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1.  Changes in plasma levels of B-type natriuretic peptide with acute exacerbations of chronic obstructive pulmonary disease 
Elevated plasma B-type natriuretic peptide (BNP) levels and their association with heart failure have been reported in subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).
To examine and compare plasma BNP levels and diastolic and systolic dysfunction in subjects with AECOPD and stable chronic obstructive pulmonary disease (COPD).
In all, 87 unselected consecutive hospitalizations due to AECOPD in 61 subjects and a total of 190 consecutive subjects with stable COPD were recruited. Plasma BNP levels were compared cross-sectionally and longitudinally. Transthoracic echocardiographic examinations were also performed in the hospitalized subjects.
In the hospitalized subjects, the median plasma BNP level (interquartile range) was 55.4 (26.9–129.3) pg/mL and was higher than that of patients with stable COPD: 18.3 (10.0–45.3) for Global Initiative for Chronic Obstructive Lung Disease grade I; 25.8 (11.0–53.7) for grade II; 22.1 (9.1–52.6) for grade III; and 17.2 (9.6–22.9) pg/mL for grade I V, all P<0.001. In 15 subjects studied prospectively, the median plasma BNP level was 19.4 (9.8–32.2) pg/mL before AECOPD, 72.7 (27.7–146.3) pg/mL during AECOPD, and 14.6 (12.9–39.0) pg/mL after AECOPD (P<0.0033 and P<0.0013, respectively). Median plasma BNP levels during AECOPD were significantly higher in ten unsuccessfully discharged subjects 260.5 (59.4–555.0) than in 48 successfully discharged subjects 48.5 (24.2–104.0) pg/mL (P=0.0066). Only 5.6% of AECOPD subjects were associated with systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <50%; a further 7.4% were considered to have impaired relaxation defined as an E/A wave velocity ratio <0.8 and a deceleration time of E >240 ms. BNP levels were weakly correlated with the E/peak early diastolic velocity of the mitral annulus (Ea) ratio (Spearman’s rank correlation coefficient =0.353, P=0.018), but they were not correlated with the LVEF (Spearman’s rank correlation coefficient =−0.221, P=0.108).
A modest elevation of plasma BNP is observed during AECOPD. It appears that AECOPD may have an impact on plasma BNP levels that is not attributable to heart failure.
PMCID: PMC3921082  PMID: 24523584
chronic obstructive pulmonary disease; acute exacerbations of chronic obstructive pulmonary disease; B-type natriuretic peptide; heart failure
2.  Limitations of Airway Dimension Measurement on Images Obtained Using Multi-Detector Row Computed Tomography 
PLoS ONE  2013;8(10):e76381.
(a) To assess the effects of computed tomography (CT) scanners, scanning conditions, airway size, and phantom composition on airway dimension measurement and (b) to investigate the limitations of accurate quantitative assessment of small airways using CT images.
An airway phantom, which was constructed using various types of material and with various tube sizes, was scanned using four CT scanner types under different conditions to calculate airway dimensions, luminal area (Ai), and the wall area percentage (WA%). To investigate the limitations of accurate airway dimension measurement, we then developed a second airway phantom with a thinner tube wall, and compared the clinical CT images of healthy subjects with the phantom images scanned using the same CT scanner. The study using clinical CT images was approved by the local ethics committee, and written informed consent was obtained from all subjects. Data were statistically analyzed using one-way ANOVA.
Errors noted in airway dimension measurement were greater in the tube of small inner radius made of material with a high CT density and on images reconstructed by body algorithm (p<0.001), and there was some variation in error among CT scanners under different fields of view. Airway wall thickness had the maximum effect on the accuracy of measurements with all CT scanners under all scanning conditions, and the magnitude of errors for WA% and Ai varied depending on wall thickness when airways of <1.0-mm wall thickness were measured.
The parameters of airway dimensions measured were affected by airway size, reconstruction algorithm, composition of the airway phantom, and CT scanner types. In dimension measurement of small airways with wall thickness of <1.0 mm, the accuracy of measurement according to quantitative CT parameters can decrease as the walls become thinner.
