Retraction Note: Living annulative π-extension polymerization for graphene nanoribbon synthesis.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41586-020-2950-0 .

Living annulative π-extension polymerization for graphene nanoribbon synthesis.

The properties of graphene nanoribbons (GNRs)1-5-such as conductivity or semiconductivity, charge mobility and on/off ratio-depend greatly on their width, length and edge structure. Existing bottom-up methods used to synthesize GNRs cannot achieve control over all three of these parameters simultaneously, and length control is particularly challenging because of the nature of step-growth polymerization6-18. Here we describe a living annulative π-extension (APEX)19 polymerization technique that enables rapid and modular synthesis of GNRs, as well as control over their width, edge structure and length. In the presence of palladium/silver salts, o-chloranil and an initiator (phenanthrene or diphenylacetylene), the benzonaphthosilole monomer polymerizes in an annulative manner to furnish fjord-type GNRs. The length of these GNRs can be controlled by simply changing the initiator-to-monomer ratio, achieving the synthesis of GNR block copolymers. This method represents a type of direct C-H arylation polymerization20 and ladder polymerization21, activating two C-H bonds of polycyclic aromatic hydrocarbons and constructing one fused aromatic ring per chain propagation step.

Statistical Verification of Anomaly in Chiral Angle Distribution of Air-Suspended Carbon Nanotubes.

Single-walled carbon nanotubes (SWCNT) have long attracted attention due to their distinct physical properties, depending on their chiral structures (chiralities). Clarifying their growth mechanism is important toward perfect chirality-controlled bulk synthesis. Although a correlation between the chirality distribution and the carbon atom configuration at an open tube edge has been predicted theoretically, lack of sufficient statistical data on metallic and semiconducting SWCNTs prohibited its verification. Here, we report statistical verification of the chirality distribution of 413 as-grown individual air-suspended SWCNTs with a length of over 20 µm using broadband Rayleigh spectroscopy. After excluding the impact of the difference in the number of possible SWCNT structures per chiral angle interval, the abundance profile with chiral angle exhibits an increasing trend with a distinct anomaly at a chiral angle of approximately 20°. These results are well explained considering the growth rate depending on armchair-shaped site configurations at the catalyst-nanotube interface.

Real-world evaluation of second line chemotherapy for patients with advanced non-small cell lung cancer harboring preexisting interstitial lung disease.

BACKGROUND: The optimal second and subsequent lines of chemotherapy for patients with non-small cell lung cancer (NSCLC) who have preexisting interstitial lung disease (ILD) are unclear. Hence, we examined the clinical efficacy and safety of second-line chemotherapy in such patients, including any exacerbation of preexisting ILD. METHODS: The medical records of patients with NSCLC and preexisting ILD who received both first- and second-line chemotherapy were retrospectively reviewed. RESULTS: Twenty-four patients with a median age of 71 years who were treated between April 2013 and March 2021 were included. The response rate after second-line chemotherapy with S-1 (n = 13), docetaxel (n = 8), pemetrexed (n = 2), or docetaxel plus ramucirumab (n = 1) was 12.5%, with a median progression-free survival (2nd line PFS) of 3.8 months. The overall survival from a start of first-line chemotherapy (1st line OS) and post-progression survival (PPS) post-first-line chemotherapy were 18.7 and 9.7 months, respectively. Spearman rank correlation and linear regression analyses showed that PPS was strongly correlated with 1st line OS (R = 0.85, P < 0.00001). Importantly, the 2nd line PFS was also significantly correlated with 1st line OS (R = 0.71, P = 0.0001). While second-line chemotherapy-related acute exacerbation of ILD was observed in 7 patients (29.2%), there were no treatment-related fatalities. Conslusions. Second-line chemotherapy has a strong positive impact on the OS of patients with NSCLC who have preexisting ILD. Given the findings of this study, second-line chemotherapy may be valuable in terms of prolonging long-term OS.

Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-disease small-cell lung cancer (LD-SCLC): TORG 0604.

