From Report from degrees in 2006（No.37）

C. 学
位
取
得
者
学位取得者一覧（2006 年）
1. 村上
広島大医卒（呼吸器グループ）
甲-3929
2. 大下慎一郎
平成 10 年広島大医卒（呼吸器グループ）
甲-3931
3. 風呂中
平成 9 年
山口大医卒（呼吸器グループ）
甲-3932
平成 8 年
広島大医卒（内分泌グループ）
甲-3937
5. 土井美帆子
平成 7 年
広島大医卒（呼吸器グループ）
甲-3976
6. 北原
良洋
平成 7 年
広島大医卒（呼吸器グループ）
甲-4041
7. 平井
隆之
平成9年
広島大医卒（腎臓グループ）
甲-4045
8. 日域
邦昭
平成 9 年
東京医大卒（内分泌グループ）
甲-4068
4. 亀井
晴泰
修
望
平成 8 年
村上
晴泰
平成 8 年
広大医卒
甲-3929
2006/3/23
Murakami H, Yokoyama A, Kondo K, Nakanishi S, Kohno N, Miyake M*.
Circulating aminopeptidase N/CD13 is an independent prognostic
factor in patients with non-small cell lung cancer.
Clin Cancer Res 11: 8674-79, 2005
Purpose: Aminopeptidase N (APN), also known as CD13, has important roles in
tumor metastasis and angiogenesis. Its expression in tumor tissue has been
reported to be associated with poor prognosis. However, the clinical significance
of circulating APN/CD13 in patients with solid tumors is unknown. We
previously developed an APN/CD13-specific monoclonal antibody (mAb)
MH8-11, which inhibits cell motility and angiogenesis in vitro. The aim of this
study was to evaluate the clinical significance of circulating APN/CD13 protein
detected by mAb MH8-11 in patients with non-small cell lung cancer (NSCLC).
Experimental Design: We used electrochemiluminescence immunoassay with
mAb MH8-11 to determine circulating APN/CD13 levels in 90 healthy volunteers
and 90 patients with NSCLC. Circulating APN/CD13 levels were measured in
sera taken prior to treatment, and evaluated for a relationship with clinical
outcomes.
Results: A significant correlation was found between tumor progression and
serum APN/CD13 concentrations (r = 0.23; p = 0.029). High serum APN/CD13
levels (n = 17) were associated with advanced stage (p = 0.004) or poor
performance status (p = 0.001). The overall survival rate for patients with high
serum APN/CD13 levels (n = 17) was significantly less than that of patients with
low serum APN/CD13 levels (n = 73; p<0.0001). In a multivariate survival
analysis in patients with NSCLC, serum APN/CD13 levels had an independent
influence on survival (relative risk, 4.1; 95% confidence interval, 1.9-8.8).
Conclusions: Our data suggest that a high level of circulating APN/CD13 at
diagnosis is an independent prognostic factor in patients with NSCLC.
大下慎一郎
平成 10 年
広大医卒
甲-3931
2006/3/23
Ohshimo S, Yokoyama A, Hattori N, Ishikawa N, Hirasawa Y, Kohno N.
KL-6, a human MUC1 mucin, promotes proliferation and survival
of lung fibroblasts.
Biochem Biophys Res Commun 338: 1845-1852, 2005
The serum level of KL-6, a MUC1 mucin, is a clinically useful marker for
various interstitial lung diseases. Previous studies demonstrated that KL-6
promotes chemotaxis of human fibroblasts. However, the pathophysiological
role of KL-6 remains poorly understood. Here, we further investigate the
functional aspects of KL-6 in proliferation and apoptosis of lung fibroblasts.
KL-6 accelerated the proliferation and inhibited the apoptosis of all human
lung fibroblasts examined. An anti-KL-6 monoclonal antibody counteracted
both of these effects induced by KL-6 on human lung fibroblasts. The pro
-fibroproliferative and anti-apoptotic effects of KL-6 are greater than and
additive to those of the maximum effective concentrations of platelet-derived
growth factor, basic fibroblast growth factor, and transforming growth
factor-β. These findings indicate that increased levels of KL-6 in the
epithelial lining fluid may stimulate fibrotic processes in interstitial lung
diseases and raise the possibility of applying an anti-KL-6 antibody to treat
interstitial lung diseases.
