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1.  Efficacy of tyrosine kinase inhibitors in non-small-cell lung cancer patients undergoing dose reduction and those with a low body surface area 
Molecular and Clinical Oncology  2014;2(4):604-608.
The objective of this study was to evaluate the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients undergoing dose reduction and in those with a low body surface area (BSA). The association between dose reduction, low BSA and efficacy, including response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), were evaluated in patients prescribed TKIs between September, 2002 and May, 2013. A total of 282 patients received EGFR-TKIs during the study period, 53 (18.8%) of whom underwent a dose reduction (21.4 and 31.6% of the patients with a BSA of <1.5 and <1.25 m2, respectively). Eleven (20.8%) of these 53 patients had a dose reduction due to adverse events (AEs) >grade 3. In either gefitinib or erlotinib treatment, the RR, DCR, PFS and OS in EGFR-mutated patients with a BSA of <1.5 m2 were not different from those in patients with a BSA of >1.5 m2. In addition, there were no differences in these parameters between patients with and those without a dose reduction of TKIs. The dose of TKIs in patients with AEs and in those with low BSA should be determined with caution. To confirm the equal efficacy of TKIs in patients undergoing a dose reduction, prospective observational studies with less patient heterogeneity are required.
PMCID: PMC4051560  PMID: 24940504
body surface area; dose reduction; epidermal growth factor receptor-tyrosine kinase inhibitor; gefitinib; erlotinib; non-small-cell lung cancer
2.  Potential Involvement of IL-17F in Asthma 
Journal of Immunology Research  2014;2014:602846.
The expression of IL-17F is seen in the airway of asthmatics and its level is correlated with disease severity. Several studies have demonstrated that IL-17F plays a pivotal role in allergic airway inflammation and induces several asthma-related molecules such as CCL20. IL-17F-induced CCL20 may attract Th17 cells into the airway resulting in the recruitment of additional Th17 cells to enhance allergic airway inflammation. We have recently identified, for the first time, that bronchial epithelial cells are its novel cell source in response to IL-33 via ST2-ERK1/2-MSK1 signaling pathway. The receptor for IL-17F is the heterodimeric complex of IL-17RA and IL-17RC, and IL-17F activates many signaling pathways. In a case-control study of 867 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL-17F gene was associated with asthma. In atopic patients with asthma, prebronchodilator baseline FEV1/FVC values showed a significant association with the H161R variant. Moreover, this variant is a natural antagonist for the wild-type IL-17F. Moreover, IL-17F is involved in airway remodeling and steroid resistance. Hence, IL-17F may play an orchestrating role in the pathogenesis of asthma and may provide a valuable therapeutic target for development of novel strategies.
PMCID: PMC4009148  PMID: 24829928
3.  Long-term safety of budesonide/formoterol for the treatment of elderly patients with bronchial asthma 
The long-term safety of budesonide/formoterol (BUD/FM) inhalation has not been fully evaluated, particularly in elderly patients with bronchial asthma. To evaluate the 12-month safety of BUD/FM inhalation for elderly asthmatic patients, the changes in serum potassium levels and pulse rate were examined. A retrospective chart review was conducted of consecutive patients who were treated with BUD/FM inhalation (two inhalations of 160/4.5 mg, twice daily; Symbicort Turbuhaler, AstraZeneca) at a hospital between February 2010 and January 2012. A total of 350 patients were treated with BUD/FM inhalation during the study period and were followed up over 12 months. The mean age of the patients was 60 years, and 19.4% and 21.4% of the patients were aged 65–74 years and ≥75 years, respectively. One hundred and fourteen (32.6%) of the 350 patients continued the inhalation therapy for >12 months. Compared with the pretreatment data, reductions in serum potassium levels at 1, 6 and 12 months were not observed, even in the patients aged 65–74 and ≥75 years. There was also no increase in the pulse rate at 1, 6 and 12 months, even in the patients aged 65–74 and ≥75 years. The usual dosage of BUD/FM showed no adverse effects on the serum potassium levels and pulse rate in the adults, including the elderly with persistent asthma.
