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Abstract Background The AmoyDx Pan lung cancer PCR panel (AmoyDx PLC panel) has been approved as a companion diagnostic tool for multiple anticancer agents in patients with non‐small cell lung cancer (NSCLC). However, the suitability of cytology specimens as samples for the AmoyDx PLC panel remains unclear. We evaluated the performance of frozen cell pellets from cytology specimens (FCPs) in the Amoy 9‐in‐1 assay, a preapproval assay of the AmoyDx PLC panel. Methods We retrospectively collected data of NSCLC patients enrolled in LC‐SCRUM‐Asia from the Shizuoka Cancer Center between September 2019 and May 2021. Results A total of 49 cases submitted FCPs for evaluation of oncogenic driver alterations and were assessed using Amoy 9‐in‐1 and next‐generation sequencing (NGS) assays. The success rates of DNA and RNA analyses using the Amoy 9‐in‐1 were both 100%, compared with 86% and 45%, respectively, using NGS assays. Oncogenic driver alterations were detected in 27 (55%) and 23 (47%) patients using Amoy 9‐in‐1 and NGS, respectively. No inconsistent results were observed among 19 cases in which both assays showed successful detection. In the remaining 30 cases, 10 had inconsistent results: nine oncogenic driver alterations (3 MET, 2 ALK, 2 ROS1, and 2 KRAS) were detectable only in Amoy 9‐in‐1, and one epidermal growth factor receptor (EGFR) mutation was detectable only in NGS. Conclusion FCPs can be successfully used in the AmoyDx PLC panel, with higher success rate compared with the NGS assay. The AmoyDx PLC panel may be an option in cases when insufficient tissue sample is available for the NGS assay.

Background Patients with heart failure exhibiting low systolic blood pressure (SBP) have a poor prognosis. Sacubitril/valsartan reduces cardiovascular events; however, its use in patients with low SBP has not been fully examined. Therefore, in this study, we aimed to investigate the association between baseline SBP and adverse events (AEs) in patients starting sacubitril/valsartan therapy using data from a real-world registry in Japan.Methods We analysed data from a multicentre retrospective study, including patients who initiated sacubitril/valsartan between August 2020 and August 2021. The patients were categorised into five groups based on their baseline SBP (

Abstract Background Next-generation sequencing (NGS) is essential for lung cancer treatment. It is important to collect sufficient tissue specimens, but sometimes we cannot obtain large enough samples for NGS analysis. We investigated the yield of NGS analysis by frozen cytology pellets using an Oncomine Comprehensive Assay or Oncomine Precision Assay. Methods We retrospectively enrolled patients with lung cancer who underwent bronchoscopy at Kobe University Hospital and were enrolled in the Lung Cancer Genomic Screening Project for Individualized Medicine. We investigated the amount of extracted DNA and RNA and determined the NGS success rates. We also compared the amount of DNA and RNA by bronchoscopy methods. To create the frozen cytology pellets, we first effectively collected the cells and then quickly centrifuged and cryopreserved them. Results A total of 132 patients were enrolled in this study between May 2016 and December 2022; of them, 75 were subjected to frozen cytology pellet examinations and 57 were subjected to frozen tissue examinations. The amount of DNA and RNA obtained by frozen cytology pellets was nearly equivalent to frozen tissues. Frozen cytology pellets collected by endobronchial ultrasound-guided transbronchial needle aspiration yielded significantly more DNA than those collected by transbronchial biopsy methods. (P

Abstract The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

Abstract Background It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. Methods We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. Results Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. Conclusions For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Effective phosphorus (P) management is crucial for optimal blueberry production. However, a comprehensive understanding of phosphorus distribution across soil depths and types after two decades of blueberry cultivation remains a challenge. This study examines pH, EC, SOC (soil organic carbon), Total N (total nitrogen), and phosphorus fractions in soils from Japanese blueberry fields that have been cultivated for over 20 years. The soils selected for this study represent typical soils from long-term blueberry-growing regions in Japan, ensuring the relevance of the findings to these key agricultural areas. Soil samples were gathered from depths of 0–30 cm and 30–60 cm, revealing significant variations in phosphorus content that are influenced by soil properties and fertilization history. Soil types such as KS (Kuroboku soils) and FS (Fluvic soils) show higher Total P accumulation in deeper layers, whereas BFS (Brown Forest soils) and RYS (Red-Yellow soils) accumulate more in shallower layers. Long-term cultivation has led to greater non-labile phosphorus (NLP) accumulation in shallower layers of KS, BFS, and FS soils, indicating strong phosphorus fixation. BFS soil also exhibits increased organic phosphorus (NaOH-Po) at deeper depths. NaOH-Po and NaHCO3-Po, through their interactions with EC and pH, critically modulate the transformation of NLP into labile phosphorus (LP), thereby influencing overall phosphorus and nitrogen dynamics in the soil. These findings underscore the importance of tailored phosphorus fertilization strategies based on blueberry field characteristics, providing a basis for low-input phosphorus fertilization approaches.

