Original Article

ネコ32匹について,10% urethane-1% chloralose(5ml/kg)の腹腔内麻酔を行ない,横隔膜運動神経を機能的単一神経発射としてとり出し,その基本的特性と換気機構との相関および横隔膜神経支配について検討した。1)横隔膜運動神経線維について,機能的単一神経発射115本の発射パターンを自発呼吸下における気速曲線と対比し,I〜IV型に分類した。2)横隔膜神経におけるこれらの線維の構成は,I型40%,II型48%,III型10%そしてIV型は2%以下であった。3)I・II・III型の線維の基本的特性は,気道抵抗を加えた場合および呼気反射における発射パターンの変化からI型は相動性の要素を有し,II・III型は緊張性の要素を有している。4)これらの線維と換気機構の相関をみると,I型の線維は,主として効果的な吸気を瞬間的に行なうためにdynamicであり,II型の線維は,静的状態における吸気に主役を演じstaticである。さらに初期の呼出を円滑に行なわせるのにおもな役割を果たしている。III型は,主として腹圧に拮抗した緊張性の線維と考えられる。IV型については,ガンマ-運動線維である可能性について考察した。6)横隔膜筋支配については,腰部はI型,肋骨部は,I・II・III型の線維によって支配されていると考えられる。32 cats weighing 1.8 to 3.4 kg were intraperitoneally anesthetized with 10% urethane and 1% chloralose (5 ml/kg). 115 functionally unitary discharges of the phrenic nerve classified into four different types. Type I fibres initiate their firings after the beginning of the inspiratory phase and cease their activities prior to the onset of the expiratory flow change. Type II fibres fire with the very onset of the inspiratory phase and extend their activites untill the initial part of the expiration. The firings of Type III fibres dominate the whole inspiratory phase and initial two thirds of the expiration. Type IV showed continuously tonic firing throughout the whole respiratory cycle and increase their activities slightly during the inspiratory phase. Type I and II occupied more than 80% of all pattern. Modification of firing mode of each fibre type was observed under spontaneous respiration with air-way resistance and deflation reflex. The results may indicate characteristic features of each fibre type. Type I fibres may contribute to the kinetic contraction of the diaphragm and Type II the tonic one. Type III fibres were more tonic than Type II and may keep diaphragmatic tension against the intra-abdominal pressure. Type IV fibres probably belong to gamma motoneurons. Electromyographic observations suggested dominant innervation of Type I fibres to the pars cruralis. Pars costalis was mainly innervated by Type II fibres

Effect of saline stress on the physiology and growth of maize hybrids and their related inbred lines

Salinity is one major abiotic stress that restrict plant growth and crop productivity. In maize (Zea mays L), salt stress causes significant yield loss each year. However, indices of maize response to salt stress are not completely explored and a desired method for maize salt tolerance evaluation is still not established. A Chinese leading maize variety Jingke968 showed various resistance to environmental factors, including salt stress. To compare its salt tolerance to other superior maize varieties, we examined the physiological and growth responses of three important maize hybrids and their related inbred lines under the control and salt stress conditions. By compar- ing the physiological parameters under control and salt treatment, we demonstrated that different salt tolerance mechanisms may be involved in different genotypes, such as the elevation of superoxide dismutase activity and/ or proline content. With Principal Component Analysis of all the growth indicators in both germination and seedling stages, along with the germination rate, superoxide dismutase activity, proline content, malondialdehyde content, relative electrolyte leakage, we were able to show that salt resistance levels of hybrids and their related inbred lines were Jingke968 > Zhengdan958 > X1132 and X1132M > Jing724 > Chang7-2 > Zheng58 > X1132F, respectively, which was consistent with the saline field observation. Our results not only contribute to a better understanding of salt stress response in three important hybrids and their related inbred lines, but also this evaluation system might be applied for an accurate assessment of salt resistance in other germplasms and breeding material

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene–age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291MORN1, whose effect was significantly modified by age (HRdiscovery = 1.018, p = 4.07 × 10−07, FDR-q = 3.67 × 10−02; HRvalidation = 1.058, p = 8.09 × 10−03; HRcombined = 1.019, p = 7.36 × 10−10). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291MORN1 and age (HRinteraction = 0.284; 95% CI, 0.135–0.597; p = 9.04 × 10−04). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291MORN1–age interaction (HRhigh vs. low = 3.66, 95% CI: 2.40–5.60, p = 1.93 × 10−09). By adding 24 significant gene–age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC3-year = 0.80, AUC5-year = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291MORN1 and age on OSCC survival, providing a potential therapeutic target for OSCC patients