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風呂中修
平成 9 年山大医卒
甲- 3932
Furonaka O, Takeshima Y, Awaya H, Ishida H, Kohno N, Inai K.
2006/3/23
Aberrant methylation of p14ARF, p15INK4b and p16INK4a genes and
location of the primary site in pulmonary squamous cell carcinoma.
Pathol Int 54: 549-555, 2004
Aberrant methylation of cytosines in CpG islands of the promoter regions of
tumor suppressor genes is found in human tumors as a common mechanism of
gene silencing. We investigated the methylation status of the chromosome 9p21
gene cluster (p14ARF, p15INK4b and p16INK4a genes) by methylation-specific
polymerase chain reaction in 20 central and 40 peripheral types of pulmonary
squamous cell carcinoma (SqCC) in order to determine the differences between
the pathogeneses of the central and peripheral types of SqCC. The frequencies of
methylation were 30% for the p14ARF gene, 20% for the p15INK4b gene and 40%
for the p16INK4a gene in the central type and 25% for the p14ARF gene, 10% for the
p15INK4b gene and 38% for the p16INK4a gene in the peripheral type. Cases in
which there was methylation of the p16INK4a gene had a higher smoking index in
the peripheral type (P = 0.007). This trend was not detected in the central type.
Methylation of two or three genes was observed in 55% of methylation in at least
one gene of the central type but in only 17% of the peripheral type. This overlap
methylation of the chromosome 9p21 gene cluster was found more frequently in
the central type (P = 0.02). These findings suggest one of the epigenetic
differences between the central and peripheral types of SqCC.
Furonaka O, Takeshima Y, Awaya H, Kushitani K, Kohno N, Inai K.
Aberrant
methylation
and
loss
of
expression
of
6
O -methylguanine-DNA methyltransferase in pulmonary squamous
cell carcinoma and adenocarcinoma
Pathol Int 55: 303-309, 2005
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that
protects cells against the carcinogenic effects of alkylating agents.
We
investigated methylation status of the MGMT gene by methylation-specific PCR
and expression status by immunohistochemistry in 70 cases of pulmonary
squamous cell carcinoma (SqCC), including 23 cases of the central type and 47
cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary
adenocarcinoma (AC).
The frequency of MGMT methylation was 36% in SqCC
and 42% in AC. Cases with MGMT methylation correlated significantly with T
factor in SqCC (P=0.047) and AC (P=0.03).
In SqCC, the frequency of MGMT
methylation was 26% in the central type and 40% in the peripheral type, a
significant correlation was not found (P=0.29).
In AC with mixed subtypes
showed MGMT methylation, the level of MGMT expression in the BAC area
(non-invasive status) was significantly higher than that in the papillary or acinar
AC area (invasive status) (P=0.0002). This trend was not found in AC with
mixed subtypes showed no MGMT methylation (P=0.10).
Our findings suggest
that MGMT inactivation is an event that occurs in the late carcinogenic process in
SqCC and AC, and that AC progress from non-invasive status to invasive status
with MGMT inactivation induced by the promoter DNA methylation.
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亀井
望
平成 8 年
広大医卒
甲-3937
2006/3/23
Kamei N, Yamane K, Nakanishi S, Ishida K, Ohtaki M, Okubo M, Kohno N.
Effects of a westernized lifestyle on the association between fasting
serum nonesterified fatty acids and insulin secretion in Japanese
men.