The greater muscle fiber cross-sectional area (CSA) is associated with greater skeletal muscle mass and strength, whereas muscle fiber atrophy is considered a major feature of sarcopenia. Muscle fiber size is a polygenic trait influenced by both environmental and genetic factors. However, the genetic variants underlying inter-individual differences in muscle fiber size remain largely unknown. The aim of our study was to determine whether 1535 genetic variants previously identified in a genome-wide association study of appendicular lean mass are associated with the CSA of fast-twitch muscle fibers (which better predict muscle strength) in the m. vastus lateralis of 148 physically active individuals (19 power-trained and 28 endurance-trained females, age 28.0 ± 1.1; 28 power-trained and 73 endurance-trained males, age 31.1 ± 0.8). Fifty-seven single-nucleotide polymorphisms (SNPs) were identified as having an association with muscle fiber size (p < 0.05). Of these 57 SNPs, 31 variants were also associated with handgrip strength in the UK Biobank cohort (n = 359,729). Furthermore, using East Asian and East European athletic (n = 731) and non-athletic (n = 515) cohorts, we identified 16 SNPs associated with athlete statuses (sprinter, wrestler, strength, and speed–strength athlete) and weightlifting performance. All SNPs had the same direction of association, i.e., the lean mass-increasing allele was positively associated with the CSA of muscle fibers, handgrip strength, weightlifting performance, and power athlete status. In conclusion, we identified 57 genetic variants associated with both appendicular lean mass and fast-twitch muscle fiber size of m. vastus lateralis that may, in part, contribute to a greater predisposition to power sports.

Background: Compression therapy is widely used as a therapeutic option for edema; however, concerns regarding its safety in patients with heart failure (HF) arose, particularly due to increased venous return, which increases pulmonary artery blood pressure. This study aimed to investigate the safety of compression therapy in patients with chronic HF. Methods: This study retrospectively enrolled patients with stable chronic HF who initiated treatment with compression therapy for lower extremity edema. The primary outcome was New York Heart Association (NYHA) class changes after 1 month of compression therapy, and adverse events were evaluated. Results: We analyzed 101 patients who initiated compression therapy. The number of patients continuing compression therapy at one month was 86. Overall, 61.6 % were female and the median age was 81 years. The proportion of patients with heart failure and preserved ejection fraction (HFpEF) was 50.4 %. Brain natriuretic peptide levels were significantly lower than baseline levels at 1 month, (baseline vs 1 month: 486 (360–696) vs 311 (211–511), p

Background: Clinical characteristics and the risk of cardiovascular events in patients with cardiac sarcoidosis (CS) according to the age of initial diagnosis are unclear. Methods: This study is a sub-analysis of the ILLUMINATE-CS registry, which is a retrospective, multicenter registry that enrolled patients with CS between 2001 and 2017. Patients were divided into three groups according to the tertile of age at the time of initial diagnosis of CS. The study compared the clinical background at the time of CS diagnosis and the incidence rate of cardiac events across age categories. Results: A total of 511 patients were analyzed in this study. In baseline, older patients were more likely to be female. History of hypertension, heart failure admission, and atrioventricular block were more common in patients with older age. There was no significant difference in the history of ventricular arrhythmias and left ventricular ejection fraction among all age groups. During a median follow-up period of 3.2 [IQR: 1.7–4.2] years, 35 deaths, 56 heart failure hospitalization, and 98 fatal ventricular arrhythmias was observed. The incidence rate of all-cause death and heart failure hospitalization was significantly higher in patients with older age (p