PMCID: PMC3965132  PMID: 24669267
bronchial asthma; budesonide/formoterol; inhalation; elderly; pulse rate; serum potassium
4.  Brain metastasis as an isolated late recurrence in small-cell lung cancer 
Molecular and Clinical Oncology  2013;2(2):305-307.
The brain is one of the most common sites of metastasis of small-cell lung cancer (SCLC). In this study, we reported 6 cases with isolated brain relapse of SCLC ≥1 year after the completion of the initial treatment for SCLC. Of the 6 patients, 2 had a solitary brain metastasis and 4 had ≥2 brain metastatic sites. The metastases were identified during a regular check-up computed tomography (CT) scan and were successfully treated. The median interval from the initial diagnosis to the development of brain metastasis was 16 months (range, 13–30 months). All patients received whole-brain irradiation and achieved a complete response. Only one patient developed disturbances of the higher cerebral function. The median interval from whole-brain irradiation to death or last follow-up was 33 months (range, 8–90 months). To the best of our knowledge, these are the first reported cases with isolated brain relapse of SCLC. Although a rare finding, clinicians should be alert on the possibility of such recurrence, particularly in patients who refused prophylactic cranial irradiation.
PMCID: PMC3919122  PMID: 24649352
isolated brain metastasis; relapse; small-cell lung cancer
5.  Th17-Associated Cytokines as a Therapeutic Target for Steroid-Insensitive Asthma 
Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL)-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th) 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.
PMCID: PMC3886588  PMID: 24454477
6.  Retroperitoneal abscess shortly after chemotherapy for lung cancer: A case report 
Molecular and Clinical Oncology  2013;2(2):302-304.
To the best of our knowledge, the formation of a retroperitoneal abscess due to acute appendicitis shortly after administration of chemotherapy for lung cancer has not been previously reported. This is the case report of a 59-year-old male who was admitted to the Mito Medical Center (Mito, Japan) and diagnosed with lung adenocarcinoma with pleuritis carcinomatosis. Although no distant metastasis was identified, combination chemotherapy with cisplatin and pemetrexed was administered. Nine days after initiating chemotherapy, the patient developed right lower quadrant abdominal pain and high fever. Computed tomography (CT) of the abdomen and pelvis revealed the collection of gas and fluid in the retroperitoneum adjacent to the cecum. The abscess was locally drained; however, the infection continued to spread, with subsequent development of a scrotal abscess. Consequently, appendectomy was performed. The patient recovered well and the lung adenocarcinoma was treated with additional courses of chemotherapy following the remission of the local inflammation. Retroperitoneal abscess due to acute appendicitis is an unusual finding; however, this rare complication should be considered during or shortly after chemotherapy in patients with lung cancer.
PMCID: PMC3917762  PMID: 24649351
retroperitoneal abscess; chemotherapy; lung cancer
7.  Genome-Wide Association Study for Levels of Total Serum IgE Identifies HLA-C in a Japanese Population 
PLoS ONE  2013;8(12):e80941.
Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10−10). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.
PMCID: PMC3851760  PMID: 24324648
8.  Expression and Function of Allergin-1 on Human Primary Mast Cells 
PLoS ONE  2013;8(10):e76160.
Mast cells (MC) play an important role in allergic and non-allergic immune responses. Activation of human MC is modulated by several cell surface inhibitory receptors, including recently identified Allergin-1 expressed on both human and mouse MC. Although Allergin-1 suppresses IgE-mediated, mast cell–dependent anaphylaxis in mice, the expression profile and function of Allergin-1 on human primary MC remains undetermined. Here, we established a seven-color flow cytometry method for assessing expression and function of a very small number of human primary MC. We show that Allergin-1S1, a splicing isoform of Allergin-1, is predominantly expressed on human primary MC in both bronchoalveolar lavage (BAL) fluid and nasal scratching specimens. Moreover, Allergin-1S1 inhibits IgE-mediated activation from human primary MC in BAL fluid. These results indicate that Allergin-1 on human primary MC exhibits similar characteristics as mouse Allergin-1 in the expression profile and function.
PMCID: PMC3792105  PMID: 24116093
9.  Volume doubling time of lung cancers detected in a chest radiograph mass screening program: Comparison with CT screening 
Oncology Letters  2012;4(3):513-516.