Metabolism 54: 713-718, 2005
The effects of the prolonged elevation of nonesterified fatty acid (NEFA) levels
on insulin secretion have been controversial and thought to be sex-specific. To
investigate the association between a westernized lifestyle and the effects of
NEFA on insulin secretion in Japanese men, we examined 67 nondiabetic
Japanese-American men and 220 nondiabetic native Japanese men who
underwent a 75-g oral glucose tolerance test (OGTT). Most Japanese Americans
we surveyed are genetically identical to Japanese living in Japan, but their
lifestyle is more westernized. Sets of multiple regression analyses were performed
to evaluate the relationship between the sum of the immunoreactive insulin (IRI)
levels during the OGTT (∑ IRI) and clinical parameters. Japanese Americans had
higher levels of fasting IRI, ∑ IRI, and a higher insulin resistance index
(homeostasis model assessment for insulin resistance [HOMA-IR]) than native
Japanese, whereas there were no significant differences in fasting NEFA and
triglyceride levels. A multiple regression analysis adjusted for age, fasting
triglycerides, and body mass index (BMI) demonstrated that the fasting NEFA
level was an independent determinant of the ∑ IRI only in Japanese-American
men (P = .001), but not in native Japanese men (P = .054). Even when HOMA-IR
was included in models instead of BMI, the NEFA level was a significant variable
of ∑ IRI only in Japanese Americans (P < .001), and not in native Japanese (P
= .098). In addition, a multiple regression analysis adjusted for age, fasting
triglycerides, and BMI demonstrated that the fasting NEFA level was the only
independent determinant of ∑ C-peptide in Japanese-American men (P = .041). In
conclusion, NEFA seems to be associated with insulin secretion independent of
obesity or HOMA-IR. A westernized lifestyle may increase the effects of serum
fasting NEFA levels on total insulin secretion after a glucose load in Japanese
men.
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土井
美帆子
平成 7 年
広大医卒
甲-3976
2006/3/23
Doi M, Yokoyama A, Kondo K, Ohnishi H, Ishikawa N, Hattori N,
Kohno N.
Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody
through exposure of surface molecules by MUC1 capping.
Cancer Sci 97: 420-429, 2006
Human polymorphic epithelial mucin (MUC1) is a heavily glycosylated large
protein that is frequently overexpressed on the surface of many human
adenocarcinomas. Studies using monoclonal antibodies (mAb) identified MUC1
as a tumor associated antigen that has been intensely studied as a target for cancer
immunotherapy. We previously identified a mouse IgG1 mAb that recognizes a
sialylated sugar chain, designated as KL-6, classified in‘Cluster 9 (MUC1)’.
Using the anti-KL-6 mAb, we investigated antitumor effects of anti-MUC1 mAb
on breast cancer cell lines expressing MUC1 abundantly. We showed that
anti-KL-6 mAb induced capping of MUC1 and facilitated E-cadherin-mediated
cell-cell interaction in the breast cancer cell lines YMB-S and ZR-75-1S, which
proliferate in suspension culture without aggregation. Moreover, anti-KL-6 mAb
enhanced the cytotoxic activity of lymphokine-activated killer cells. These results
indicate that the capping of MUC1 restores cell surface proteins, such as adhesion
molecules and tumor antigens, to work in cell-cell interactions, leading to
inhibition of tumor proliferation due to cell-cell adhesion and increased
accessibility to effector cells that are needed to kill tumor cells.
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北原
良洋
平成 7 年
広大医卒
甲-4041
2006/5/29
Kitahara Y, Hattori N, Yokoyama A, Nakajima M, Kohno N.
Effect of CPAP on brachial-ankle pulse wave velocity in patients
with OSAHS: An open-labelled study.
Respir Med 100:2160-2169, 2006
Pulse wave velocity (PWV) is a good indicator of arterial stiffness and an
important predictor of cardiovascular events. Recent studies have revealed that
PWV increases in patients with obstructive sleep apnea-hypopnea syndrome
(OSAHS) and it also correlates with its severity. However, the therapeutic effect
of continuous positive airway pressure (CPAP) on PWV remains undetermined.
To clarify this point, we started CPAP treatment on 17 OSAHS patients.