Faktor-Faktor Yang Mempengaruhi Pengungkapan Tanggung Jawab Sosial

Penelitian ini bertujuan untuk menentukan faktor-faktor yang mempengaruhi luasnya tingkat pengungkapan tanggung jawab sosial Perusahaan (Corporate Social Responsibility) dengan menguji pengaruh ukuran Perusahaan, profitabilitas, leverage, kepemilikan insti­tusional, ukuran dewan komisaris, ukuran dewan direksi, dan ukuran komite audit. Sampel yang digunakan adalah Perusahaan sektor pertambangan terdaftar di Bursa Efek Indonesia selama 2010-2012. Data diperoleh dari laporan keuangan auditan dan laporan tahunan serta laporan keberlanjutan (sustainability report) jika ada. Penelitian ini menggunakan pendekatan kuantitatif dengan analisis regresi linear berganda. Penelitian ini menunjukkan bahwa ukuran Perusahaan dan komite audit memiliki pengaruh positif terhadap peng­ungkapan tanggung jawab sosial. Tidak ditemukan bukti pengaruh profitabilitas, leverage, kepemilikan institusional, ukuran dewan komisaris, dan ukuran dewan direksi terhadap terhadap pengungkapan tanggung jawab sosial

Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival

Genetic intratumor heterogeneity is associated with tumor occurrence, development and overall outcome. The present study aims to explore the association between mutant-allele fraction (MAF) heterogeneity and patient overall survival in lung cancer. Somatic mutation data of 939 non-small cell lung cancer (NSCLC) cases were obtained from The Cancer Genome Atlas. Entropy-based mutation allele fraction (EMAF) score was used to describe the uncertainty of individual somatic mutation patterns and to further analyze the association with patient overall survival. Results indicated that association between EMAF and overall survival was significant in the discovery set [hazard ratio (H)R=1.62; 95% confidence interval (CI): 1.08–2.41; P=0.018] and replication set (HR=1.63; 95% CI: 1.11–2.37; P=0.011). In addition, EMAF was also significantly different in lung adenocarcinoma and squamous cell carcinoma. Furthermore, a significant difference was indicated in early-stage patients. Results from c-index analysis indicated that EMAF improved the model predictive performance on the 3-year survival beyond that of traditional clinical staging, particularly in early-stage patients. In conclusion, EMAF successfully reflected MAF heterogeneity among patients with NSCLC. Additionally, EMAF improved the predictive performance in early-stage patient prognosis beyond that of traditional clinical staging. In clinical application, EMAF appears to identify a subset of early-stage patients with a poor prognosis and therefore may help inform clinical decisions regarding the application of chemotherapy after surgery

Characteristics and candidate genes associated with excellent stalk strength in maize (Zea mays L.)

Lodging is a major problem in maize production, which seriously affects yield and hinders mechanized harvesting. Improving stalk strength is an effective way to improve lodging. The maize inbred line Jing2416 (J2416) was an elite germplasm in maize breeding which had strong stalk mechanical strength. To explore the characteristics its stalk strength, we conducted physiological, metabolic and transcriptomic analyses of J2416 and its parents Jing24 (J24) and 5237. At the kernel dent stage, the stalk rind penetrometer strength of J2416 was significantly higher than those of its two parents in multiple environments. The rind thickness, sclerenchyma tissue thickness, and cellulose, hemicellulose, and lignin contents of J2416 were significantly higher than those of its parents. Based on the significant differences between J2416 and 5237, we detected metabolites and gene transcripts showing differences in abundance between these two materials. A total of 212 (68.60%) metabolites and 2287 (43.34%) genes were up-regulated in J2416 compared with 5237. The phenylpropanoid and glycan synthesis/metabolism pathways were enriched in metabolites and genes that were up-regulated in J2416. Twenty-eight of the up-regulated genes in J2416 were involved in lignin, cellulose, and hemicellulose synthesis pathways. These analyses have revealed important physiological characteristics and candidate genes that will be useful for research and breeding of inbred lines with excellent stalk strength

Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC

BACKGROUND: KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival. METHODS: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation. RESULTS: DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50, P = 1.1 × 10-4; HRcg26662347 = 1.88, 95%CI, 1.37-2.60, P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 for KDM2A, P = 1.3 × 10-10; cg26662347 for KDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance. CONCLUSIONS: These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets

A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer

B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51-2.21] and the independent validation set (HR=1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR=0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71×10-3). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk

SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis

Smoking cessation prolongs survival and decreases mortality of patients with non‐small‐cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome‐wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two‐stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early‐stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology‐stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rate‐q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology‐specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 × 10-7]. Further, the effect of smoking cessation on early‐stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 × 10-3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 2.1835; 95% CI: 1.27-3.74; P = 4.46 × 10−3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting