified radiographic findings, such as bilateral shadow pattern, traction bronchiectasis, and partial remission, may have possibility of predictive factors for COP relapse. Larger-scale studies are required to confirm if any are independent predictors of COP relapse.

Significant Difference in Semiconducting Properties of Isomeric All-Acceptor Polymers Synthesized via Direct Arylation Polycondensation.

The direct arylation polycondensation (DArP) appeared as an efficient method for producing semiconducting polymers but often requires acceptor monomers with orienting or activating groups for the reactive carbon-hydrogen (C-H) bonds, which limits the choice of acceptor units. In this study, we describe a DArP for producing high-molecular-weight all-acceptor polymers composed of the acceptor monomers without any orienting or activating groups via a modified method using Pd/Cu co-catalysts. We thus obtained two isomeric all-acceptor polymers, P1 and P2, which have the same backbone and side-chains but different positions of the nitrogen atoms in the thiazole units. This subtle change significantly influences their optoelectronic, molecular packing, and charge-transport properties. P2 with a greater backbone torsion has favorable edge-on orientations and a high electron mobility µe of 2.55 cm2 V-1 s-1 . Moreover, P2-based transistors show an excellent shelf-storage stability in air even after the storage for 1 month.

Neutropenia related to an azathioprine metabolic disorder induced by an inosine triphosphate pyrophosphohydrolase (ITPA) gene mutation in a patient with PR3-ANCA-positive microscopic polyangiitis
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A 68-year-old Japanese man was monitored for chronic kidney disease (CKD), with unknown primary disease starting in 2014. His serum creatinine (sCr) was stable at ~ 2.5 mg/dL for ~ 2 years. Two weeks before admission, he had bloody sputum, and sCr increased to 4.63 mg/dL. Soon after admission, the patient developed a high fever with pigment spots on the legs. A kidney biopsy was performed. The kidney specimens showed necrotizing and crescentic glomerulonephritis without granuloma formation. An additional blood-sampling test revealed high titers of PR3-ANCA, and we diagnosed PR3-ANCA-positive microscopic polyangiitis (MPA). Treatment with intravenous steroid pulse therapy and intermittent pulse intravenous cyclophosphamide therapy was started for remission induction. With these treatments, sCr improved to ~ 3.0 mg/dL. Azathioprine (AZA) was added for remission-maintenance therapy. Three days later, the dose of AZA was increased from 50 to 100 mg/day, and the number of neutrophils decreased to 30/µL. After withdrawal of AZA, neutrophil levels gradually recovered. We suspected that an abnormal metabolism of AZA was responsible for the neutropenia. Therefore, we analyzed three AZA metabolism-associated genes for mutations: thiopurine S-methyltransferase (TPMT), inosine triphosphate pyrophosphohydrolase (ITPA), and nucleoside diphosphate linked moiety X-type motif 15 (NUDT15), and we identified ITPA 94C>A mutation. This was a rare case of PR3-positive MPA with AZA-induced severe neutropenia that was possibly due to an ITPA gene mutation. This case suggests that ITPA gene mutation is related to the adverse reactions of AZA in Japanese patients. We have to pay attention to severe neutropenia when we use AZA, especially in Asian patients with CKD.
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Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit.

A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information.

Design and synthesis of an in vivo-efficacious PIM3 kinase inhibitor as a candidate anti-pancreatic cancer agent.

Serine/threonine kinase PIM3 is a potential therapeutic target for pancreatic cancer. Here, we describe the evolution of our previous PIM1 inhibitor 1 into PIM3 inhibitor 11 guided by use of the crystal structure of PIM1 as a surrogate to provide a basis for rational modification. Compound 11 potently inhibits PIM3 kinase activity, as well as growth of several pancreatic cancer cell lines. In a mouse xenograft model, 11 inhibited growth of human pancreatic cancer cell line PCI66 with negligible body weight loss. Thus, 11 appears to be a promising lead compound for further optimization to develop new anti-pancreatic cancer agents.

Ultrasonic humidifier lung with a reversed halo sign: A case report.

