Sulfonamide derivative,E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin alpha2 subunit on endothelium

In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.     

Evaluation of endoscopic mucosal resection and nodal micrometastasis in pN0 submucosal gastric cancer

Endoscopic mucosal resection (EMR) is a minimally invasive, standard treatment for intramucosal (early) gastric cancers, but is not standard for submucosal gastric cancers based on existing criteria. We evaluated the possibility of extending EMR as a therapy for submucosal gastric cancers by analyzing nodal micrometastasis through immunohistochemical staining in patients with apparent node-negative submucosal gastric cancer, the patients for whom EMR might be appropriate. We used anti-cytokeratin (AE1/AE3) antibody to immunohistochemically detect nodal micrometastasis that was not identified by routine pathological examination in 162 patients (total, 2048 lymph nodes) with apparent node-negative submucosal gastric cancer. The relationship between the incidence of nodal micrometastasis and clinicopathological factors was analyzed. Micrometastasis was detected in 45 of 2048 nodes (2.2%), representing 31 of 162 patients (19%). A significantly high incidence of nodal micrometastasis was found with submucosal cancers of large size (>2 cm), as well as with tumors that showed lymphatic or venous invasion and deeper submucosal invasion (p<0.0001). Nodal micrometastasis was also recognized in 2 cases of histologically well-differentiated tumors with focal submucosal invasion without venous or lymphatic invasion. Of the 162 patients, only 2 died of recurrent disease regardless of nodal involvement. Based on the present results, risk factors for nodal micrometastasis are tumor size, presence of lymphatic-vascular invasion, and depth of tumor, which are nearly the same as those established in previous pathological studies that used hematoxylin and eosin staining. We conclude that EMR is not recommended for patients with submucosal gastric cancer.     

A single nucleotide polymorphism in the extracellular domain of TRAIL receptor DR4 at nucleotide 626 in gastric cancer patients in Japan

Death receptor 4 (DR4) is a member of the tumor necrosis factor-related apoptosis-inducing ligand receptor genes. A single nucleotide polymorphism (Thr or Arg, C or G) in the extracellular domain was reported to be associated with a risk of lung cancer, head and neck cancer, and bladder cancer. In this study, we examined the association between the DR4 polymorphism and gastric cancer. The Thr/Thr, Thr/Arg and Arg/Arg genotypes were found in 250 (91.2%), 23 (8.4%) and 1 (0.4%) of 274 gastric cancer patients and in 317 (92.2%), 21 (6.1%) and 6 (1.7%) of 344 control subjects, respectively. The OR of Thr/Arg or Arg/Arg genotype did not reveal a significantly enhanced risk of 1.13 (95% CI, 0.63-2.00) compared to Thr/Thr genotype, suggesting that the DR4 polymorphism did not modify the risk of gastric cancer. In patients, no association between the genotype and clinicopathological characteristics (depth of invasion, lymph node metastasis, distant metastasis, stage and grade of differentiation) of gastric carcinoma was found. DR4 was constantly expressed in gastric carcinoma, but not in non-neoplastic gastric epithelium in immunohistochemistry. In conclusion, a Thr to Arg single nucleotide polymorphism in the extracellular domain of DR4 could not be associated with the development and progression of gastric cancer.     

The T-helper 1/T-helper 2 balance in peripheral blood of women with hyperemesis gravidarum

OBJECTIVE: The purpose of this study was to evaluate the T-helper 1/T-helper 2 balance and its relation with pregnancy-related hormones in hyperemesis gravidarum. STUDY DESIGN: The T-helper 1/T-helper 2 ratio and plasma progesterone and estrogen levels were examined in the peripheral blood of 22 women with hyperemesis gravidarum and normal pregnancies. The proportion of CD4-positive cells that expressed intracellular cytokines (interferon gamma and interleukin-4) were analyzed by blood flow cytometry. The ratio of interferon gamma-secreting cells to interleukin-4-secreting cells was taken as the T-helper 1/T-helper 2 ratio. RESULTS: In hyperemesis gravidarum, the proportions of interleukin-4-secreting cells increased, and the T-helper 1/T-helper 2 ratio averaged 8.4 +/- 0.9, which was significantly lower than in normal pregnancy (11.6 +/- 1.1, P <.05). The changes in the T-helper 1/T-helper 2 ratio in hyperemesis gravidarum were accompanied by the elevation of progesterone and estrogen levels. CONCLUSION: A further shift of the T-helper 1/T-helper 2 balance to the T-helper 2 dominance in hyperemesis gravidarum may be related to the increase of progesterone and estrogen levels.     

Plasma nitric oxide levels and the expression of P-selectin on platelets in preeclampsia

OBJECTIVE: The purpose of this study was to investigate the correlation of plasma nitric oxide levels with the expression of P-selectin on platelets in preeclampsia. STUDY DESIGN: Plasma levels of nitrite and nitrate (the stable nitric oxide metabolites) and the expression of P-selectin on platelets (a platelet activation marker) were measured in 25 normal pregnant women and 25 women with preeclampsia. The effects of the inhibition of nitric oxide synthesis on the expression of P-selectin also was measured in vitro. RESULTS: Plasma nitrate levels and the expression of P-selectin averaged 30.5 +/- 2.2 micromol/L and 8.9% +/- 1.1% (SEM), respectively, in preeclampsia, which was significantly higher than in normal pregnancy (P <.05). Nitric oxide synthesis inhibition in vitro significantly increased the expression of P-selectin in normal pregnancy by 284% (P <.05), which was significantly higher than in preeclampsia (156%, P <.05). CONCLUSION: The inhibitory effects of increased nitric oxide on the expression of P-selectin is attenuated in preeclampsia, which may contribute partly to the pathogenesis of preeclampsia.     

