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A 78-year-old woman with multiple lung nodules, epithelial growth factor receptor (EGFR) exon 20 insertion mutations, and diagnosed with advanced lung adenocarcinoma (cT4N3M1a, stage IVA), was referred to our hospital. She received immune checkpoint inhibitor (ICI) therapy. The therapy showed remarkable antitumor effects; only a single nodule remained in the right upper lobe. The nodule was diagnosed as adenocarcinoma through a biopsy. We subsequently performed right upper lobectomy for multiple primary lung cancer (MPLC). The surgical specimen contained EGFR exon 19 deletion mutations and not exon 20 insertion mutations.

Background/aim Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have recently been shown to have clinical benefits in patients with advanced non-small cell lung cancer (NSCLC). The novel tumour responses to these agents are changing the management of patients with cancer. Pseudo-progression of disease (pseudo-PD), that is, an initial flare followed by shrinkage of the tumour, has been described as a distinctive response to ICIs. However, pseudo-PD manifest initial progression and is difficult to segregate with hyper progressive disease (HPD). We, therefore, analysed a case with pseudo-PD histologically. Patients and methods A 68-year-old Japanese man with stage IV non-small cell lung carcinoma (NSCLC) was treated by anti-PD-1 antibody (pembrolizumab). Four weeks later after second time treatment with pembrolizumab, the patient showed severe melena followed by Trousseau syndrome and died at day 174 after first treatment by pembrolizumab, suggesting HPD clinically. Primary lesion and metastatic lesions were analysed histologically. Results Histological analysis revealed that NSCLC cells expressed PD-L1, and CD8+ tumor-infiltrated lymphocytes (TILs) were observed. CD8+ TILs showed higher rates of PD-1 indicating that lesions were of the inflamed type and the case was pseudo-PD. Furthermore, it was found that cancer cells expressed MUC1. Conclusion The clinical appearance of the case was aggressive after treatment by pembrolizumab, and the case seemed to be HPD; however, histological analysis revealed that the case was likely pseudo-PD. Therefore, careful histological evaluation is important when investigating the clinical response to an ICI and mucin expression might be a predictive marker for Trousseau syndrome.

Fishery-independent surveys using sea surface trawl nets for Pacific saury Cololabis saira in the western North Pacific since 2003 have enabled the investigation of their annual distribution patterns and total biomass during June and July, prior to the main fishing season in Japan. We compared biomass estimates and their associated variances derived based on five different post-stratification approaches in a swept area method, and then observed that these approaches have little effect on biomass estimates and their precision, owing to well-organized survey designs and homogeneously allocated sampling stations. We were able to utilize decreasing biomass estimates for 15 years as an essential abundance index in the ongoing stock assessment. Notably, examination based on stratification along with longitudinal survey lines indicated that the estimated biomass had decreased in the western survey area, resulting in an eastward shift in the gravity center of Pacific saury distribution after 2010. We recommend biomass estimation in an east–west direction based on longitudinal stratification as an effective measure to develop population dynamics models which reflect westward migration into the fishing grounds around Japanese coastal waters, and to forecast the expected catch during the subsequent fishing period.

Background Thymic large cell neuroendocrine carcinoma (LCNEC) is extremely rare. The detailed clinical features of thymic LNCECs remain unknown. Case presentation A 90-year-old man with a history of diabetes mellitus, chronic renal failure, and an abdominal aortic aneurysm underwent computed tomography for follow-up, which showed an anterior mediastinal tumor, measuring 31 mm × 28 mm in diameter. Magnetic resonance imaging showed an iso-intensity mass on T1-weighted images and high intensity on T2-weighted images. 18F-Fluorodeoxyglucose-positron emission tomography showed marked uptake in the mass, which was diagnosed as invasive thymoma or thymic carcinoma. Video-assisted thoracic surgery through the left thoracic cavity was converted to median sternotomy due to severe adhesions between the left lung and the chest wall. Partial thymectomy and combined partial resection of left upper lobectomy and the first and the second costal cartilages were performed. The pathologic diagnosis was thymic LCNEC, Masaoka stage III. The patient developed pleural dissemination and left lung metastases in 5 months and died 12 months after surgery. Conclusions Thymic LCNEC has high malignant potential. More cases need to be studied.