The aim of this study was to evaluate the volume doubling time (VDT) of lung cancer detected in our annual chest radiograph screening program and to compare it with those previously reported for computed tomography (CT) screening. In total, 209 patients who had a measurable tumor shadow and a history of participating in our chest radiograph mass screening program between 2006 and 2009 were included in this study. Indirect roentgenograms for patients with lung cancer were converted into digital images, and the section showing the tumor was enlarged on the monitor to a size of 0.01 mm. The mean VDT for all the patients was 158 days. Only 3.8% of the patients had a VDT of more than 400 days. In 140 patients with adenocarcinoma, the mean VDT was 177 days, and 5.0% of these patients had a VDT of more than 400 days. In the 44 patients with squamous cell carcinoma, the mean VDT was 133 days, and only 2.3% of these patients had a VDT of more than 400 days. These results were different from those previously reported for CT screening. In several reports on CT screening, more than 20% of the lung cancers had VDTs of more than 400 days. Since it is common knowledge that there are ‘indolent’ lung cancers with a VDT of more than 400 days, screening by annual chest radiography with rare overdiagnosis may need to be reconsidered.
PMCID: PMC3439160  PMID: 22970048
volume doubling time; lung cancer; chest radiograph; mass screening program
10.  Isolated solitary brain metastasis as a relapse of small cell lung cancer 
Oncology Letters  2013;6(4):1108-1110.
The brain is one of the most common sites for the metastasis of small cell lung cancer (SCLC). The present study describes two cases of an isolated solitary brain metastasis as a relapse of SCLC, which occurred more than one year after the completion of the initial successful treatment for SCLC. The tumors were identified during a regular check-up computed tomography (CT) scan and were successfully treated. To the best of our knowledge, this is the first study to report the cases of two patients with an isolated solitary brain metastasis as a relapse of SCLC. Although extremely rare, the possibility of such recurrences should be considered, particularly in patients who have refused prophylactic cranial irradiation.
PMCID: PMC3796411  PMID: 24137472
isolated solitary brain metastasis; relapse; small cell lung cancer
11.  Erlotinib for elderly patients with non-small-cell lung cancer: Subset analysis from a population-based observational study by the Ibaraki Thoracic Integrative (POSITIVE) Research Group 
Molecular and Clinical Oncology  2013;1(5):828-832.
The incidence and mortality of lung cancer have increased worldwide over the last decades, with an observed increased incidence particularly among elderly populations. It has not yet been determined whether erlotinib therapy exhibits the same efficacy and safety in elderly and younger patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective subgroup analysis of data from a population-based observational study was to assess the efficacy and safety of erlotinib in an elderly (≥75 years, n=74) and a younger group of patients (<75 years, n=233) who received treatment for NSCLC. The time to treatment failure was similar in the elderly [median, 62 days; 95% confidence interval (95% CI): 44–80 days] compared with the younger group (median, 46 days; 95% CI: 35–53 days) (P=0.2475). The overall survival did not differ between the elderly and younger groups (median, 170 days; 95% CI: 142–239 days vs. median, 146 days; 95% CI: 114–185 days, respectively) (P=0.7642). The adverse events did not differ in incidence between the groups and were manageable, regardless of age. Among the NSCLC patients receiving erlotinib treatment, the outcomes of the elderly (≥75 years) and younger (<75 years) groups of patients were similar in our population-based observational study.