The reversed halo sign was initially reported as a representative computed tomography scan finding of cryptogenic organizing pneumonia. Since then, however, it has been reported in various diseases and is now considered a nonspecific finding. However, there are no cases of humidifier lung with the reversed halo sign. An 82-year-old Japanese male patient presented with moving difficulties 48 days after starting darolutamide treatment for prostate cancer. He was admitted to the hospital due to acute pneumonia, which presented as bilateral extensive nonsegmental ground-glass opacities in the peripheral regions and extensive areas of ground-glass opacity with a circumferential halo of consolidation, with the reversed halo sign on computed tomography scan. After darolutamide discontinuation with the concomitant administration of antibiotics, the patient's pneumonia improved, and he was discharged from the hospital. However, within a few days, he was again admitted to the hospital due to pneumonia. He was found to have been using an ultrasonic humidifier at home and was then diagnosed with humidifier lung based on the bronchoscopy and provocative testing findings. Hence, ultrasonic humidifier lung should be considered as a differential diagnosis in patients presenting with the reversed halo sign, and a detailed medical history must be taken.

Estimation of Sound Transmission Loss in Nanofiber Nonwoven Fabrics: Comparison of Conventional Models and the Simplified Limp Frame Model.

Although the sound absorption coefficients of conventional and nanofiber nonwoven fabrics (NF-NWFs) have been the subject of many previous studies, few studies have considered the estimation of transmission loss. Reported herein is an experimental and theoretical study into estimating the transmission loss of NF-NWFs using four estimation models, i.e., the Rayleigh, Miki, and Komatsu models, and the simplified limp frame model (SLFM), with the model results compared against the experimental data. The transmission loss of the NF-NWF was determined from the propagation constant, and characteristic impedance was calculated using the estimation model and the transfer matrix method. The validity of each estimation method was examined by comparing its estimated values with the experimental values measured using a four-microphone impedance measurement tube. The proposed SLFM is more suitable for estimating the transmission loss of NF-NWFs than the conventional Rayleigh, Miki, and Komatsu models.

Association between serum ferritin level and decreased diffusion capacity 3 months after the onset of COVID-19 pneumonia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonia can have prolonged sequelae and lead to respiratory dysfunction, mainly because of impaired diffusion capacity for carbon monoxide (DLCO). The clinical factors associated with DLCO impairment, including blood biochemistry test parameters, remain unclear. METHODS: Patients with COVID-19 pneumonia who underwent inpatient treatment between April 2020 and August 2021 were included in this study. A pulmonary function test was performed 3 months after onset, and the sequelae symptoms were investigated. Clinical factors, including blood test parameters and abnormal chest shadows on computed tomography, of COVID-19 pneumonia associated with DLCO impairment were investigated. RESULTS: In total, 54 recovered patients participated in this study. Twenty-six patients (48%) and 12 patients (22%) had sequelae symptoms 2 and 3 months after, respectively. The main sequelae symptoms at 3 months were dyspnea and general malaise. Pulmonary function tests showed that 13 patients (24%) had both DLCO <80% predicted value (pred) and DLCO/alveolar volume (VA) <80% pred, and appeared to have DLCO impairment not attributable to an abnormal lung volume. Clinical factors associated with impaired DLCO were investigated in multivariable regression analysis. Ferritin level of >686.5 ng/mL (odds ratio: 11.08, 95% confidence interval [CI]: 1.84-66.59; p = 0.009) was most strongly associated with DLCO impairment. CONCLUSIONS: Decreased DLCO was the most common respiratory function impairment, and ferritin level was a significantly associated clinical factor. Serum ferritin level could be used as a predictor of DLCO impairment in cases of COVID-19 pneumonia.

Subsequent treatment for locally advanced non-small-cell lung cancer that progressed after definitive chemoradiotherapy and consolidation therapy with durvalumab: a multicenter retrospective analysis (TOPGAN 2021-02).