The human DNA molecule is a 2–m-long polymer collapsed into the micrometer space of the cell nucleus. This simple consideration rules out any “Maxwell demon”-like explanation of regulation in which a single regulatory molecule (e.g., a transcription factor) finds autonomously its way to the particular target gene whose expression must be repressed or enhanced. A gene-by-gene regulation is still more contrasting with the physical reality when in the presence of cell state transitions involving the contemporary expression change of thousands of genes. This state of affair asks for a statistical mechanics inspired approach where specificity arises from a selective unfolding of chromatin driving the rewiring of gene expression pattern. The arising of “expression waves” marking state transitions related to chromatin structural reorganization through self-organized critical control of whole-genome expression will be described in the present paper. We adopt as a model system the gene expression time course of a cancer cell (MCF-7) population exposed to an efficient stimulus causing a state transition in comparison with an ineffective stimulus. The obtained results will be put into the perspective of biological adaptive systems living on the edge of chaos.

Through our studies on whole genome regulation, we have demonstrated the existence of self-organized critical control (SOC) of whole gene expression - genomic self-organization mechanism through the emergence of a critical point (CP) at both the cell population and single cell level. In this paper, based on HRG and EGF-stimulated MCF-7 breast-cancer cell line, we shed light on the origin of critical transitions stemming from coordinated chromatin remodeling. In so doing, we validated the core of the SOC control mechanism through the application of a non-linear signal analysis technique (Recurrence Quantification Analysis: RQA), and of Principal Component Analysis (PCA). The main findings were: Transcriptional co-regulation follows a strong and invariant exponential decay as between gene spacing along the chromosome is increased. This shows that the co-regulation occurs on a mainly positional basis reflecting local chromatin organization.There are two main fluctuation modes on the top of the cell-kind specific gene expression values spanning the entire genome expression. These modes establish an autonomous genomic critical control system (genome-engine) through the activation of the CP for cell-fate guiding critical transitions revealed by SOC analysis.The elucidation of the link between spatial position on chromosome and co-regulation together with the identification of specific locations on the genome devoted to the generalization of perturbation stimuli, give a molecular basis to the self-organization dynamics of genome expression and cell-fate decision.

A correction to this paper has been published: https://doi.org/10.1007/s12562-021-01506-9

Pacific saury (Cololabis saira) is an important fisheries resource and an ecologically important fish in the Northwestern Pacific Ocean. Some evidence indicates that its distribution is affected by the environmental variability, but the relative importance of environmental effects versus those of other unmodelled spatiotemporal processes has not been investigated. For this reason, fisheries data from members of the North Pacific Fisheries Commission, were analyzed using a geostatistical modelling approach to examine interannual variation in the spatiotemporal distribution of Pacific saury in the Northwestern Pacific Ocean during the fishing season (May–December) from 2001–2017. The objectives were to investigate the extent to which this can be attributed to changes in the local (e.g., sea surface temperatures), regional environmental variables (e.g., Southern Oscillation Index), and the unmodelled spatiotemporal variables (e.g., species interaction). We found that the centroid of gravity of Pacific saury had an apparent eastward shifting after 2013, and a further shift with a lower relative abundance in 2017. We also found that neither a single local or regional environmental variable nor any combination of them could explain the distributional shift of Pacific saury. Instead, the change in spatial distribution is mostly attributed to the “unmodelled” spatiotemporal variables. We emphasize that developing a quantitative understanding of the underlying mechanisms is a critical area for future work. In the future, environmental data is expected to become increasingly available. However, we caution that before projecting the Pacific saury distribution resulting from climate change or other environmental phenomena, analysts should first determine whether the hypothesized driving variables account for a meaningful proportion of variability in the historical distribution data.