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Aims Given the various effects of sacubitril/valsartan in heart failure, a deeper understanding of atrial natriuretic peptide (ANP) actions is warranted. Natriuresis is a fundamental action of ANP in acute heart failure (AHF), whereas the diuretic effect of ANP is different in each patient according to the diversity of renal response to ANP, which is affected by baseline plasma ANP status and deficiency of circulating ANP. Meanwhile, associations between other neuroendocrine hormones and the diuretic response to ANP are unclear. This study investigated the impact of pivotal neuroendocrine hormones on the diuretic effects of exogenous ANP, carperitide. Methods and results Plasma ANP, renin, aldosterone, and vasopressin levels and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 75 patients with AHF. Lower ANP levels were significantly associated with a greater diuretic response to exogenous ANP (r = −0.35, P = 0.002). Additionally, higher vasopressin levels were significantly related to the poor diuretic effects of exogenous ANP (r = −0.54, P

Abstract Basket clam soup, a popular Asian dish, is prepared by boiling clams in hot water. The soup is generally cloudy, and it is considered that increased cloudiness enhances taste. However, the composition of the whitening ingredients and their association with taste enhancement remains unclear. In this study, we aimed to identify the components contributing to the white colour of the boiled soup. The white component upon precipitation with trichloroacetic acid reacted positively with ninhydrin, indicating the presence of proteins. The separation of proteins using sodium dodecyl sulphate–polyacrylamide gel electrophoresis revealed an intense band of size 33 kDa. Peptide mass fingerprinting of the identified protein using matrix-assisted laser desorption/ionisation-time-of-flight tandem mass spectrometry revealed the protein as tropomyosin. To validate the involvement of tropomyosin in the turbidity of the soup, tropomyosin was expressed and extracted from Escherichia coli. As expected, the purified protein suspended in water resulted in turbid appearance. To determine whether lipids have any association with the observed cloudiness of the soup, the amounts of fatty acids were measured. The proportion of estimated fatty acids was very low compared to that of proteins. Overall, we identified the major component contributing to soup cloudiness as tropomyosin forming micelles.

Abstract Previous studies have reported that a high neutrophil-to-lymphocyte ratio (NLR) is associated with disease severity and poor prognosis in COVID-19 patients. We aimed to investigate the clinical implications of NLR in patients with COVID-19 complicated with cardiovascular diseases and/or its risk factors (CVDRF). In total, 601 patients with known NLR values were selected from the CLAVIS-COVID registry for analysis. Patients were categorized into quartiles (Q1, Q2, Q3, and Q4) according to baseline NLR values, and demographic and clinical parameters were compared between the groups. Survival analysis was conducted using the Kaplan–Meier method. The diagnostic performance of the baseline and follow-up NLR values was tested using receiver operating characteristic (ROC) curve analysis. Finally, two-dimensional mapping of patient characteristics was conducted using t-stochastic neighborhood embedding (t-SNE). In-hospital mortality significantly increased with an increase in the baseline NLR quartile (Q1 6.3%, Q2 11.0%, Q3 20.5%; and Q4, 26.6%; p

Abstract Introduction Success of next generation sequencing (NGS) analysis is becoming indispensable in the treatment of advanced lung cancer. However, the advantages and disadvantages of each sampling method in the NGS analysis have not yet been clarified. Methods We compared the success rates of NGS analysis, and DNA and RNA yields for transbronchial biopsy (TBB), endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA), computed tomography (CT)‐guided biopsy, fluid sample, and surgical biopsy for NGS analysis in patients through the lung cancer genomic screening project for individualized medicine (LC‐SCRUM)‐Asia, a nationwide NGS screening project. In case, sufficient samples could not be collected by TBB and EBUS‐TBNA, re‐biopsy (genome re‐biopsy) was performed. Results A total of 223 patients were enrolled and success rates of NGS analysis were not different between samples obtained through TBB, EBUS‐TBNA, and CT‐guided biopsy; however, success rates for fluid samples and surgical biopsy samples were significantly higher than those of other methods. The risk of genome re‐biopsy was higher with TBB for centrally located lesions. CT‐guided biopsy yielded more samples but had a lower success rate for analysis of RNA‐based NGS than TBB. Conclusions TBB is the mainstay of sampling methods, but for centrally located lesions, EBUS‐TBNA may be a better strategy. For CT‐guided biopsy, the success rate of RNA‐based NGS analysis is low. Fluid samples are expected to yield successful results as surgical biopsy samples, but the latter are better for sample preservation. Determining the optimal method for genome biopsy for each case is important.