PMCID: PMC3792973  PMID: 24116105
3.  Hyperglycemia is a significant prognostic factor of hepatocellular carcinoma after curative therapy 
AIM: To evaluate whether metabolic factors are related to distant recurrence of hepatocellular carcinoma (HCC) and survival after curative treatment.
METHODS: This retrospective study included 344 patients whose HCC was treated curatively by radiofrequency ablation (RFA) therapy. The mean age was 67.6 years and the mean observation period was 4.04 years. The etiological background of liver disease was hepatitis B virus infection in 30, hepatitis C virus infection in 278, excessive alcohol drinking in 9, and other in 27 patients. The Child-Pugh classification grade was A (n = 307) or B (n = 37). The number of HCC nodules was one in 260, two in 61, and three in 23 patients. For surveillance of HCC recurrence after curative therapy with RFA, patients were radiologically evaluated every 3 mo. Factors associated with distant recurrence of HCC or survival were studied.
RESULTS: Inadequate maintenance of blood glucose in diabetic patients was associated with higher incidence of distant recurrence. The 1-, 2-, and 3-year recurrence rates were significantly higher in diabetic patients with inadequate maintenance of blood glucose compared with the others: 50.6% vs 26.8%, 83.5% vs 54.4%, and 93.8% vs 73.0%, respectively (P = 0.0001). Inadequate maintenance of blood glucose was an independent predictor of distant recurrence [adjusted relative risk 1.97 (95%CI, 1.33-2.91), (P = 0.0007)] after adjustment for other risk factors, such as number of HCC nodules [2.03 (95%CI, 1.51-2.73), P < 0.0001] and initial level of serum alpha fetoprotein (AFP) [1.43 (95%CI, 1.04-1.97), P = 0.028]. Obesity was not an independent predictor of recurrence. The incidence of distant recurrence did not differ between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients. Among 232 patients who had HCC recurrence, 138 had a second recurrence. The 1-, 2-, and 3-year rates of second recurrence were significantly higher in diabetic patients with inadequate maintenance of blood glucose than in the others: 9.0% vs 5.9%, 53.1% vs 24.3%, and 69.6% vs 42.3%, respectively (P = 0.0021). Inadequate maintenance of blood glucose in diabetic patients [1.99 (95%CI, 1.23-3.22), P = 0.0049] and presence of multiple HCC nodules [1.53 (95%CI, 1.06-2.22), P = 0.024] were again significantly associated with second HCC recurrence. Inadequate maintenance of blood glucose in diabetic patients was also a significant predictor of poor survival [2.77 (95%CI, 1.38-5.57), P = 0.0046] independent of excessive alcohol drinking [6.34 (95%CI, 1.35-29.7), P = 0.019], initial level of serum AFP [3.40 (95%CI, 1.88-6.18), P < 0.0001] and Child-Pugh classification grade B [2.24 (95%CI, 1.12-4.46), P = 0.022]. Comparing diabetic patients with inadequate maintenance of blood glucose vs the others, the 1-, 2-, and 3-year survival rates were significantly lower in diabetic patients with inadequate maintenance of blood glucose: 92% vs 99%, 85% vs 96%, and 70% vs 92%, respectively (P = 0.0003).
CONCLUSION: Inadequate maintenance of blood glucose in diabetic patients is a significant risk factor for recurrence of HCC and for poor survival after curative RFA therapy.
PMCID: PMC3547569  PMID: 23345948
Hyperglycemia; Hepatocellular carcinoma; Recurrence; Radio frequency ablation; Survival
4.  Generation of Naive-Like Porcine-Induced Pluripotent Stem Cells Capable of Contributing to Embryonic and Fetal Development 
Stem Cells and Development  2012;22(3):473-482.