Highlights • Ovariectomy accelerates doxycycline-induced acute liver injury. • The expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1 genes were strongly upregulated in ovx mice. • Apocynin, totally improved DOXY-induced liver injury in both sham and ovx mice. • NADPH oxidase is responsible for the development of drug-induced acute liver injury, To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx) mice against doxycycline (DOXY)-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip) 8 weeks after the operation, 30 min after apocynin (5 mg/kg) or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox) inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.

The narrow-ridged finless porpoise Neophocaena asiaeorientalis is a coastal ceta - cean that is threatened by various human activities. Bycatch mortality is a particular danger to the porpoise population in Ariake Sound and Tachibana Bay, Japan. To evaluate the impact of bycatch mortality on the viability of this population, we simulated changes in population size over the next 100 yr, using a Leslie matrix model. The simulation trials were repeated for 3 scenarios of possible bycatch mortality rates. If bycatch mortality remains at the reported level, the estimated annual rate of decrease is 0.671 to 3.87%, and the estimated population size reduction over 3 gen- erations is 29.6 to 86.3%. A population size reduction of ≥30% was predicted in almost half the simulation trials, even in the most optimistic scenario. The reported bycatch mortalities would pose a serious threat to the viability of this porpoise population; therefore, the population should be classified at least as 'Vulnerable' according to Criterion A4, as defined in the IUCN Red List. Our predictions were sensitive to annual bycatch mortality rate estimates. Hence, the collection of current abundance and bycatch data should be promoted in order to minimize uncertainty in risk assessments.

Standardization of catch per unit effort is an effective way to not only extract temporal abundance trends but also understand distribution shifts of fish resources. Chub mackerel in the Northwest Pacific has recently been of great concern to fishermen and fisheries managers because the total catch has been increasing, and fishing grounds have expanded from the Japanese exclusive economic zone eastward to high-sea areas. Understanding the spatiotemporal dynamics of chub mackerel is urgently needed for evaluating the current status (i.e., abundance and distribution) and considering future exploitation. Here we constructed two recruitment indices from pelagic trawl survey data of the Pacific chub mackerel. For recruitment indices of age-0 fish, we integrated an algorithm for automatic area stratification into the delta-GLM that combines two separate generalized linear models (for encounter probability and positive catch rates) to simultaneously investigate changes in relative abundance and distribution. Recruitment indices were high in the recent years of 2013, 2016, and 2017, especially at around 160 °E longitude within the high-sea areas, suggesting simultaneous changes in abundance and distribution. Furthermore, we found that our approach had better predictive ability, especially for positive catch rates, than that of a generalized additive model by cross validation, and the obtained standardized indices mitigated potential bias in stock assessment estimates. Our integrated approach will be useful for understanding the spatiotemporal dynamics of fishes and standardizing abundance indices for stock assessment and management.

The finless porpoise Neophocaena asiaeorientalis inhabits coastal waters and rivers in East Asia and is exposed to various human activities. This species is listed on the IUCN Red List of Threatened Species due to a reduction in abundance. Although human-induced mortality can be a threat to porpoise populations, future anthropogenic impacts have not been quantitatively evaluated due to lack of demographic information. Adequate future population projections are needed to form the basis for conservation measures before the population declines to critical levels. We conducted a population viability analysis for the population of finless porpoise in the Inland Sea, Japan using a Leslie matrix model composed of age-specific survival and fertility rates. We described the uncertainty in the annual rate of increase (λ) for the finless porpoise using randomly sampled estimates of survival rate for other cetaceans with similar life histories. Plausible median estimates of λ ranged from 1.041 (age at first reproduction [AFR] = 7) to 1.056 (AFR = 5). Future population changes and extinction probabilities were predicted after combining these estimates with a predicted human-induced mortality rate (M) and available abundance estimates. The extinction probability after 100 years was 0 %. However, the probability of the quasi-extinction (