PURPOSE: For patients with locally advanced non-small-cell lung cancer (LA-NSCLC) that progressed after definitive chemoradiotherapy (CRT) and durvalumab consolidation therapy, no subsequent standard treatment exists. The type of treatment selected for each timing of disease progression and its efficacy have not been investigated. METHODS: We retrospectively enrolled patients with LA-NSCLC or inoperable NSCLC that progressed after definitive CRT and durvalumab consolidation therapy at 15 Japanese institutions. Patients were classified into the following: Early Discontinuation group (disease progression within 6 months after durvalumab initiation), Late Discontinuation group (disease progression from 7 to 12 months after durvalumab initiation), and Accomplishment group (disease progression from 12 months after durvalumab initiation). RESULTS: Altogether, 127 patients were analyzed, including 50 (39.4%), 42 (33.1%) and 35 (27.5%) patients from the Early Discontinuation, Late Discontinuation, and Accomplishment groups, respectively. Subsequent treatments were Platinum plus immune checkpoint inhibitors (ICI) in 18 (14.2%), ICI in 7 (5.5%), Platinum in 59 (46.4%), Non-Platinum in 35 (27.6%), and tyrosine kinase inhibitor in 8 (6.3%) patients. In the Early Discontinuation, Late Discontinuation, and Accomplishment groups, 4 (8.0%), 7 (16.7%), and 7 (20.0%) patients were receiving Platinum plus ICI; 21 (42.0%), 22 (52.4%), and 16 (45.7%) were receiving Platinum, and 20 (40.0%), 8 (19.0%), and 7 (20.0%) were receiving Non-Platinum, respectively. No significant difference in progression-free survival was observed in the timing of disease progression. CONCLUSION: In patients with LA-NSCLC hat progressed after definitive CRT and durvalumab consolidation therapy, subsequent treatment may change depending on the timing of disease progression.

Simplified Limp Frame Model for Application to Nanofiber Nonwovens (Selection of Dominant Biot Parameters).

This study aimed to discover an easy and precise prediction model for the acoustic properties of nanofiber nonwoven fabrics. For this purpose, a prediction model focusing on the two dominant parameters in the Limp frame model-bulk density and flow resistivity-was suggested. The propagation constant and characteristic impedance was generated from the effective density and effective volume modulus generated by the predictive model and treated as a one-dimensional transfer matrix. The sound absorption coefficient was then estimated using the transfer matrix approach. The trend of the normal Incident sound absorption coefficient measured and the sound absorption coefficient obtained from the predictive model were consistent. Thus, it is suggested that the predictive model for the proposed nanofiber nonwoven composite sheet is valid.

Impact of emphysema on the prognosis of Mycobacterium avium complex pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major comorbid disease of Mycobacterium avium complex pulmonary disease (MAC-PD). Emphysema is one of the main pathological findings in COPD, a risk factor for chronic pulmonary aspergillosis (CPA), and is associated with poor prognosis. We aimed to clarify the effect of emphysema on mortality in MAC-PD. METHODS: We retrospectively analyzed 203 patients with MAC-PD at The Jikei Daisan Hospital between January 2014 and December 2018. We investigated the mortality and CPA development rates after MAC-PD diagnosis in patients with or without emphysema. RESULTS: Multivariate Cox proportional hazards regression analysis showed the following negative prognostic factors in patients with MAC-PD: emphysema (hazard ratio [HR]: 11.46; 95% confidence interval [CI]: 1.30-100.90; P = 0.028); cavities (HR: 3.12; 95% CI: 1.22-7.94; P = 0.017); and low body mass index (<18.5 kg/m2) (HR: 4.62; 95% CI: 1.63-13.11; P = 0.004). The mortality and occurrence of CPA were higher in MAC-PD patients with than without emphysema (log-rank test, P < 0.0001 and P < 0.0001). CONCLUSION: Our study findings showed that emphysema detected by computed tomography was associated with an increased risk of CPA development and mortality in MAC-PD.

Allergic bronchopulmonary aspergillosis in a patient with ankylosing spondylitis treated with adalimumab.

We herein report a case of allergic bronchopulmonary aspergillosis (ABPA) that occurred in a man treated with adalimumab for ankylosing spondylitis (AS). A 69-year-old man with a history of ankylosing spondylitis treated by adalimumab, an anti-tumour necrosis factor-α (TNF-α) antibody, developed cough and wheezing. Chest computed tomography showed obstruction of dilated left upper lobe bronchus by high attenuation mucus as well as central bronchiectasis. Both Aspergillus-specific immunoglobulin E (IgE) and Aspergillus precipitating antibody were positive and Aspergillus fumigatus was detected in a sputum culture. According to the new diagnostic criteria, the patient was diagnosed with ABPA. His condition rapidly improved after the withdrawal of adalimumab and initiation of prednisolone and itraconazole. Anti-TNF-α antibody might cause ABPA through both aggravation of the host's T-helper 2 immunological response and anti-fungal response.