In pluripotent stem cells (PSCs), there are 2 types: naive and primed. Only the naive type has the capacity for producing chimeric offspring. Mouse PSCs are naive, but human PSCs are in the primed state. Previously reported porcine PSCs appear in the primed state. In this study, putative naive porcine-induced pluripotent stem cells (iPSCs) were generated. Porcine embryonic fibroblasts were transduced with retroviral vectors expressing Yamanaka's 4 genes. Emergent colonies were propagated in the presence of porcine leukemia inhibitory factor (pLIF) and forskolin. The cells expressed pluripotency markers and formed embryoid bodies, which gave rise to cell types from all 3 embryonic germ layers. The naive state of the cells was demonstrated by pLIF dependency, 2 active X chromosomes (when female), absent MHC class I expression, and characteristic gene expression profiles. The porcine iPSCs contributed to the in vitro embryonic development (11/24, 45.8%) as assessed by fluorescent markers. They also contributed to the in utero fetal development (11/71, 15.5% at day 23; 1/13, 7.7% at day 65). This is the first demonstration of macroscopic fluorescent chimeras derived from naive-like porcine PSCs, although adult chimeras remain to be produced.
PMCID: PMC3549629  PMID: 22889279
5.  Magnified Endoscopy Combined with Narrow Band Imaging of Minimal Superficial Esophageal Neoplasia—Indicators to Differentiate Intraepithelial Neoplasias 
Clinical application of narrow band imaging facilitates diagnosis of esophageal neoplasia. However, no previous investigation has been conducted on magnifying endoscopy combined with narrow band imaging in detection of minimal superficial esophageal neoplasia, which is defined as neoplasia <10 mm in diameter. The aim of this retrospective study was to evaluate the usefulness of this combined technique in the differential diagnosis of minimal superficial esophageal neoplasia.
Between January 2005 and November 2011, 53 minimal superficial esophageal neoplasias in 40 patients were diagnosed by screening upper gastrointestinal endoscopy with narrow band imaging at our hospital. We investigated findings including brownish dots, brownish epithelium, and demarcation line of minimal superficial esophageal neoplasia diagnosed histopathologically as low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and squamous cell carcinoma.
Significantly more brownish dots (P < 0.05) and brownish epithelium (P < 0.005) were observed in intraepithelial papillary capillary loops in high-grade neoplasia compared with low-grade neoplasia. When minimal superficial esophageal neoplasia was diagnosed as high-grade intraepithelial neoplasia or squamous cell carcinoma, sensitivity, specificity, positive predictive value, and negative predictive value were 88.9, 42.9, 44.4, and 88.2 %, respectively, for brownish dots; 94.4, 51.4, 50.0, and 94.7 %, respectively, for brownish epithelium; and 66.7, 62.9, 48.0, and 78.6 %, respectively, for demarcation line.
The combined technique was useful in the differential diagnosis of minimal superficial esophageal neoplasia.
PMCID: PMC3523113  PMID: 22618519
Endoscopy; Esophageal neoplasms; Carcinoma; Squamous cell carcinoma; Narrow band imaging; Magnifying endoscopy
6.  Prognostic factors for colectomy in refractory ulcerative colitis treated with calcineurin inhibitors 
Calcineurin inhibitors (CNIs) such as cyclosporin A (CSA) and tacrolimus (FK506) are efficacious in patients with steroid-refractory or steroid-dependent ulcerative colitis (UC). We retrospectively investigated patients with refractory UC treated with CNIs to elucidate the prognostic factors for a colectomy. Data from 59 patients (35 men and 24 women) were analyzed. CSA and FK506 were administered by intravenous infusion and peroral administration, respectively. The efficacy of the CNIs was assessed using Seo’s complex integrated disease activity index. Categorical data analyses were also conducted. The results revealed that the response rates for CSA and FK506 were similar (CSA, 66.6%; FK506, 63.6%). However, oral FK506 had a slower onset of action than intravenous CSA. The risk factors for CNI non-responsiveness were: i) more than 10,000 mg of prednisolone used prior to CNI treatment; and ii) positivity for cytomegalovirus antigenemia (C7-HRP). The factors affecting the rate of colectomy were: i) CNI non-responsiveness; ii) more than 10,000 mg of prednisolone used prior to the initiation of CNI treatment; and iii) positivity for C7-HRP. The addition of azathioprine (AZA) following CNI treatment significantly reduced the incidence of colectomy. Our results revealed the prognostic factors affecting the efficacy of CNI therapy and the need for colectomy in patients with refractory UC. Importantly, some of these factors may be obtained prior to or shortly following the start of CNI treatment. Furthermore, AZA is an important agent for averting colectomy once a patient responds to CNIs.