O tecido adiposo perivascular (PVAT) da aorta torácica (AT) possui ação anticontrátil (AC). O PVAT da AT e das artérias mesentéricas de resistência (AM) possuem diferentes características. Na obesidade ocorre expansão do PVAT. Nós avaliamos a modulação da contração pelo PVAT da AT e AM em camundongos controles (CT) e obesos (OB) e a participação do sistema renina-angiotensina (SRA), por meio do tratamento com antagonista do receptor AT1 (BRA). PVAT da AT e AM apresentaram ação AC. Ação AC do PVAT das AM, mas não da TA, foi abolida no grupo OB. BRA resgatou a ação AC do PVAT das AM no grupo OB, que foi abolida pelo antagonismo do receptor AT2 e pela inibição da óxido nítrico (NO) sintase (NOS). Em AM, a expressão dos receptores AT1 e AT2 não foi modificada e da NOS endotelial foi aumentada em AM e reduzida no PVAT da AM no grupo OB. BRA aumentou a expressão da eNOS no PVAT das AM nos dois grupos. Assim, concluímos que a obesidade induz disfunção do PVAT de AM e há envolvimento do SRA. BRA corrige a função do PVAT de AM por mecanismo dependente do receptor AT2 e NO. The perivascular adipose tissue (PVAT) of thoracic aorta (TA) has an anticontractile (AC) action. TA and resistance mesenteric arteries (MA) PVAT have different characteristics. Expansion of PVAT occurs in obesity. We evaluated the modulation of contraction by PVAT of TA and MA in control (CT) and obese (OB) mice and the participation of the renin-angiotensin system (RAS), by treating mice with AT1 receptor antagonist (ARB). PVAT of both TA and MA showed an AC action. The AC action of MA PVAT, but of TA PVAT, was abolished in the OB group. ARB recovered the AC action of MA PVAT in OB group, which was abolished by both AT2 receptor antagonism and nitric oxide (NO) synthase (NOS) inhibition. In MA, the expression of AT1 and AT2 receptors was not changed and the expression of eNOS was increased in MA and reduced in MA PVAT of OB group. ARB increased the expression of eNOS in MA PVAT in both CT and OB groups. In conclusion, obesity induced MA PVAT dysfunction, in which RAS is involved. ARB recovered the MA PVAT function by mechanisms that depend on the AT2 receptor and NO.

Background A fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization. Principal Findings Building upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change. Conclusion and Significance 'Whole-genome' regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non-equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression.

Background: Recent reports suggest that small airway as well as large airway involvement in asthma is important. We investigate the therapeutic effects of a meter-dose inhaler of chrolofluorocarbon-beclomethasone dipropionate (CFC-BDP) and dry-powder fluticasone (DP-FP). Methods: Lung specimens obtained at operation due for small size lung cancer in 16 asthmatic patients and 16 controls were evaluated immunohistochemically using antibodies of EG2 (eosinophil), AA1 (mast cell), CD68 (macrophage), and CD34 (pluripotent hematopoietic stem cell). We calculated the number of each cell type in 5 fields in the inner and outer areas of large airways (luminal diameter; ≥2 mm) and small airways (