BACKGROUND: The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated. METHODS: Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0-2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m2). Primary objective of the phase II study was overall responce rate. RESULTS: Forty-three patients were enrolled and forty-one were finally analyzed (median age: 75 years [range 70-86 years); males 31; PS 0/1/2, n = 22/18/1]. Two patients were excluded because of protocol violation (ascertained to be extensive disease). Twelve patients were accrued at phase I and the number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and -2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose, total of 35 patients. The median number of chemotherapy cycles was 4 (range 1-4), and the median radiation dose was 54Gy (range 36-60). Toxicities were generally mild. There were 4 complete and 27 partial responses (response rate 88.6%). With a median follow-up of 52 months, the median progression-free and overall survival times of phase II were 11.2 and 27.1 months, respectively. CONCLUSIONS: Induction chemotherapy of carboplatin plus irinotecan and sequential TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional confirmatory studies are warranted. TRIAL REGISTRATION: Trial registration number: UMIN000007352 Name of registry: UMIN. Date of registration: 1/Dec/2006. Date of enrolment of the first participant to the trial: 6/Feb/2007. Clinical trial registration date: 1/Feb/2006 (prospective).

Impact of Smoking History on the Efficacy of Gefitinib in Patients with Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations.

BACKGROUND: Gefitinib treatment has come to be recognized as the standard therapy for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, resistance to gefitinib has been observed in certain subpopulations of these patients. The purpose of this study was to evaluate the impact of smoking status on the efficacy of gefitinib in patients with NSCLC harboring EGFR mutations. METHODS: The records of NSCLC patients harboring EGFR mutations who were treated with gefitinib at Kitasato University Hospital were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: In 153 patients with NSCLC harboring EGFR mutations, the overall response rate and progression-free survival (PFS) were 66.7% and 9.0 months, respectively. PFS differed significantly among the current smokers and never-smokers/former light smokers (10.7 vs. 5.4 months, p=0.0002), and the response rate was significantly higher in the never-smokers/former light smokers than in the current smokers (72.3 vs. 55.8%, p=0.04). Multivariate analysis identified smoking status as an independent predictor of PFS. CONCLUSION: The clinical data obtained in this study provide a valuable rationale for considering smoking status as a predictor of the efficacy of gefitinib in patients with NSCLC harboring activating EGFR mutations.

Aminophylline increases respiratory muscle activity during hypercapnia in humans.

BACKGROUND: Theophylline is an old drug traditionally used as a bronchodilator, although it was recently shown to possess anti-inflammatory properties, enhance the actions of corticosteroid actions, and stimulate the respiratory neuronal network. Theophylline has been recognized as an important drug for not only asthma but also corticosteroid-insensitive chronic obstructive pulmonary disease (COPD). To clarify the role of theophylline in hypercapnic ventilatory responses in humans, we analyzed the effects of aminophylline administered at the usual clinical therapeutic doses on ventilation and augmentation of respiratory muscle contractility in room air and under 3 conditions of hypercapnia. STUDY DESIGN: We performed electromyography (EMG) of the parasternal intercostal muscle (PARA) and transversus abdominis muscle (TA) in 7 healthy subjects and recorded both ventilatory parameters and EMG data in room air and under 3 conditions of hypercapnia before (control) and during aminophylline administration. RESULTS: Before aminophylline administration (control), hypercapnic stimulation elicited ventilatory augmentation in a hypercapnia intensity-dependent manner. Ventilatory parameters (tidal volume, frequency of respiration, and minute ventilation) showed significant increases from lower PaCO2 levels during aminophylline administration when compared with the corresponding values before aminophylline administration. EMG activity of both PARA and TA increased significantly at each level of hypercapnia, and those augmentations were shown from lower PaCO2 levels during aminophylline administration. CONCLUSION: Aminophylline administered at the usual clinical therapeutic dose increases ventilation and EMG activity of both inspiratory and expiratory muscles during hypercapnia in healthy humans.

[A Case Strongly Suspected of Being Pulmonary Toxocariasis Showing Multiple Pulmonary Nodules with a Disappearing and Reappearing Halo Sign].

We report herein on a case strongly suspected of being pulmonary toxocariasis. A 22-year-old Indonesian man referred to our hospital presented with abnormal chest shadows upon medical examination. He had no symptoms. He did not have any pets nor did he eat raw beef or chicken. Hematological examination revealed eosinophilia and elevation of IgE. Chest computed tomography revealed 3 pulmonary nodules with the halo sign. We suspected a parasite infection and performed antiparasite antibody testing. Ascaris suum was slightly positive on the screening test. As specific antibody against the larval excretory-secretory products of Toxocara canis, measured at the National Institute of Infectious Diseases, was positive (level 3 up to 8). Subsequently, the abnormal chest shadows disappeared. However, two months later, 2 pulmonary nodules with the halo sign reappeared in other places. Diagnostic therapy with albendazole was performed for 8 weeks. Mild hepatic impairment emerged during therapy, but it was within the allowed range. Thereafter, the results improved for the imaging findings, eosinophilia, serum IgE level, and specific antibody. The antibody level became negative two months after the treatment had ended. We should consider toxocariasis in the differential diagnosis of migratory nodular shadows with the halo sign on chest computed tomography, and immunoserological testing is useful for the diagnosis.