PMCID: PMC3915644  PMID: 24649255
erlotinib; elderly; non-small-cell lung cancer; observational study; population-based
12.  The search for common pathways underlying asthma and COPD 
Recently, several genes and genetic loci associated with both asthma and chronic obstructive pulmonary disease (COPD) have been described as common susceptibility factors for the two diseases. In complex diseases such as asthma and COPD, a large number of molecular and cellular components may interact through complex networks involving gene–gene and gene–environment interactions. We sought to understand the functional and regulatory pathways that play central roles in the pathobiology of asthma and COPD and to understand the overlap between these pathways. We searched the PubMed database up to September 2012 to identify genes found to be associated with asthma, COPD, tuberculosis, or essential hypertension in at least two independent reports of candidate-gene associations or in genome-wide studies. To learn how the identified genes interact with each other and other cellular proteins, we conducted pathway-based analysis using Ingenuity Pathway Analysis software. We identified 108 genes and 58 genes that were significantly associated with asthma and COPD in at least two independent studies, respectively. These susceptibility genes were grouped into networks based on functional annotation: 12 (for asthma) and eleven (for COPD) networks were identified. Analysis of the networks for overlap between the two diseases revealed that the networks form a single complex network with 229 overlapping molecules. These overlapping molecules are significantly involved in canonical pathways including the “aryl hydrocarbon receptor signaling,” “role of cytokines in mediating communication between immune cells,” “glucocorticoid receptor signaling,” and “IL-12 signaling and production in macrophages” pathways. The Jaccard similarity index for the comparison between asthma and COPD was 0.81 for the network-level comparison, and the odds ratio was 3.62 (P < 0.0001) for the asthma/COPD pair in comparison with the tuberculosis/ essential hypertension pair. In conclusion, although the identification of asthma and COPD networks is still far from complete, these networks may be used as frameworks for integrating other genome-scale information including expression profiling and phenotypic analysis. Network overlap between asthma and COPD may indicate significant overlap between the pathobiology of these two diseases, which are thought to be genetically related.
PMCID: PMC3558318  PMID: 23378757
COPD; asthma; network; common pathways; aryl hydrocarbon receptor signaling
13.  Use of tiotropium in patients with COPD aged 80 years and older 
The purpose of this study was to examine clinical features and treatment modality approaches in patients with chronic obstructive pulmonary disease (COPD), particularly in those aged 80 years and older. Using databases available at Mito Kyodo General Hospital (Japan), the medical records of COPD patients between April 2009 and December 2011 were retrospectively reviewed. The patient population was divided into three age groups; less than 70 years (the <70 age group), between 70–79 years (the 70–79 age group) and 80 years or older (the ≥80 age group). Demographic data, as well as the efficacy and safety of tiotropium, were compared between the three groups. Patients in the ≥80 age group comprised 35.6% of the study population with COPD (n=174). The ≥80 and 70–79 age groups demonstrated a higher proportion of comorbid disease compared with the <70 age group. A subjective improvement of dyspnea on effort as well as no additional adverse effects were observed in the ≥80 age group, similar to the other two age groups. However, higher incidence of acute exacerbation of COPD in patients aged ≥80 years old was found, particularly in those with comorbid disease. The efficacy and safety of tiotropium in COPD patients in the ≥80 age group were almost identical to patients <80 years old, however, physicians must be cautious with acute exacerbation of COPD in the extremely elderly population with comorbid disease.
PMCID: PMC3627447  PMID: 23596463
chronic obstructive pulmonary disease; tiotropium; elderly; octogenarian; comorbid disease
14.  Observational study on the efficacy and safety of erlotinib in patients with non-small cell lung cancer 
Oncology Letters  2012;5(2):435-439.
To evaluate the efficacy and safety of erlotinib for non-small cell lung cancer (NSCLC), we performed a population-based observational study. The study involved 307 patients treated with erlotinib at 14 sites (17 departments) in Ibaraki (Japan) between December 2007 and December 2010. The tumor response and disease control rates were 11.1 and 46.3% in all patients, respectively. The median time to treatment failure and survival time were 1.6 months (95% confidence interval, 41–57 days) and 5.3 months (134–181 days) in all patients, respectively. Survival was significantly prolonged in EGFR mutation-positive patients compared with negative patients. EGFR mutation-negative patients who presented with a skin rash had significantly prolonged survival compared with those without a skin rash. The most common adverse event was skin disorder, followed by diarrhea. Although 45.6% of the patients in this study received erlotinib as a fourth-line or subsequent treatment, the results from this study were similar to those of clinical studies. We deduce that erlotinib is effective against NSCLC and is tolerated in clinical practice.
PMCID: PMC3572994  PMID: 23420613
erlotinib; non-small cell lung cancer; observational study; population-based
15.  Specific organ metastases and survival in small cell lung cancer 
Oncology Letters  2012;4(4):617-620.