OBJETIVOS: avaliar o desempenho da citogenética e das técnicas de hibridização in situ fluorescente (FISH) e reação em cadeia da polimerase (PCR) no estudo das aneuploidias cromossômicas numéricas e na determinação do sexo fetal em amostras de abortos espontâneos. MÉTODOS: duzentos e dezenove amostras de produtos de abortos espontâneos foram submetidas a estudo citogenético. Deste total, 40 amostras foram também submetidas à técnica de PCR-nested para a determinação do sexo fetal: 32 foram selecionadas devido à falha de crescimento no estudo citogenético e oito foram escolhidas ao acaso. Vinte amostras foram selecionadas para detecção de aneuploidias cromossômicas pela técnica de FISH, utilizando-se sondas para os cromossomos 13, 18, 21, X e Y: 13 casos foram submetidos a FISH devido à falha de crescimento no estudo citogenético e sete foram escolhidos ao acaso. Foi calculada a taxa de sucesso (obtenção de cariótipo) de cada técnica. Para comparação das taxas de sucesso foi utilizado o teste de chi2, sendo considerados significantes resultados com pPURPOSE: to evaluate the performance of cytogenetic analysis, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) in the study of numerical chromosomal anomalies and in fetal sex determination of spontaneous abortion material. METHODS: cytogenetic analysis was performed on 219 spontaneous abortion specimens. Forty of these cases were also submitted to fetal sex determination using nested-PCR. Thirty-two of these cases were selected due to failed cytogenetic culture and the other eight were selected randomly. Twenty samples were submitted to the FISH technique, using probes for chromosomes 13, 18, 21, X and Y. Thirteen of these samples were selected due to failed cytogenetic culture and the other seven were randomly selected. The success rates of each technique were compared using the chi2 test and an established p

The small airway disease in asthma is characterized by airway wall thickening associated with eosinophilic inflammation and hypervascularity. In our study, predicted forced expiratory volume in 1 s (% FEV 1 correlated with the vascularity in the inner layers of large airways but not for small airways. High-resolution computed tomography (CT) scans of 0.5 mm collimation during acute mild exacerbations revealed mucus plugging, air-space nodules and ground-glass opacities. Mean lung density on CT in acute exacerbations was significantly increased compared with that in remission. These results suggest that the involvement of the small airways and lung parenchyma would be increased during exacerbations. Pathologically, eosinophils were significantly reduced by treatment with chlorofluorocarbon- beclomethasone dipropionate (BDP) in the large airways, but not in the small airways. New fine-particle inhaled corticosteroids (ICS), such as hydrofluoroalkane- BDP, can reach the small airways and lung parenchyma in asthmatic patients. From the results of peak inspiratory flow (PIF) through each dry powder inhaler in Japanese people, measurement of PIF should be recommended before the use of dry powder inhaler. In the present review, we address small airway disease in asthmatic patients using pathological and radiological methods and discuss the critical problems of current ICS therapy.

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.

BACKGROUND:The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue in bioscience. We addressed it in terms of phase transition by a systemic approach based on both density analysis and characteristics of temporal fluctuation for the time-course mRNA expression in differentiating MCF-7 breast cancer cells. METHODOLOGY:In a recent work, we suggested criticality as an essential aspect of dynamic control of genome-wide gene expression. Criticality was evident by a unimodal-bimodal transition through flattened unimodal expression profile. The flatness on the transition suggests the existence of a critical transition at which up- and down-regulated expression is balanced. Mean field (averaging) behavior of mRNAs based on the temporal expression changes reveals a sandpile type of transition in the flattened profile. Furthermore, around the transition, a self-similar unimodal-bimodal transition of the whole expression occurs in the density profile of an ensemble of mRNA expression. These singular and scaling behaviors identify the transition as the expression phase transition driven by self-organized criticality (SOC). PRINCIPAL FINDINGS:Emergent properties of SOC through a mean field approach are revealed: i) SOC, as a form of genomic phase transition, consolidates distinct critical states of expression, ii) Coupling of coherent stochastic oscillations between critical states on different time-scales gives rise to SOC, and iii) Specific gene clusters (barcode genes) ranging in size from kbp to Mbp reveal similar SOC to genome-wide mRNA expression and ON-OFF synchronization to critical states. This suggests that the cooperative gene regulation of topological genome sub-units is mediated by the coherent phase transitions of megadomain-scaled conformations between compact and swollen chromatin states. CONCLUSION AND SIGNIFICANCE:In summary, our study provides not only a systemic method to demonstrate SOC in whole-genome expression, but also introduces novel, physically grounded concepts for a breakthrough in the study of biological regulation.