PMCID: PMC3460266  PMID: 23060930
ulcerative colitis; calcineurin inhibitor; cyclosporin A; tacrolimus; colectomy
7.  Airflow limitation or static hyperinflation: which is more closely related to dyspnea with activities of daily living in patients with COPD? 
Respiratory Research  2011;12(1):135.
Dyspnea while performing the activities of daily living has been suggested to be a better measurement than peak dyspnea during exercise. Furthermore, the inspiratory capacity (IC) has been shown to be more closely related to exercise tolerance and dyspnea than the FEV1, because dynamic hyperinflation is the main cause of shortness of breath in patients with COPD. However, breathlessness during exercise is measured in most studies to evaluate this relationship.
To evaluate the correlation between breathlessness during daily activities and airflow limitation or static hyperinflation in COPD.
We examined 167 consecutive outpatients with stable COPD. The Baseline Dyspnea Index (BDI) was used to evaluate dyspnea with activities of daily living. The relationship between the BDI score and the clinical measurements of pulmonary function was then investigated.
The Spearman rank correlation coefficients (Rs) between the BDI score and the FEV1(L), FEV1(%pred) and FEV1/FVC were 0.60, 0.56 and 0.56, respectively. On the other hand, the BDI score also correlated with the IC, IC/predicted total lung capacity (TLC) and IC/TLC (Rs = 0.45, 0.46 and 0.47, respectively). Although all of the relationships studied were strongly correlated, the correlation coefficients were better between dyspnea and airflow limitation than between dyspnea and static hyperinflation. In stepwise multiple regression analyses, the BDI score was most significantly explained by the FEV1 (R2 = 26.2%) and the diffusion capacity for carbon monoxide (R2 = 14.4%) (Cumulative R2 = 40.6%). Static hyperinflation was not a significant factor for clinical dyspnea on the stepwise multiple regression analysis.
Both static hyperinflation and airflow limitation contributed greatly to dyspnea in COPD patients.
PMCID: PMC3203060  PMID: 21988843
Chronic obstructive pulmonary disease; Airflow limitation; Hyperinflation; Dyspnea; Baseline Dyspnea Index
8.  Non–SCF-type F-box protein Roy1/Ymr258c interacts with a Rab5-like GTPase Ypt52 and inhibits Ypt52 function 
Molecular Biology of the Cell  2011;22(9):1575-1584.
Non–SCF-type F-box protein Roy1 interacts with the Rab5-like small GTPase Ypt52. Skp1 is indispensable for the interaction of Roy1 and Ypt52. Roy1 binds to GDP and the nucleotide-free form of Ypt52 and inhibits the formation of GTP-bound, active Ypt52. Roy1 negatively modulates cell viability and intracellular transport by suppressing Ypt52.
Skp1/Cul1/F-box (SCF)–type F-box proteins are a component of the Cullin-RING SCF ubiquitin E3 ligase, which is involved in numerous cellular processes. However, the function of non–SCF-type F-box proteins remains largely unknown. The Rab5-like small guanosine 5′-triphosphatase Vps21/Ypt51 is a key regulator of intracellular transportation; however, deletion of its isoforms, Ypt52 and Ypt53, results in only a modest inhibition of intracellular trafficking. The function of these proteins therefore remains largely elusive. Here we analyze the role of a previously uncharacterized non–SCF-type F-box protein, Roy1/Ymr258c, in cell growth and intracellular transport in Saccharomyces cerevisiae. Roy1 binds to Ypt52 under physiological conditions, and Skp1 is indispensable for the association of Roy1 with Ypt52. The vps21Δ yeast cells exhibit severe deficiencies in cell growth and intracellular trafficking, whereas simultaneous deletion of roy1 alleviates the defects caused by deletion of vps21. However, additional disruption of ypt52 in roy1Δvps21Δ cells largely suppresses the cell growth and trafficking observed in roy1Δvps21Δ cells. We demonstrate that Roy1 interacts with guanosine 5′-diphosphate–bound and nucleotide-free Ypt52 and thereby inhibits the formation of guanosine 5′-triphosphate–bound, active Ypt52. These results thus indicate that Roy1 negatively modulates cell viability and intracellular transport by suppressing Ypt52.