To promote the use of waxy barley bran, an underutilized resource, samples of waxy barley were divided into three parts: polished waxy barley powder (PWBP), inner bran layer powder (IBLP), and outer bran layer powder (OBLP). The color and appearance, general properties, minerals, vitamins, β-glucan, antioxidant properties, and aroma of each part were compared. In terms of appearance and color, IBLP and OBLP appeared more yellow than PWBP; general components that were more abundant in IBLP and OBLP compared with PWBP were protein, fat, and ash. IBLP and OBLP had characteristically high values of Mg and Zn, monounsaturated and polyunsaturated fatty acids, vitamin B1, total polyphenol content, H-ORAC, and DPPH. In particular, the vitamin B1 content of OBLP was approximately 10 times higher than that of PWBP, and Mg and Zn content was more than five times higher than in PWBP. The β-glucan content of IBLP and OBLP was lower than that of PWBP, but relatively high. GC–MS analysis revealed that hexanal was the aroma component common to all three samples, and the peak areas were in the order of PWBP > OBLP > IBLP.

Abstract Background It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs. Methods We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS). Results A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007). Conclusions The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.

Abstract Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Abstract Background Takotsubo syndrome is a stress-induced disease that makes up 2–3% of acute coronary syndrome cases. However, its onset mechanism remains unclear. Although females are overwhelmingly affected, males end up having more cardiac complications. Case presentation We examined the differences in stress responses in the myocardium between sexes in patients with takotsubo syndrome. We biopsied samples from an over 70-year-old Japanese male and an over 80-year-old Japanese female. Tissues from the left ventricle apex in the acute phase and the apical ballooning-type were examined using histopathology and deoxyribonucleic acid (DNA) microarray analysis. Our data showed that left ventricular ejection fractions were 38% and 56%, and peak creatinine kinase concentrations during hospitalization were 629 U/L and 361 U/L, for the male and female patient, respectively. The pulmonary capillary wedge pressure was 26 mmHg and 11 mmHg for the male and female patient, respectively. Negative T did not return to normal in the male subject after 6 months. Histopathology results indicated that contraction band necrosis and lymphocyte infiltration were more common in the male subject. Conclusions We noticed that possible differences may exist between male and female patients using pathological examination and some DNA analyses. In particular, it may help treat acute severity in males. We will elucidate the mechanism of takotsubo syndrome development by increasing the number of samples to support the reliability of the data in the future.

Abstract Healthcare workers (HCWs) treating and caring for patients with emerging infectious diseases often experience psychological distress. However, the psychological impact and behavior change of the coronavirus disease 2019 (COVID-19) pandemic among HCWs are still unknown. This study aimed to investigate the worries and concerns of HCWs regarding the COVID-19 pandemic. In this cross-sectional survey, a web-based questionnaire was distributed among HCWs working in hospitals or clinics across Japanese medical facilities from April 20 to May 1, 2020. The questionnaire comprised items on demographics, worries and concerns, perceptions regarding the sufficiency of information, and behavioral changes pertaining to the COVID-19 pandemic. A total of 4386 HCWs completed the survey; 1648 (64.7%) were aged 30–39 years, 2379 (54.2%) were male, and 782 (18.1%) were frontline HCWs, directly caring for patients with COVID-19 on a daily basis. 3500 HCWs (79.8%) indicated that they were seriously worried about the pandemic. The most frequent concern was the consequence of becoming infected on their family, work, and society (87.4%). Additionally, the majority (55.5%) had restricted social contact and almost all HCWs endorsed a shortage in personal protective equipment (median, 8/9 (interquartile range; 7–9) on a Likert scale). There was no significant difference in the degree of worry between frontline and non-frontline HCWs (8/9 (7–9) vs. 8/9 (7–9), p = 0.25). Frontline HCWs, compared to non-frontline HCWs, were more likely to have the need to avoid contact with families and friends (24.8% vs. 17.8%, p