Understanding the basic mechanism of the spatio-temporal self-control of genome-wide gene expression engaged with the complex epigenetic molecular assembly is one of major challenges in current biological science. In this study, the genome-wide dynamical profile of gene expression was analyzed for MCF-7 breast cancer cells induced by two distinct ErbB receptor ligands: epidermal growth factor (EGF) and heregulin (HRG), which drive cell proliferation and differentiation, respectively. We focused our attention to elucidate how global genetic responses emerge and to decipher what is an underlying principle for dynamic self-control of genome-wide gene expression. The whole mRNA expression was classified into about a hundred groups according to the root mean square fluctuation (rmsf). These expression groups showed characteristic time-dependent correlations, indicating the existence of collective behaviors on the ensemble of genes with respect to mRNA expression and also to temporal changes in expression. All-or-none responses were observed for HRG and EGF (biphasic statistics) at around 10-20 min. The emergence of time-dependent collective behaviors of expression occurred through bifurcation of a coherent expression state (CES). In the ensemble of mRNA expression, the self-organized CESs reveals distinct characteristic expression domains for biphasic statistics, which exhibits notably the presence of criticality in the expression profile as a route for genomic transition. In time-dependent changes in the expression domains, the dynamics of CES reveals that the temporal development of the characteristic domains is characterized as autonomous bistable switch, which exhibits dynamic criticality (the temporal development of criticality) in the genome-wide coherent expression dynamics. It is expected that elucidation of the biophysical origin for such critical behavior sheds light on the underlying mechanism of the control of whole genome.

Background Candesartan, an AT 1 receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients. Methods and Results Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor–induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups. Conclusions Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.

The effects of isoflavones (genistein and daidzein) on endometrial carcinogenesis in mice were investigated in two experiments. In the short-term experiment (2 weeks), single subcutaneous (s.c.) administration of genistein [1 mg / 30 g body weight (b.w.)] significantly decreased the levels of estradiol-17beta (E(2)) (5 ppm in diet)-induced expression of c-jun, interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the uteri of ovariectomized mice (P < 0.005, P < 0.05 and P < 0.01, respectively). Daidzein significantly inhibited E(2)-induced expression of c-fos and IL-1alpha (P < 0.01, P < 0.01 respectively). In the long-term experiment (30 weeks), 140 female ICR mice were given N-methyl-N-nitrosourea-containing solution (1 mg / 100 g b.w.) and normal saline (as controls) into their left and right uterine corpora, respectively. They were divided into six groups; group 1 was given E(2) (in diet) alone. Group 2 was given E(2) and genistein (1 mg / 30 g b.w., s.c., every four weeks). Group 3 was exposed to E(2) and daidzein (1 mg / 30 g b.w., s.c., every four weeks). Groups 4 and 5 respectively received genistein and daidzein, and were kept on the basal diet. Group 6 was kept on the basal diet and served as a control. At the termination of the experiment, incidences of endometrial adenocarcinoma and atypical endometrial hyperplasia of the group given E(2) and genistein or daidzein were significantly lower than of the group with E(2) alone (P < 0.01 and P < 0.05, respectively). It is suggested that both genistein and daidzein have an inhibitory effect on estrogen-related endometrial carcinogenesis in mice, possibly by suppressing expression of estrogen-induced estrogen-related genes c-fos and c-jun, and internal cytokines IL-1alpha and TNF-alpha through a cytokine and estrogen receptor-mediated pathway.