Increased plasma adenosine concentrations and the severity of preeclampsia

OBJECTIVE: To investigate the relationship between changes in plasma adenosine and the severity of preeclampsia, and norepinephrine and tumor necrosis factor-alpha concentrations. METHODS: Plasma concentrations of adenosine, norepinephrine, and tumor necrosis factor-alpha relating to the pathogenesis of preeclampsia were measured in women with mild (n = 21) and severe (n = 21) preeclampsia and normal pregnancies (n = 21), matched for age, gestational age, and parity, in the third trimester of pregnancy. We then evaluated the relationships among plasma adenosine, norepinephrine, tumor necrosis factor-alpha concentrations, and the severity of preeclampsia. RESULTS: Mean plasma adenosine, norepinephrine, and tumor necrosis factor-alpha concentrations were significantly higher in women with mild and severe preeclampsia than in normal control subjects (P <.05). In women with preeclampsia, plasma adenosine concentrations increased according to the severity of preeclampsia (0.60 +/- 0.03 micromol/L and 0.72 +/- 0.03 micromol/L, respectively, versus 0.41 +/- 0.03 micromol/L for normal subjects), which correlated with increases of norepinephrine and tumor necrosis factor-alpha concentrations (r =.58, P <.05; r =.49, P <.05, respectively). In preeclampsia, norepinephrine concentration also correlated with maternal blood pressure (r =.50, P <.05). CONCLUSION: Adenosine is an established suppressor of the effects of norepinephrine and tumor necrosis factor-alpha. The increased plasma concentrations of adenosine in preeclampsia might serve to counteract further progression of the complication.     

Serum adenosine deaminase activity in women with pre-eclampsia

The present study investigated serum adenosine deaminase (ADA) activity and the patterns of two ADA isoenzymes, ADA1 and ADA2, and to evaluate the possible role of cell-mediated immunity as causes of the changes in ADA activity in pre-eclampsia. We measured serum activities of total ADA, ADA1 and ADA2 in pre-eclampsia (n = 22) and normal pregnancy (n = 22). Peripheral blood monocyte counts and neopterin levels, reflecting the activation of the monocyte-macrophage cell system, were also measured. In pre-eclampsia, serum total ADA and ADA2 activities were significantly increased compared with normal pregnancy (p < 0.05), which were accompanied by increases in serum neopterin levels. These results suggest that increased total ADA activity reflects increases in ADA2 activity, which may be in part related to enhanced cell-mediated immunity during pre-eclampsia.     

Plasma 5'-nucleotidase activities and uric acid levels in women with pre-eclampsia

The present study investigated plasma activity of 5'-nucleotidase, a key enzyme in the production of adenosine, in pre-eclampsia, and evaluated the relationship between changes in 5'-nucleotidase activity, and levels of uric acid, endproduct of the purine metabolism, and the severity of pre-eclampsia. We measured plasma 5'-nucleotidase activities and uric acid levels in women with 18 normal pregnancies, mild and severe pre-eclampsia. In mild and severe pre-eclampsia, plasma 5'-nucleotidase activities and uric acid levels were significantly increased compared with those in normal pregnancy (p < 0.05). Plasma 5'-nucleotidase activity increased according to increases in uric acid levels and the severity of pre-eclampsia. These results suggest that increased plasma 5'-nucleotidase activity may, at least in part, be related to changes in purine metabolism in pre-eclampsia.     

Demographic,clinical, and virological characteristics of hepatocellular carcinoma in Asia: survey of 414 patients from four countries

Demographic, etiological, clinical characteristics and treatment of hepatocellular carcinoma (HCC) were surveyed in 414 patients in Asia, including 107 from China, 15 from India, 101 from Indonesia and 191 from Japan. Males predominated in all countries, accounting for up to 75%. The mean +/- SD age at the development of HCC was about 10 years older for the patients from Japan (63.8 +/- 9.5, P < 0.001) and India (63.1 +/- 11.2, P < 0.05) than those from China (54.0 +/- 13.7) and Indonesia (53.7 +/- 14.2). Hepatitis B surface antigen (HBsAg) in serum was detected in 67% of patients from China who were tested, 27% from India, 21% from Indonesia and 18% from Japan, whereas antibody to hepatitis C virus was detected in 4%, 53%, 40% and 70%, respectively; co-occurrence of hepatitis B and C infections was seen only in 7%, 0%, 2%, and 1%, leaving an etiology other than hepatitis viruses in 22%, 20%, 36% and 11%. HCC was diagnosed primarily by ultrasonography in China (43%) and Japan (52%), and on physical examination in India (60%) and Indonesia (52%). The size of the largest tumor exceeded 5.0 cm in diameter only in 24% of the patients from Japan, much less often than in 67%, 87%, and 71%, respectively, of those from China, India and Indonesia (P < 0.001). The most favored treatment was chemolipidolization in China (81%) and Japan (81%), whereas it was transarterial embolization in India (13%) and Indonesia (26%). These results highlight common as well as distinct characteristics of HCC in Asia, and warrant the need for close cooperation toward early diagnosis and effective treatment of HCC.