Abstract Aims Exogenous atrial natriuretic peptide (ANP) may be a logical treatment for heart failure (HF) patients with ANP deficiency. Lower ANP concentrations may result from HF with preserved ejection fraction (HFpEF), which also results in lower brain natriuretic peptide levels in HFpEF relative to HF with reduced ejection fraction (HFrEF), although clinical features regarding circulating ANP in HFpEF and HFrEF have not been fully investigated during acute HF. Here, we characterized the differential regulation of circulating ANP and the efficacy of exogenous ANP (carperitide) in patients with acute HF, especially HFpEF. Methods and results Serum ANP levels before treatment and the diuretic effect of 0.0125 μg/kg/min of carperitide alone for the first 6 h were prospectively evaluated in 113 patients with acute HF who were divided into two groups: HFpEF vs. HFrEF. We mainly analysed the impact of baseline ANP levels and the presence of HFpEF on the diuretic effect of exogenous ANP. There was an inverse relationship between ANP levels and the diuretic effect of exogenous ANP (r2 = 0.19, P

Abstract Background Myasthenia gravis (MG) is an autoimmune disease caused by antibodies that block or destroy nicotinic acetylcholine receptors at the neuromuscular junction. Most of MG patients need immunosuppression agents in addition to treatments that alleviate the symptoms. Intravenous immunoglobulin (IVIg) and plasma exchange are specific treatments given to patients with severe MG and myasthenia gravis crisis. IVIg therapy can cause an increase in serum viscosity; therefore, the risk for thromboembolic events, such as stroke, myocardial infarction, and pulmonary embolism, are reported after IVIg therapy. Case presentation An MG patient was treated with pyridostigmine bromide and prednisolone. The patient’s symptoms worsened 26 days after the commencement of treatment and was presented with head drop and dyspnea. The patient was diagnosed with MG crisis and IVIg was initiated. However, the patient reported chest pain and dyspnea 3 days after IVIg had started. An electrocardiogram (ECG) revealed ST elevations in leads II, III, and aVF. A cardiac catheterization was performed and stenosis, obstruction, and sclerosis were ruled out. Glyceryl trinitrate relieved the patient’s symptoms, suggesting coronary spastic angina (CSA). Conclusions We report the first case of CSA after IVIg. Practitioners should be aware of the potential risks of CSA when administering IVIg for MG patients, in particular in old patients with vascular risk factors.

Alloy anode materials in lithium batteries usually suffer from fatal structural degradation due to the large volume change during cycling. Here the authors report a design in which Al foil serves as both anode and current collector to circumvent the strain.

Abstract Background MET-deregulated non-small cell lung cancer represents an urgent clinical need because of the lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET gene alterations, no conclusive data are currently available. Therefore, we designed the Co-MET study, a single-arm phase II study to assess the efficacy and safety of crizotinib in patients with advanced non-small cell lung cancers harboring MET gene alterations. Methods Co-MET is an open-label, multi-center, single-arm, phase II trial to assess the safety and efficacy of oral crizotinib in patients with advanced non-small cell lung cancer harboring MET exon 14 skipping mutation (cohort 1) or a high MET gene copy number of ≥ 7 (cohort 2). We will identify MET gene alterations using RT-PCR and/or next-generation sequencing. Oral crizotinib 250 mg BID will be administered until disease progression or unacceptable toxicity. A radiology committee will review tumor scans according to the RECIST criteria. The primary endpoint is the objective response rate. Assuming a null hypothesis of 20% objective response rate and an alternative hypothesis of 50% objective response rate for cohort 1, and a one-sided alpha error of 0.05 and 80% power based on the exact binomial distribution, the required number of evaluable patients is 19. We set the exploratory sample size for cohort 2 at 10 patients. Discussion The results of this study are expected to provide evidence regarding the usefulness of oral crizotinib for advanced MET exon 14 skipping mutation-positive or MET high gene copy number-positive non-small cell lung cancer. Trial registration This study was registered with the University Hospital Medical Information Network Clinical Trials Registry as UMIN000031623 on 3 March 2018.