[Two Cases of Rapidly Progressive Community-acquired Pneumonia Due to Pseudomonas aeruginosa].

Pseudomonas aeruginosa is a significant causative bacterium in hospital-acquired pneumonia and nursing and healthcare-associated pneumonia, but it seems to be rare in community-acquired pneumonia (CAP). We report two cases of severe CAP due to P. aeruginosa. Case 1: A 52-year-old man was referred to our hospital for chest and back pain. He was being treated for diabetes mellitus and had a long history of smoking. Chest images showed consolidation in the right upper lobe. Soon after hospitalization, he developed sepsis shock and died seven hours later. Case 2: A 73-year-old man with a history of heavy smoking was referred to our hospital for right chest pain. Chest images showed right upper lobe pneumonia. Although wide-spectrum antimicrobial agents were administrated, he died ten hours after admission. In both cases, there was a rapid progression to death, despite administration of a broad spectrum of antibiotics and treatment for sepsis. In cases of CAP involving the right upper lobe, the possibility of bacteremia and rapid progress should be considered.

Evaluation of amrubicin as a third or later line of chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Currently, there are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy of amrubicin monotherapy as a salvage treatment in heavily pretreated NSCLC patients. METHODS: The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at a Kitasato University Hospital between January 2009 and December 2012 were retrospectively reviewed. Amrubicin was administered to patients by intravenous injection at a dose of 35 or 40 mg/m(2) daily on 3 consecutive days, and cycles were repeated at 3-week intervals. RESULTS: There were 36 patients who met the inclusion criteria. Their median number of prior chemotherapy treatments was 4 (range 2-7), and the median number of chemotherapy cycles per patient was 4 (range 1-9). Grade 3 or 4 hematologic toxicities included neutropenia (61.1%), leukopenia (58.3%), thrombocytopenia (22.2%) and anemia (11.1%). Febrile neutropenia occurred in 8 patients (22.2%). Nonhematologic toxicities were mild. The overall response rate, median progression-free survival time and median survival time were 8.3%, 1.7 months, and 6.3 months, respectively. Progression-free survival time was the same, i.e. 1.7 months in both groups i.e. the 35- and the 40-mg/m(2)-dose groups. CONCLUSION: Amrubicin exhibits modest activity and acceptable toxicity when used as a third or later line of chemotherapy for advanced NSCLC.

Pemetrexed for previously treated patients with non-small cell lung cancer and differences in efficacy according to thymidylate synthase expression.

The purpose of this study was to evaluate the efficacy of pemetrexed monotherapy in previously treated patients with advanced non-small cell lung cancer (NSCLC) including salvage treatment, and to evaluate whether thymidylate synthase (TS) expression is a predictor for pemetrexed efficacy. Hundred and four previously treated patients with advanced NSCLC who received pemetrexed monotherapy were retrospectively evaluated for clinical efficacy and toxicity. If available, tissue specimens of patients were also analyzed immunohistochemically for TS expression. The patients' median age was 65 years (range: 43-82). An overall response rate of 9.6% and a median progression-free survival (PFS) time of 3.4 months were achieved. The response rates for the second-line, third-line, fourth-line or further treatments were 9.1, 9.3 and 10.2% (p = 0.33); the median PFS were 3.3, 3.2 and 3.8 months (p = 0.21). The median follow-up duration was 14.9 months; the median overall survival (OS) was 11.9 months. The median PFS and OS were significantly longer in the TS-negative group than in the TS-positive group (5.8 months vs. 1.6 months; p = 0.03, and 14.7 months vs. 8.6 months; p = 0.04, respectively). Pemetrexed monotherapy could be considered as an option in the fourth or later lines of treatment of previously treated patients with advanced NSCLC as well as a second- or third-line treatment, and TS expression may be a potentially predictive factor for pemetrexed efficacy in NSCLC patients.

[Efficacy of chemotherapy with carboplatin-paclitaxel plus bevacizumab for previously treated patients with advanced non-small cell carcinoma].