婦人科癌化学療法後の血小板減少症を示した, 20症例, 31コースに関して検討した。血小板数10万以下となった症例に対して, 十全大補湯とM-CSFを併用投与した。上記加療にて, 31コース中28コースは血小板輸血を回避したが, 3例3コースは血小板輸血を施行した。また, 化療後で十全大補湯単独投与の前後では, TGF-β1は著増し, 抗腫瘍作用を高める可能性があると考えられた。したがって, 抗癌化学療法中の血小板減少症に対して, 十全大補湯とM-CSFの併用療法は有用な補助療法と考えられた。

Short- and long-term experiments were conducted to examine the effects of Glycyrrhizae radix (Gl radix) extract on mouse endometrial carcinogenesis. Gl radix treatment (2 weeks) decreased the levels of c-fos/jun mRNA and the corresponding oncoproteins induced by estradiol-17β (E 2 ) in castrated mice uteri, as determined by reverse transcription-polymerase chain reaction and Southern blot analysis, and immunohistochemical methods, respectively. For the long-term assays, 98 female ICR mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body wt.) and normal saline (as controls) into their left and right uterine corpora, respectively. They were divided into four groups as follows: group 1 was given 0.625% Gl radix- and 5 ppm E 2 -containing diet; group 2, 5 ppm E 2 -containing diet; group 3, 0.625% Gl radix-containing diet; and group 4, the basal diet alone. Gl radix treatment significantly decreased uterine weights and the incidences of uterine endometrial atypical hyperplastic and malignant lesions. It is suggested that Gl radix has inhibitory effects on E 2 -related endometrial carcinogenesis in mice, through suppression of estrogen-induced c-fos/jun-expressions.

Two experiments were conducted to determine the effect of tamoxifen (TAM) in mouse endometrium in comparison with that of 17beta-estradiol (E2). In a medium-term assay, TAM as well as E2 treatment semi-dose-dependently increased the levels of fos/jun mRNA and their oncoproteins (Fos/Jun). The long-term effect of TAM on mouse endometrial carcinogenesis was also examined in the following model. A total of 150 female ICR mice, 12-13 weeks of age, were used. Of these, 125 mice received an injection of N-methyl-N-nitosourea (MNU) solution (1 mg/100 g body weight) into their left uterine tube and saline into the right. One week later, they were divided into four groups: groups 1 (35 mice) and 2 (30 mice) were given 25 ppm and ppm E2-containing diet, respectively, while group 3 (30 mice) was fed 5 ppm TAM-containing diet. Group 5 (30 mice) was fed basal diet alone. The remaining 25 mice (group 4) received 5 ppm TAM-containing diet alone. At the termination of the experiment (30 weeks), endometrial carcinomas were confirmed to be present in the groups exposed to MNU. TAM increased the incidence of preneoplastic lesions of the endometrium, while E2 enhanced the occurrence of the carcinoma. No carcinomas were found in the group given TAM alone. In the ovaries, corpora lutea were lacking in most of the mice exposed to TAM, suggesting that the animals were not cycling. Such findings indicated that TAM has an enhancing effect on endometrial carcinogenesis in mice, probably via a mechanism involving overexpression of Fos/Jun proteins.

Three women less than 35 years old, who wanted to preserve their fertility, were conservatively treated with repeated endometrial curettage and medroxyprogesterone acetate (600mg/d) for endometrial carcinoma. Treatments were given once a month for 6 to 8 months. No patient had evidence of recurrence for at least 16 months after the treatment, and 1 patient subsequently delivered 2 full-term babies. This conservative treatment by endometrial curettage with progestogens may be considered for young patients with early endometrial lesions who wish to preserve their fertility.

An increase in the number of Ag-NORs has been described as a possible marker for histopathological cancer diagnosis. The ultrastructural correlation of the reaction, however, has never been elucidated. In tissue samples of the endocervix of the uterus, we compared the ultrastructural configuration of Ag-NORs with the number of Ag-NORs dots. Light microscopic studies showed that the number of Ag-NORs in adenocarcinoma cells significantly increased, but the relation to the bromodeoxyuridine labeling index was not determined. By electron microscopy, Ag-NORs were only observed in the nucleoli and the nuclear bodies of nuclei. Ag-NORs were localized on all components of the nucleolar structure, but the dense fibrillar component was the predominant site in several cases. The nuclear bodies were exclusively found in adenocarcinoma cells and were argyrophilic. A spotted distribution of Ag-NORs was often found in the nucleoli of adenocarcinoma cells that showed an increased Ag-NOR count. The number of Ag-NORs was attributed not only to the number of nucleoli and nuclear bodies in a nucleus but also to the speckled distribution of silver deposits in a nucleolus. These results imply that the Ag-NOR count is a more definitive indicator of a hyperactive state of the cells than the combined number of nucleoli and nuclear bodies in adenocarcinoma of the uterine cervix.