Objectives Predictive algorithms to inform risk management decisions are needed for patients with COVID-19, although the traditional risk scores have not been adequately assessed in Asian patients. We aimed to evaluate the performance of a COVID-19-specific prediction model, the 4C (Coronavirus Clinical Characterisation Consortium) Mortality Score, along with other conventional critical care risk models in Japanese nationwide registry data.Design Retrospective cohort study.Setting and participants Hospitalised patients with COVID-19 and cardiovascular disease or coronary risk factors from January to May 2020 in 49 hospitals in Japan.Main outcome measures Two different types of outcomes, in-hospital mortality and a composite outcome, defined as the need for invasive mechanical ventilation and mortality.Results The risk scores for 693 patients were tested by predicting in-hospital mortality for all patients and composite endpoint among those not intubated at baseline (n=659). The number of events was 108 (15.6%) for mortality and 178 (27.0%) for composite endpoints. After missing values were multiply imputed, the performance of the 4C Mortality Score was assessed and compared with three prediction models that have shown good discriminatory ability (RISE UP score, A-DROP score and the Rapid Emergency Medicine Score (REMS)). The area under the receiver operating characteristic curve (AUC) for the 4C Mortality Score was 0.84 (95% CI 0.80 to 0.88) for in-hospital mortality and 0.78 (95% CI 0.74 to 0.81) for the composite endpoint. It showed greater discriminatory ability compared with other scores, except for the RISE UP score, for predicting in-hospital mortality (AUC: 0.82, 95% CI 0.78 to 0.86). Similarly, the 4C Mortality Score showed a positive net reclassification improvement index over the A-DROP and REMS for mortality and over all three scores for the composite endpoint. The 4C Mortality Score model showed good calibration, regardless of outcome.Conclusions The 4C Mortality Score performed well in an independent external COVID-19 cohort and may enable appropriate disposition of patients and allocation of medical resources.Trial registration number UMIN000040598.

Abstract Background Two important regulators for circulating lipid metabolisms are lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In relation to this, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) has been shown to have a vital role in LPL lipolytic processing. However, the relationships between skeletal muscle mass and lipid metabolism, including LPL, GPIHBP1, and HTGL, remain to be elucidated. Demonstration of these relationships may lead to clarification of the metabolic dysfunctions caused by sarcopenia. In this study, these relationships were investigated in young Japanese men who had no age-related factors; participants included wrestling athletes with abundant skeletal muscle. Methods A total of 111 young Japanese men who were not taking medications were enrolled; 70 wrestling athletes and 41 control students were included. The participants’ body compositions, serum concentrations of lipoprotein, LPL, GPIHBP1 and HTGL and thyroid function test results were determined under conditions of no extreme dietary restrictions and exercises. Results Compared with the control participants, wrestling athletes had significantly higher skeletal muscle index (SMI) (p

The sowing-to-harvest period for the medicinal plant Ginseng (Panax ginseng Meyer) is 4–6 years. Although one of the primary soils used to cultivate ginseng in Japan is Andosol, there have been few studies of the changes in the soil’s chemical properties during the cultivation of ginseng in Andosol soil. Here, we investigated the chemical properties of Andosol soil by collecting soil samples from cultivation sites with various numbers of years of ginseng cultivation. A significant negative correlation was observed between the years of cultivation and the soil’s pH, indicating that soil acidification increased with an increasing number of years of cultivation. Similarly, exchangeable calcium (Ca) showed a significant negative correlation with the years of cultivation. The soluble aluminum (Al) concentration showed a significant positive correlation with the years of cultivation and was significantly negatively correlated with the exchangeable Ca and magnesium (Mg) contents. These results suggest that a decrease in pH due to Ca absorption by ginseng, increasing Al dissolution, and a further accelerated decrease in pH occur during the cultivation of ginseng in Andosols. The increase in soluble Al with increasing years of cultivation also affected the dynamics of essential trace elements in the soil, showing significant negative correlations with the soil’s soluble copper (Cu) and zinc (Zn) contents, indicating that the Cu and Zn contents decreased with increasing Al. Our findings indicate that in the cultivation of ginseng on Andosol soil, the soil’s soluble Al content is an essential factor in changes in the soil’s chemical properties.