The aim of our retrospective study was to evaluate the clinicopathological features associated with distant metastasis from small cell lung cancer (SCLC). We reviewed patients diagnosed with SCLC metastasis at the time of presentation between 1999 and 2010. Among the consecutive 251 SCLC patients diagnosed, 152 (60.6%) patients had distant metastasis, of which 20.3, 18.3, 15.5, 10.0 and 6.0% of patients had liver, bone, brain, lung and adrenal gland metastasis, respectively. In a multivariate analysis using Cox’s proportional hazards model, we identified that liver, bone and brain metastasis as well as the presence of pleural and/or pericardial fluids were unfavorable prognostic factors. However, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factors. With regard to the treatment of SCLC patients, particularly those with liver, bone and brain metastasis or pleural and/or pericardial fluids, we should take the metastasizing organs into consideration.
PMCID: PMC3506697  PMID: 23205072
small cell lung cancer; metastasis; survival
16.  Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma 
Thymic stromal lymphopoietin (TSLP) triggers dendritic cell–mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)–1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter–reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β2-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14–1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.
PMCID: PMC3159073  PMID: 20656951
asthma; TSLP; bronchial epithelial cells; combination therapy; genetic polymorphisms
17.  Age-dependent decline in renal function in patients with lung cancer 
Oncology Letters  2012;4(1):38-42.
The aim of this study was to clarify the effect of aging on renal function. Serum creatinine (SCr), blood urea nitrogen (BUN) and 24-h creatinine clearance (measured-CrCl) were examined in lung cancer patients and the measured-CrCl were compared with CrCl estimates by employing two commonly used equations. In total, 787 lung cancer patients who were diagnosed between 2001 and 2010 were retrospectively analyzed. SCr and urine creatinine, BUN and measured-CrCl were evaluated prior to treatment. The Cockcroft-Gault (CG) and modification of diet in renal disease (MDRD) formulae were also used to estimate CrCl. SCr, BUN and measured-CrCl showed a significant decline in the elderly. In the 787 lung cancer patients, a significant correlation coefficient was found between measured-CrCl and age. However, in patients aged 80 years or older, no significant correlation coefficient was found between measured-CrCl and age. In the comparison between the measured CrCl and the CrCls estimated by the two formulae, the CG-CrCl levels were lower than those of the measured-CrCl, whereas the MDRD-CrCl levels were higher. Age is a crucial factor influencing renal function in patients with lung cancer. Particularly in the elderly, a decline in CrCl and greater individual variability in CrCl, as well as discrepancies in measured-CrCl and estimated CrCls are significant factors.
PMCID: PMC3398364  PMID: 22807956
renal function; creatinine clearance; lung cancer; elderly
18.  Serum levels of cystatin C in elderly lung cancer patients 
Oncology Letters  2011;3(2):303-306.
The purpose of this study was to confirm the correlation between serum levels of cystatin C (Cys-C) and those of creatinine (Cre), the most widely used index of renal function in clinical practice, and to evaluate serum levels of Cys-C, with a particular focus on the effects of aging, body mass index (BMI), C-reactive protein (CRP) and disease extent in patients with lung cancer. Serum Cys-C levels in a total of 39 patients (median 72 years), who were diagnosed as having lung cancer were analyzed retrospectively. The serum Cys-C was determined using colloidal gold particles coated with anti-Cys C antibodies. A significant correlation coefficient was found between serum levels of Cys-C and those of Cre (P=0.001), but only moderate agreement. Serum Cys-C levels increased in an age-dependent manner with significant differences among 3 age groups: patients younger than 65 years, those aged 65 to 74 years and those aged 75 years or older (P=0.001). However, no correlation was observed between Cys-C and BMI, Cys-C and CRP, or Cys-C and disease extent of lung cancer. Estimation of renal function is important since renal insufficiency is directly correlated to increased chemotherapeutic complications in oncological practice. Thus, estimation of serum Cys-C levels may be important, but adjustment of Cys-C for age should be taken into consideration.
PMCID: PMC3362379  PMID: 22740900
cystatin C; elderly; lung cancer
19.  Variants of C-C Motif Chemokine 22 (CCL22) Are Associated with Susceptibility to Atopic Dermatitis: Case-Control Studies 
PLoS ONE  2011;6(11):e26987.
Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1st population, 916 cases and 1,032 controls; 2nd population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10−6; OR, 0.74; 95% CI, 0.65–0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.