PMCID: PMC3084679  PMID: 21389113
9.  Clinical pathway for acute exacerbations of chronic obstructive pulmonary disease: method development and five years of experience 
Randomized controlled trials, evidence-based medicine, clinical guidelines, and total quality management are some of the approaches used to render science-based health care services. The clinical pathway for hospitalized patients suffering from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is poorly established, although a clinical pathway is an integral part of total quality management.
To evaluate the outcomes of patients hospitalized with AECOPD in Japan, treated with a clinical pathway following published guidelines.
Prospective data were collected for patients with AECOPD admitted to a general hospital over a 5-year period since 2003. The clinical pathway was designed to establish general rules for the entire treatment protocol. The clinical pathway indicates which treatments and interventions should be performed, and when. In this study, health care providers were required to check the clinical pathway sheets to determine the next step of treatment.
This study analyzed 276 hospitalizations in 165 patients. The clinical pathway was interrupted and defined as a dropout in 45 cases (16.3%). Nine patients died during hospitalization (3.3%). Oxygen was administered in 232 hospitalizations (84.1%). Noninvasive positive pressure ventilation (NPPV) treatment was administered in 110 hospitalizations (39.9%). The rate of intubation in those cases where NPPV treatment had been administered was 8.2% (9 cases out of 110). The average length of stay (LOS) was 20.3 days, and the median value was 15 days. The LOS was longer than 30 days in 34 admissions (12.3%), mainly due to complications.
AECOPD can be managed using a clinical pathway. This clinical pathway could fill the gap between guidelines and clinical practice.
PMCID: PMC3133508  PMID: 21760723
COPD; AECOPD; mortality; pulmonary rehabilitation
10.  Interleukin-28B polymorphisms are associated with an early viral response in patients receiving hepatitis C therapy 
Prediction of the efficacy of pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy against hepatitis C (HCV) infection is valuable for determining its applications. This study investigated the relationship between the early response of HCV to PEG-IFN/RBV therapy and the inter-leukin (IL)-28B genetic polymorphism in patients with HCV infection. The genotypes of IL-28B rs8099917 T>G single nucleotide polymorphism were determined in 144 patients with HCV infection. Among them, 59 were treated with PEG-IFN/RBV. The frequency of IL-28B TT homozygosity was 75.2% in patients with HCV serotype 1 and 84.6% in patients with serotype 2. Multivariate analysis showed that IL-28B TT homozygosity (P=0.014) and the platelets number (P=0.030) was associated with the early suppression of HCV-RNA at 12 weeks after the start of PEG-IFN/RBV therapy. The IL-28B polymorphism was a significant pre-treatment predictor of the response to PEG-IFN/RBV therapy in patients with HCV infection.
PMCID: PMC3440742  PMID: 22977564
hepatitis C; interferon; interleukin-28
11.  Linking Cell Cycle to Asymmetric Division: Aurora-A Phosphorylates the Par Complex to Regulate Numb Localization 
Cell  2008;135(1):161-173.
Drosophila neural precursor cells divide asymmetrically by segregating the Numb protein into one of the two daughter cells. Numb is uniformly cortical in interphase but assumes a polarized localization in mitosis. Here, we show that a phosphorylation cascade triggered by the activation of Aurora-A is responsible for the asymmetric localization of Numb in mitosis. Aurora-A phosphorylates Par-6, a regulatory subunit of atypical protein kinase C (aPKC). This activates aPKC, which initially phosphorylates Lethal (2) giant larvae (Lgl), a cytoskeletal protein that binds and inhibits aPKC during interphase. Phosphorylated Lgl is released from aPKC and thereby allows the PDZ domain protein Bazooka to enter the complex. This changes substrate specificity and allows aPKC to phosphorylate Numb and release the protein from one side of the cell cortex. Our data reveal a molecular mechanism for the asymmetric localization of Numb and show how cell polarity can be coupled to cell-cycle progression.