Abstract Advanced cancer genomics technologies are now being employed in clinical sequencing, where next-generation sequencers are used to simultaneously identify multiple types of DNA alterations for prescription of molecularly targeted drugs. However, no computational tool is available to accurately detect DNA alterations in formalin-fixed paraffin-embedded (FFPE) samples commonly used in hospitals. Here, we developed a computational tool tailored to the detection of single nucleotide variations, indels, fusions, and copy number alterations in FFPE samples. Elaborated multilayer noise filters reduced the inherent noise while maintaining high sensitivity, as evaluated in tumor-unmatched normal samples using orthogonal technologies. This tool, cisCall, should facilitate clinical sequencing in everyday diagnostics. It is available at https://www.ciscall.org.

Mechanisms of acquired resistance to RET tyrosine kinase inhibitors in lung cancers are largely unknown. Here, the authors report in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13C-glucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would not be not detectable in FDG-PET.

EGFR mutations in lung adenocarcinoma are more frequent in East Asians compared to other populations. Here, the authors carry out a genome-wide association study in EGFRmutant cancers and identify loci that are associated with risk of developing this molecular subtype of cancer.

We investigated the effect of temperature during the ripening period on the rice yield and arsenic (As) concentration in brown rice, using temperature gradient chambers (TGCs). Rice grown in Wagner pots (1/5000a) was placed in three TGCs (each TGC was set at four temperature levels: ambient, mildly-high temperature, moderately-high temperature, and super-high temperature) from one week after heading until harvest. In the TGCs, a range of mean air temperatures was observed in the range of 2 °C above the ambient temperature. There was a significant negative correlation between the brown rice yield and the air and soil temperatures, and the increase in air and soil temperatures resulted in a decrease in the yield. The reduction in yield was significantly mitigated by the application of calcium silicate. The concentration of As in the brown rice was significantly positively correlated with the air and soil temperature, and the concentration of As increased with increasing air and soil temperatures. When calcium silicate was applied, the concentration of As in brown rice was significantly lower at all temperature ranges, and its application was effective in reducing the arsenic concentration even at high temperatures. These results suggest that the application of silicate material may help mitigate the decrease in yield and the increasing As concentration in brown rice even under high-temperature conditions.

Background: East Asian desert dust storms that occur during mainly spring are called Asian dust storms (ADS). Our objective was to study the association of pollen and ADS with symptoms of adult asthma patients in Japan. Methods: We designed a telephone survey to investigate the upper and lower respiratory, ocular, and skin symptoms of asthma patients during ADS in February, March, and December on 2009. Peak expiratory flow (PRF) was also measured from February to May. Results: We surveyed 106 patients in February, 101 patients in March, and 103 patients in December. In February and March, Japanese cedar and/or cypress pollen was also in the atmosphere during ADS, but no pollen was identified during December survey. Worsening of upper or lower respiratory, ocular, or skin symptoms was noted by 20.8% of patients in February, 33.7% in March, and 16.5% in December. Worsening of symptoms was significantly more common in March than in February or December. Two patients needed emergency treatment for exacerbation during ADS in March, but no patient needed hospitalization in any period. There was no significant difference of the daily morning PEF/personal best PEF ratio between ADS days and control days. However, in patients with worsening of upper and/or lower respiratory tract symptoms, the daily morning PEF/personal best ratio was significantly associated with the atmospheric level of particulate matter, but not with levels of pollen or other air pollutants. Conclusions: Pollen augmented symptoms in adult asthma patients, but ADS on its own also were able to aggravate symptoms and pulmonary function.

Background: Severe wind storms during spring in East Asia, called Asian dust storms (ADS), have been assessed in the past for their effect on health in Asian countries. Our objective was to study the ADS association with asthma symptoms in adult patients in Japan. Methods: We designed a telephone survey to assess ADS influence on upper and lower respiratory, ocular and cutaneous symptoms in 98 patients with adult asthma from April to May 2007. Peak expiratory flow (PEF) was also measured from February to May. Results: Worsening lower respiratory symptoms were noted by 22 of 98 patients during ADS in April, when Japanese cedar pollen levels also increased. During ADS in May, however, Japanese cedar and cypress pollen levels were not elevated, 11 patients had worsening of lower respiratory symptoms. None required emergency treatment for the exacerbation. Lower respiratory symptoms worsening most were cough and sputum; this was more common in patients with allergic rhinitis or atopy than in those without (P < 0.05). Min%Max differed significantly at 88.7 ± 6.6% during dust dispersion period, defined as the ADS day plus the next 6 days, versus 92.0 ± 5.3% during the 7-day period before a dust storm. Conclusions: We found that ADS aggravated lower respiratory symptoms in adult patients with asthma, but this influence was mild.