PMCID: PMC3219642  PMID: 22125604
20.  Safety creatinine clearance level for platinum chemotherapy in lung cancer patients 
Oncology Letters  2011;3(2):311-314.
The present study was carried out to evaluate whether measured-creatinine clearance (measured-CrCl) and Cockcroft and Gault-CrCl (CG-CrCl) are capable of appropriately detecting a decline in renal function in lung cancer patients, including elderly patients, and to clarify a CrCl level with which to discriminate between patients with or without renal impairment. The measured-CrCl prior and subsequent to platinum-based chemotherapy of lung cancer patients was retrospectively analyzed. Measured-CrCl and CG-CrCl were evaluated prior and subsequent to platinum-based chemotherapy for lung cancer. Measured-CrCl and CG-CrCl in 59 lung cancer patients including 25 patients aged ≥65 years were retrospectively analyzed. In patients treated with carboplatin-based chemotherapy, measured-CrCl was indicative of a decline in renal function, whereas CG-CrCl was not. The optimal measured-CrCl level was <60 ml/min post-pretreatment and >90 ml/min at pre-treatment. In cases with pre-treatment measured-CrCl levels of >90 ml/min, favorable renal function is necessary in order to carry out platinum-based chemotherapy in lung cancer patients, including the elderly.
PMCID: PMC3362439  PMID: 22740902
renal function; creatinine clearance; lung cancer; elderly
21.  Role of Nrf2 in Host Defense against Influenza Virus in Cigarette Smoke-Exposed Mice ▿  
Journal of Virology  2011;85(10):4679-4690.
Influenza virus is a common respiratory tract viral infection. Although influenza can be fatal in patients with chronic pulmonary diseases such as chronic obstructive pulmonary disease, its pathogenesis is not fully understood. The Nrf2-mediated antioxidant system is essential to protect the lungs from oxidative injury and inflammation. In the present study, we investigated the role of Nrf2 in protection against influenza virus-induced pulmonary inflammation after cigarette smoke exposure with both in vitro and in vivo approaches. For in vitro analyses, peritoneal macrophages isolated from wild-type and Nrf2-deficient mice were treated with poly(I:C) and/or cigarette smoke extract. For in vivo analysis, these mice were infected with influenza A virus with or without exposure to cigarette smoke. In Nrf2-deficient macrophages, NF-κB activation and the induction of its target inflammatory genes were enhanced after costimulation with cigarette smoke extract and poly(I:C) compared with wild-type macrophages. The induction of antioxidant genes was observed for the lungs of wild-type mice but not those of Nrf2-deficient mice after cigarette smoke exposure. Cigarette smoke-exposed Nrf2-deficient mice showed higher rates of mortality than did wild-type mice after influenza virus infection, with enhanced peribronchial inflammation, lung permeability damage, and mucus hypersecretion. Lung oxidant levels and NF-κB-mediated inflammatory gene expression in the lungs were also enhanced in Nrf2-deficient mice. Our data indicate that the antioxidant pathway controlled by Nrf2 is pivotal for protection against the development of influenza virus-induced pulmonary inflammation and injury under oxidative conditions.
PMCID: PMC3126158  PMID: 21367886
22.  IL-17F Induces CCL20 in Bronchial Epithelial Cells 
Journal of Allergy  2011;2011:587204.
IL-17F plays a crucial role in airway inflammatory diseases including asthma, but its function has not been fully elucidated. CCL20 is also involved in allergic airway inflammation, while its regulatory mechanisms remain to be defined. To further identify a novel role of IL-17F, the expression of CCL20 by IL-17F in bronchial epithelial cells and the signaling mechanisms involved were investigated. Bronchial epithelial cells were stimulated with IL-17F, and the levels of CCL20 gene and protein measured, with the effects of the addition of various kinase inhibitors and siRNAs also investigated. IL-17F significantly induced the expression of CCL20 gene and protein. Pretreatment with inhibitors for MEK1/2, Raf1 and MSK1, and overexpression of a Raf1 dominant-negative mutant significantly diminished IL-17F-induced CCL20 production. Moreover, transfection of the siRNAs targeting MSK1, p90RSK, and CREB blocked CCL20 expression. These findings suggest that IL-17F is able to induce CCL20 via Raf1-MEK1/2-ERK1/2-MSK1/p90RSK-CREB signaling pathway in bronchial epithelial cells. The IL-17F/CCL20 axis may be a novel pharmacological target for asthma.