PMCID: PMC2989779  PMID: 18854163
12.  Cellobiose Prevents the Development of Dextran Sulfate Sodium (DSS)-Induced Experimental Colitis 
Cellobiose is produced from cellulose using specific bacterial enzymes, and is hydrolyzed into glucose by the enzymes cellobiosidase and cellulase. In this study, we examined the effects of cellobiose on colonic mucosal damage in a dextran sulfate sodium (DSS) colitis model. BALB/c mice were divided into two groups. In the first group, the mice were fed 3.5% DSS mixed with normal chow. In the second group, the mice were fed 3.5% DSS plus 6.0 or 9.0% (weight/weight) cellobiose mixed with normal chow. The development of colitis was assessed on day 21. Mucosal cytokine expression was analyzed by RT-PCR. Body weight loss was significantly attenuated in the 9.0% cellobiose-fed DSS mice as compared to the DSS mice. Colonic weight/length ratio, a maker of tissue edema, was significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. The disease activity index and histological colitis score were also significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. Mucosal mRNA expression for IL-1β, TNF-α, IL-17 and IP-10 were markedly reduced in the 9.0% cellobiose-fed DSS mice. In conclusion, a preventive effect of cellobiose against DSS colitis suggests its clinical use for inflammatory bowel diseases patients.
PMCID: PMC2831088  PMID: 20216942
IBD; Prebiotics; Probiotics; Butyrate; Fiber
13.  IL-6–dependent spontaneous proliferation is required for the induction of colitogenic IL-17–producing CD8+ T cells 
The Journal of Experimental Medicine  2008;205(5):1019-1027.
We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8+ T cells, which is a crucial step in the differentiation of colitogenic CD8+ T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen–driven rapid SP and IL-7/IL-15–dependent slow homeostatic proliferation. Using our novel model of CD8+ T cell–dependent colitis, we found that SP of naive CD8+ T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the influence of intestinal flora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti–IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced flora depletion, but not by anti–IL-7R mAb and/or in IL-15–deficient conditions. Concomitantly with the inhibition of SP, anti–IL-6R mAb significantly inhibited the induction of CD8+ T cell–dependent autoimmune colitis. Notably, the transfer of naive CD8+ T cells derived from IL-17−/− mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17–producing CD8+ T cell–mediated autoimmune colitis. We suggest that anti–IL-6R mAb may become a promising strategy for the therapy of colitis.
PMCID: PMC2373835  PMID: 18426983
14.  FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice 
AIM: To investigate the effects of FR167653 on the development of dextran sulfate sodium (DSS)-induced colitis in mice.
METHODS: BALB/c mice were fed rodent chow containing 3.5% (wt/wt) DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 (30 mg/kg per day). The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4+ T cell and F4/80+ macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR.
RESULTS: The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration (CD4 T cells and F4/80 macrophages), and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were found to be markedly reduced in FR167653-treated DSS mice.
CONCLUSION: Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase (MAPK)-mediated proinflammatory cytokine induction in host defense mechanisms.
PMCID: PMC2751895  PMID: 18855984
p38; Inflammatory bowel disease; Cytokine; Experimental colitis; Tumor necrosis factor-α
15.  A case of scirrhous gastric cancer with peritonitis carcinomatosa controlled by TS-1® + paclitaxel for 36 mo after diagnosis 
A 34-year-old female complaining of abdominal fullness was diagnosed as scirrhous gastric cancer (type 4’) with peritonitis carcinomatosa in July 2002. A combined chemotherapy regimen was selected to control massive ascites; TS-1® 80 mg/m2 was given orally on d 1-14, 22-35, and paclitaxel 50 mg/m2 was administered intravenously on d 1, 8, 22 and 29. After 2 courses of this regimen, the primary tumor was markedly reduced, and ascites completely vanished. Alopecia (grade 1, since d 30), leukocytopenia (grade 2, on d 34) and anemia (grade 2, on d 34) were the only adverse events throughout the following courses. The chemotherapy was effective for 28 mo, and then it was discontinued upon the patient’s own request, and she survived for 36 mo after diagnosis.
PMCID: PMC4065908  PMID: 17230622
TS-1®; Paclitaxel; Scirrhous gastric cancer; Peritonitis carcinomatosa
16.  Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2D⃞ 
Molecular Biology of the Cell  2006;17(3):1273-1285.
Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.
PMCID: PMC1382316  PMID: 16394100
17.  Augmentation of Actinobacillus actinomycetemcomitans Invasion of Human Oral Epithelial Cells and Up-Regulation of Interleukin-8 Production by Saliva CD14  
Infection and Immunity  2003;71(10):5598-5604.
It has recently been shown that human salivary glands constitutively express CD14, an important molecule in innate immunity, and that a soluble form of CD14 is secreted in saliva. The concentration of CD14 in parotid (a serous gland) saliva was comparable to that in normal serum and 10-fold the amount in whole saliva, although the physiological function of saliva CD14 remained unclear. Actinobacillus actinomycetemcomitans is a periodontopathic bacterium and is able to invade oral epithelial cells. The present study showed that upon exposure to live A. actinomycetemcomitans Y4 for 2 h, human oral epithelial HSC-2 cells produced interleukin-8 (IL-8) for a further 24 h and whole saliva augmented the production induced by A. actinomycetemcomitans Y4. Parotid saliva showed a more pronounced effect on the production of IL-8 than whole saliva. Neither saliva preparation itself had IL-8-inducing activity. Parotid saliva exhibited antibacterial activity against a low concentration of A. actinomycetemcomitans Y4, but recombinant CD14 did not show the activity. The internalization of A. actinomycetemcomitans Y4 into HSC-2 cells was inhibited by cytochalasin B, indicating that the process was actin dependent, and depletion of CD14 from parotid saliva inhibited the invasion and, as a consequence, inhibited production of IL-8. Furthermore, human recombinant CD14 augmented invasion and IL-8 production. These results suggest that saliva CD14 promoted the invasion of oral epithelial cells by A. actinomycetemcomitans and consequently augmented the production of IL-8, playing an important role in innate immunity in the oral cavity.
PMCID: PMC201103  PMID: 14500479
18.  Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo 
The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8+ T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell–deficient RAG2−/− mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8+ cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1–dependent cell–cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.
PMCID: PMC2195611  PMID: 10477547
Th1; Th2; tumor; adoptive immunotherapy; cytokine
19.  The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells  
The Journal of Experimental Medicine  1999;189(7):1121-1128.
The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.
PMCID: PMC2193012  PMID: 10190903
natural killer T cells; dendritic cells; α-galactosylceramide; interleukin 12; interleukin 12 receptor
21.  Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma 
Cancer  2013;120(2):229-237.
A new predictive biomarker for determining prognosis in patients with hepatocellular carcinoma (HCC) who receive sorafenib is required, because achieving a reduction in tumor size with sorafenib is rare, even in patients who have a favorable prognosis. Vascular endothelial growth factor (VEGF) receptor is a sorafenib target. In the current study, the authors examined changes in plasma VEGF concentrations during sorafenib treatment and determined the clinical significance of VEGF as a prognostic indicator in patients with HCC.
Plasma VEGF concentrations were serially measured in 63 patients with advanced HCC before and during sorafenib treatment. A plasma VEGF concentration that decreased >5% from the pretreatment level at 8 weeks was defined as a “VEGF decrease.” An objective tumor response was determined using modified Response Evaluation Criteria in Solid Tumors 1 month after the initiation of therapy and every 3 months thereafter.
Patients who had a VEGF decrease at week 8 (n = 14) had a longer median survival than those who did not have a VEGF decrease (n = 49; 30.9 months vs 14.4 months; P = .038). All patients who had a VEGF decrease survived for >6 months, and the patients who had both a VEGF decrease and an α-fetoprotein response (n = 6) survived during the observation period (median, 19.7 months; range, 6.5-31.0 months). In univariate analyses, a VEGF decrease, radiologic findings classified as progressive disease, and major vascular invasion were associated significantly with 1-year survival; and, in multivariate analysis, a VEGF decrease was identified as an independent factor associated significantly with survival.
A plasma VEGF concentration decrease at 8 weeks after starting sorafenib treatment may predict favorable overall survival in patients with advanced HCC.
PMCID: PMC4209122  PMID: 24122122
antiangiogenic therapy; biomarker; hepatocellular carcinoma; prognosis; α-fetoprotein

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