BACKGROUND: There have been few reports on the efficacy or safety of combination therapy with carboplatin-paclitaxel plus bevacizumab(TC+Bev)in previously treated patients with non-small cell lung carcinoma(NSCLC). PURPOSE: The objective of this study was to assess the efficacy and safety of TC+Bev as second-line therapy and beyond for previously treated NSCLC patients. METHODS: A total of 17 patients previously treated with NSCLC at the Kitasato University Hospital between April 2010 and February 2012 were enrolled in this retrospective study. On day 1 all patients received a 200mg/m2 dose of paclitaxel by intravenous infusion over a 3-h period, followed by infusion of carboplatin at a dose corresponding to an AUC of 6.0 min mg/mL, and then by Bev at a dose of 15mg/m2. The treatment course was repeated every three or four weeks. Patients continued to receive Bev monotherapy every 3 weeks thereafter until evidence of disease progression or unacceptable toxicity developed. RESULTS: Median age: 60 years old(range 39-74 years old); gender: male/female, 6/11; PS 0-1/≥2, 17/0; clinical stage:III B/IV postoperative recurrence, 0/16/1; EGFR mutation status: positive/negative/unknown, 7/9/1; histological type: adenocarcinoma in all patients; median number of prior regimens: 3. 4(1-6); median number of cycles(induction phase): 3(1-6). The objective response rate and disease control rate were 17. 6% and 70. 6%, respectively, and the median progression-free survival time was 4. 7 months. There were no treatment-related deaths, and the toxicities of the treatment regimen were acceptable. CONCLUSION: TC+Bev therapy exhibits activity in previously treated NSCLC patients and has acceptable toxicity. Further study is warranted to confirm our results.

[Pemetrexed as second-line treatment and beyond for elderly patients with advanced non-small-cell lung cancer].

BACKGROUND: In Japan, the standard first-line therapy for elderly patients with advanced non-small lung cancer(NSCLC)is docetaxel(DOC)monotherapy. However, there is very limited information about second-line and beyond chemotherapy regimens for elderly patients with advanced NSCLC. Pemetrexed(PEM)monotherapy has been recognized as a standard regimen for advanced NSCLC in second-line settings, just as DOC monotherapy has been. PURPOSE: The objective of this study was to examine the efficacy and safety of PEM as second-line therapy and beyond for elderly patients. METHODS: The records of previously -treated elderly patients with advanced NSCLC, who had been treated with PEM as second-line therapy and beyond between July 2009 and December 2010, were retrospectively reviewed. RESULTS: median age: 73 years old(range 70-79 years old); gender: male/female, 11/8; PS 0-1/≥2, 19/0; clinical stage: III B/IV/postoperative recurrence, 4/10/5; pathology: adeno/LCNEC/other, 17/1/1 patient. The objective response-rate and disease control-rate were 15. 8% and 57. 9%, respectively. Median progression-free survival time was 3. 2 months. There were no treatment-related deaths, and most of the toxicities of the treatment regimen were mild and acceptable. CONCLUSION: PEM monotherapy exhibits activity in previously treated elderly NSCLC patients and has an acceptably low toxicity. Further study is warranted to confirm our results.

Development of multisample detection system using a tag insertion primer and an electrochemical DNA chip.

We have developed a novel multisample detection system by employing a technology combining a tag insertion primer and an electrochemical DNA chip. In the first application, Helicobacter species-infected mouse samples were detected. The primers that insert a different tag sequence in each sample were prepared, and loop-mediated isothermal amplification (LAMP) reaction was carried out. Then amplification products in which a part of the sequence was different in each sample could be obtained. The target sample in which these amplification products were mixed was injected into a cassette that included the DNA chip with immobilized probes. After the cassette was set in the DNA detection system, Genelyzer, the processes of hybridization, washing, and detection were performed by the system automatically. The positive and negative concordance rates of the existing nested polymerase chain reaction (PCR) method and this method were 100% (40/40 samples) and 97.3% (117/120 samples), respectively. This is a simple high-throughput method. Moreover, the cost per sample can be drastically lowered. Therefore, it is expected to contribute to the diagnosis of infectious agents in humans and animals.

[A case of valsartan-induced pneumonitis with marked elevation of serum KL-6].