Aims We reported that interleukin-6 (IL-6) plays a protective role in the development of cisplatin-induced acute renal failure (ARF) through upregulation of anti-oxidative stress factors. In this study, we examined the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on the development of cisplatin-induced ARF in wild-type (WT) and IL-6 −/− mice to determine how IL-6 contributes to modulation of oxidative stress caused by cisplatin. Main methods WT and IL-6 −/− male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100 mg/kg) or saline was given 30 min before cisplatin or saline administration. Blood and kidney samples were collected on days 1 and 3 after cisplatin administration. Key findings In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-α, Bax and c-fos and increased the expression levels of IL-6, Bcl-x L and Nrf2 in WT mice. Reduced reactive oxygen species (ROS) by DMTU resulted in increases of IL-6, anti-apoptosis and anti-oxidant gene expression levels. In IL-6 −/− mice, DMTU also improved cisplatin-induced renal dysfunction and reduced expression levels of TNF-α, Bax and c-fos, but not Bcl-x L and Nrf2. Since Nrf2 induces IL-6 expression, IL-6 and Nrf2 may influence each other during anti-oxidant responses. The basal level of HO-1 in IL-6 −/− mice was higher than that in WT mice. Significance In IL-6 −/− mice, overproduction of ROS by cisplatin results in upregulation of HO-1 expression in order to eliminate oxidative stress. IL-6 mediates the generation and elimination of ROS during cisplatin-induced ARF.

One of the fundamental mysteries in biology is to grasp how a cell can choose a specific cellular process in coordinating complex multi-molecular interactions through DNA, RNA, proteins and metabolites. We investigated the existence of guiding principles in gene expression dynamics for three distinct processes: i) the innate immune response of macrophages to lipopolysaccharide (LPS) stimulation, ii) interleukin 12 (IL-12) and IL-4 stimulated naive CD4+ T cell differentiation into helper T1 and T2 cells, and iii) HL-60 cell differentiation into neutrophil. We found that for all processes, forming groups of genes reduces gene expression fluctuations, revealing the emergent hidden collective genome-wide (global) expression dynamics and their biological roles. This demonstrates an important role of lowly expressed genes, which have been considered insignificant and noisy, as key players for collective global dynamics. Moreover, in neutrophil differentiation, there are specific gene ensembles (collectively named “genome vehicle”) responsible for the cell fate, and the collective motion of lowly and moderately variable genes within the genome vehicle guides whole genome expression dynamics to the neutrophil cell state. Elucidation of biophysical origin for the global guiding principle might provide a breakthrough understanding of how a genome can control cellular processes such as cell fate and differentiation.

Recently, various forms of Churg-Strauss syndrome (CSS) have been reported in association with the use of leukotriene receptor antagonists. A 53-year-old woman with a 5-year history of asthma associated with chronic sinusitis presented mononeuropathy, hypereosinophilia, and positive P-ANCA in October 1999. She had been treated with pranlukast (450 mg/day) and beclomethasone dipropionate (BDP) at a dose of 1,200 microg/day which had gradually been tapered to 800 microg/day over the previous 17 months. She was found to have CSS, and 60 mg/day of prednisolone was administered instead of pranlukast, resulting in an improvement of her symptoms and eosinophilia. Later, we confirmed that serum P-ANCA had been positive before the pranlukast treatment, but CSS vasculitis had not appeared at that time. We speculated that an underlying incomplete form of CSS was being masked in this case and that the reduction of inhaled corticosteroid might have been responsible for the unmasking of CSS.