Plant-induced solubilization of soil nitrogen (N) is a key process for plants to utilize the recalcitrant form of N. Toevaluate its contribution to plant uptake, the factors affecting the contribution and the forms of N solubilized by plants, we analyzed the results of a pot experiment in which komatsuna (Brassica rapa L. var. peruviridis) was grown in 3 different soils applied with 5 types of sewage sludge as a source of N for plants. The amount of N solubilized by plants, which was defined experimentally as the difference in the amount of solubilized N between the planted and unplanted treatments, varied with the soil types more than the types of sewage sludge. This accounted for 30% (Arenosol), 15% (Fluvisol) and 1.6% (Andosol) of the amount of N uptake on average. These percentages were high when the level of soil soluble N after the experiment was below approximately 30 mg kg-1. Sequential analyses of insoluble N in soil after the experiment indicated the occurrence of plant-induced solubilization of both bio-soluble and acid-soluble N in many of the Arenosol and Fluvisol treatments and that of acid-soluble N in the Andosol treatments. The plant-induced solubilization in the Andosol resulted in the accumulation of more labile bio-soluble N rather than enhanced plant uptake. For komatsuna grown in fertilized soil, the depletion of soluble N in the root zone seems to be important for the increase in the contribution of the plant-induced solubilization to uptake but not for the occurrence of the solubilization.

TH-302 is a hypoxia-activated prodrug (HAP) of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302.The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR) oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2), with minimal effect under aerobic conditions (21% O2). Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3). Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3)), significantly delayed tumor growth.Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the appropriate tumor size and oxygen concentration.

BACKGROUND:Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of lymph node metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) related markers in cancer cells and the number of infiltrating stromal cells. MATERIAL AND METHODS:Primary lung adenocarcinomas with lymphatic permeation in the extratumoral area were retrospectively examined (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic cancer cells to evaluate their relationship to lymph node metastasis. Moreover, the number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated. RESULTS:Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for lymph node metastasis (P = 0.004, P = 0.008, and P = 0.028, respectively). Among these factors, only low ALDH1 expression in cancer cells was significantly correlated with the farther spreading of lymph node metastasis (mediastinal lymph node, pathological N2) (P = 0.046) and the metastatic lymph node ratio (metastatic/resected) (P = 0.028). On the other hand, in the primary tumors, ALDH1 expression in the cancer cells was not associated with lymph node metastasis. Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015). CONCLUSIONS:Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on lymph node metastasis. Our study also highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis.

Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)

Three-dimensional Oximetric Electron Paramagnetic Resonance Imaging using the Single Point Imaging modality generates unpaired spin density and oxygen images that can readily distinguish between normal and tumor tissues in small animals. It is also possible with fast imaging to track the changes in tissue oxygenation in response to the oxygen content in the breathing air. However, this involves dealing with gigabytes of data for each 3D oximetric imaging experiment involving digital band pass filtering and background noise subtraction, followed by 3D Fourier reconstruction. This process is rather slow in a conventional uniprocessor system. This paper presents a parallelization framework using OpenMP runtime support and parallel MATLAB to execute such computationally intensive programs. The Intel compiler is used to develop a parallel C++ code based on OpenMP. The code is executed on four Dual-Core AMD Opteron shared memory processors, to reduce the computational burden of the filtration task significantly. The results show that the parallel code for filtration has achieved a speed up factor of 46.66 as against the equivalent serial MATLAB code. In addition, a parallel MATLAB code has been developed to perform 3D Fourier reconstruction. Speedup factors of 4.57 and 4.25 have been achieved during the reconstruction process and oximetry computation, for a data set with 23×23×23 gradient steps. The execution time has been computed for both the serial and parallel implementations using different dimensions of the data and presented for comparison. The reported system has been designed to be easily accessible even from low-cost personal computers through local internet (NIHnet). The experimental results demonstrate that the parallel computing provides a source of high computational power to obtain biophysical parameters from 3D EPR oximetric imaging, almost in real-time.