Brachial-ankle PWV was measured before starting CPAP, and at 2 months and 4
months after the start of CPAP. Before the CPAP treatment, mean brachial-ankle
PWV of the patients was 15.6±0.6 m/s, and mean Epworth sleepiness scale
(ESS) score was 8.6±1.0. Brachial-ankle PWV was found to positively correlate
with heart rate, systolic and diastolic blood pressures, mean blood pressure, and
arousal index. During the study period, the CPAP treatment did not have a
significant effect on heart rate, blood pressures and serum total cholesterol levels.
However, it significantly improved ESS score at 4 months after the start of CPAP
(P = 0.001), while it effectively decreased brachial-ankle PWV at 2 months and at
4 months after the start of CPAP (P = 0.010 and P = 0.027, respectively). The
CPAP treatment was shown to decrease brachial-ankle PWV without affecting
blood pressures in OSAHS patients. Although the precise mechanism for this
effect is unclear, our finding suggests a close relationship between OSAHS and
arterial stiffness, while also reemphasizing the clinical importance of CPAP
treatment.
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平井
隆之
平成 9 年
広大医卒
甲-4045
2006/5/29
Hirai T, Masaki T, Kuratsune M, Yorioka N, Kohno N.
PDGF receptor tyrosine kinase inhibitor suppresses mesangial cell
proliferation involving STAT3 activation.
Clin and Exp Immunol 144:353-61, 2006
Proliferation of mesangial cells is a hallmark of glomerular disease, and
understanding the regulatory mechanisms is critically important. The purpose of
this study was to examine the relationship between mesangial cell proliferation
and phosphorylated signal transducer and activator of transcription (STAT) 3 and
to determine whether the PDGF receptor tyrosine kinase inhibitor STI 571
inhibited mesangial cell proliferation via modulation of STAT3. In this study, we
investigated for the first time, the glomerular expression of phosphorylated
STAT3 in paraffin sections from animals with experimental mesangial
proliferative glomeronephritis. Phosphorylated STAT3 co-localized with many
proliferating mesangial cells. We also demonstrated that treatment with STI 571
reduced mesangial cell proliferation and phosphorylated STAT3 signaling both in
vitro and in vivo. In vivo, STI 571 treatment reduced the number of glomerular
mesangial cells positive for both phosphorylated STAT3 and proliferating cell
nuclear antigen. In summary, phosphorylated STAT3 is strongly expressed during
mesangial cell proliferation and STI 571 induced suppression of mesangial cell
proliferation involves inhibition of phosphorylated STAT3 signaling.
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日域
邦昭
平成 9 年
東京医大卒
甲-4068
2006/9/28
Jitsuiki K, Yamane K, Nakajima M, Nakanishi S, Tasaki N, Watanabe H,
Kurihara H, Kohno N.
Association of Chlamydia pneumoniae infection and carotid
intima-media wall thickness in Japanese Americans.
Circ J 70: 815-819, 2006
BACKGROUND: Chlamydia pneumoniae (Cp) infection has been proposed as a
risk factor for coronary artery disease (CAD), but it remains unclear whether Cp
plays a role in the progression of early stage carotid atherosclerosis. METHODS
AND RESULTS: The associations among Cp IgG/IgA antibodies, inflammation
markers such as C-reactive protein (CRP) and interleukin (IL)-6, and the maximal
progression of carotid intima-media wall thickness (max IMT) were evaluated
using ultrasonography in 259 Japanese Americans. The presence of Cp IgG or
IgA antibodies itself did not show significant correlation with max IMT after
adjustment for age and sex. However, in the Cp IgG seropositive group, the
subjects with high IL-6 levels showed more pronounced max IMT progression
than those with low IL-6 levels after adjustment of the other CAD risk factors.
Moreover, in the Cp IgA seropositive group, the subjects with high CRP or IL-6
levels had significantly higher levels of max IMT compared with those with low
CRP or IL-6. CONCLUSIONS: The results support the hypothesis that a chronic
latent Cp infection with inflammation might accelerate the development of early
stage atherosclerotic lesions.
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