A 64-year-old man, who had been treated with valsartan for hypertension since about 2 months previously, was admitted with exertional dyspnea. A chest X-ray film on admission showed infiltrative shadows in bilateral lower lung fields. Chest computed tomographic images showed diffuse ground-glass opacities, consolidation and traction bronchiectasis. His serum KL-6 level was markedly elevated, to 7,360 U/ml. Despite the withdrawal of valsartan, his symptoms deteriorated, and a drug lymphocyte stimulation test was positive for valsartan. Based on these findings, we diagnosed valsartan-induced pneumonitis. Glucocorticoids were administered, and his symptoms, chest radiograph findings and serum KL-6 level all improved. Currently, angiotensin II receptor blockers (ARBs), including valsartan, are often used as the first drug of choice to treat hypertension, but they can cause drug-induced pneumonitis. It has been previously reported that serum KL-6 levels may reflect the clinical activity of drug-induced pneumonitis. In cases of drug-induced pneumonitis with a high level of serum KL-6, glucocorticolds should be started at an early stage.

[A case of systemic IgG4-related disease with a middle-posterior mediastinal lesion].

A 62-year-old Japanese man visited our hospital for the examination of a middle-posterior mediastinal lesion noted on a chest CT image. Magnetic resonance imaging (MRI) showed swelling of the hypophysis, bilateral orbital muscles and bilateral lacrimal and submandibular glands. CT subsequently showed a middle-posterior mediastinal lesion, centrilobular nodules in the lung fields, swelling of the pulmonary hilar lymph nodes and soft tissue tumor around the bilateral ureteropelvic junctions. The patient's serum IgG4 level was elevated, and biopsy specimens from the lacrimal gland showed abundant IgG4-positive plasma cells. These findings were consistent with systemic IgG4-related disease. Following steroid treatment, the lesions reduced. To the best of our knowledge, there are only 2 case reports regarding systemic IgG4-related disease accompanied with a middle-posterior mediastinal lesion.

Simultaneous serodetection of major rat infectious pathogens by a multiplex immunochromatographic assay.

Rapid and simple serologic tests that require only a small amount of blood without the euthanization of animals are valuable for microbial control in colonies of laboratory animals. In this study, we developed a multiplex immunochromatographic assay (ICA) for detection of antibodies to Sendai virus (also known as hemagglutinating virus of Japan), hantavirus, and sialodacryoadenitis virus, which are causative agents of major infectious diseases in rats. For this assay, an ICA strip was placed into a microtube containing 150 µl PBS and either 0.75 µl of rat serum or 1.5 µl of whole blood. Binding antibodies were visualized by using anti-rat IgG antibody-conjugated colloidal gold. Under these conditions, the multiplex ICA simultaneously and specifically detected antibodies to multiple antigens. Positive serum samples for each infectious disease were used to evaluate the sensitivity and specificity of the multiplex ICA. The sensitivities of the multiplex ICA for Sendai virus, hantavirus, and sialodacryoadenitis virus were 100%, 100%, and 81%, respectively. No nonspecific reactions were observed in any of the 52 positive sera against heterologous antigens. In addition, 10 samples of uninfected sera did not show any bands except for the control line. These observations indicate high specificity of the multiplex ICA. Moreover, the multiplex ICA could be applied to diluted blood. These results indicate that the multiplex ICA is appropriate for rapid and simple serological testing of laboratory rats.

Creation of an experimental rearing environment for microbiome animal research using an individually ventilated cage system and bioBUBBLE enclosure.

To avoid microbial contamination risk, vinyl film isolators are generally used in animal microbiome experiments involving germ-free (GF) mice and/or gnotobiotic (GB) mice. However, it can take several months to gain expertise in operating the isolator competently. Furthermore, sterilization and sterility testing, which are essential for isolator preparation, can take more than 20 days. Hence, we built an experimental rearing environment that combines an individual ventilation cage system and a bioBUBBLE clean room enclosure to easily set up an experimental animal microbiome environment for animal facilities. In this work, a three-step evaluation was conducted. First, we examined whether GF mice can be maintained in this rearing environment without bacterial contamination. Next, we examined whether GF and GB mice can be maintained without cross-contamination in one individual ventilation cage rack. Finally, we tested whether GF mice can be maintained in a biological safety cabinet controlled by negative pressure. In our series of experiments, no microbial contamination occurred over more than 3 months. These results indicated that our rearing system that combines the individual ventilation cage and bioBUBBLE systems can be used not only for experiments with GF mice but also for Biosafety Level 2 experiments that handle bacteria. Our system can mitigate various disadvantages of using vinyl film isolators. In conclusion, we established an experimental method with improved working time and efficiency compared with those of the previous vinyl isolator method.