PMCID: PMC3195431  PMID: 22013453
23.  Genome-Wide Association Study Identifies HLA-DP as a Susceptibility Gene for Pediatric Asthma in Asian Populations 
PLoS Genetics  2011;7(7):e1002170.
Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1×10−8) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (Pcombined = 2.3×10−10, odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10−10, OR = 1.52, and DPB1*0901: P = 2.0×10−7, OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.
Author Summary
Asthma is the most common chronic disorder in children, and asthma exacerbation is an important cause of childhood morbidity and hospitalization. Here, taking advantage of recent technological advances in human genetics, we performed a genome-wide association study and follow-up validation studies to identify genetic variants for asthma. By examining 6,428 Asians, we found rs987870 and HLA-DPA1*0201/DPB1*0901 were associated with pediatric asthma. The association signal was stretched in the region of HLA-DPB2, collagen, type XI, alpha 2 (COL11A2), and Retinoid X receptor beta (RXRB), but strong linkage disequilibrium in this region made it difficult to specifically identify causative variants. Interestingly, the SNP (or the HLA-DP allele) associated with pediatric asthma (Th-2 type immune diseases) in the present study confers protection against Th-1 type immune diseases, such as type 1 diabetes and rheumatoid arthritis. Therefore, the association results obtained in the present study could partially explain the inverse relationship between asthma and Th-1 type immune diseases and may lead to better understanding of Th-1/Th-2 immune diseases.
PMCID: PMC3140987  PMID: 21814517
24.  An interaction between Nrf2 polymorphisms and smoking status affects annual decline in FEV1: a longitudinal retrospective cohort study 
BMC Medical Genetics  2011;12:97.
An Nrf2-dependent response is a central protective mechanism against oxidative stress. We propose that particular genetic variants of the Nrf2 gene may be associated with a rapid forced expiratory volume in one second (FEV1) decline induced by cigarette smoking.
We conducted a retrospective cohort study of 915 Japanese from a general population. Values of annual decline in FEV1 were computed for each individual using a linear mixed-effect model. Multiple clinical characteristics were assessed to identify associations with annual FEV1 decline. Tag single-nucleotide polymorphisms (SNPs) in the Nrf2 gene (rs2001350, rs6726395, rs1962142, rs2364722) and one functional SNP (rs6721961) in the Nrf2 promoter region were genotyped to assess interactions between the Nrf2 polymorphisms and smoking status on annual FEV1 decline.
Annual FEV1 decline was associated with smoking behavior and inversely correlated with FEV1/FVC and FEV1 % predicted. The mean annual FEV1 declines in individuals with rs6726395 G/G, G/A, or A/A were 26.2, 22.3, and 20.8 mL/year, respectively, and differences in these means were statistically significant (pcorr = 0.016). We also found a significant interaction between rs6726395 genotype and smoking status on the FEV1 decline (p for interaction = 0.011). The haplotype rs2001350T/rs6726395A/rs1962142A/rs2364722A/rs6721961T was associated with lower annual decline in FEV1 (p = 0.004).
This study indicated that an Nrf2-dependent response to exogenous stimuli may affect annual FEV1 decline in the general population. It appears that the genetic influence of Nrf2 is modified by smoking status, suggesting the presence of a gene-environment interaction in accelerated decline in FEV1.
PMCID: PMC3160350  PMID: 21774808
25.  Inhaled Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis 
Rationale: Inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.
Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a PaO2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar–arterial oxygen difference [A–aDO2] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 μg Days 1–8, none Days 9–14; × six cycles; 12 wk); low-dose therapy (125 μg Days 1–4, none Days 5–14; × six cycles; 12 wk), and follow-up (52 wk).
Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A–aDO2 of 12.3 mm Hg (95% confidence interval, 8.4–16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A–aDO2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.
Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.
Clinical trial registered with (ISRCTN18931678), (JMA-IIA00013).
PMCID: PMC2894410  PMID: 20167854

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