Oxysterol binding protein‐related protein‐5 is related to invasion and poor prognosis in pancreatic cancer

In previous studies, the gene expression profiles of two hamster pancreatic cancer cells with different potentials for invasion and metastasis were analyzed. In the present study, we identified that one of the genes expressed strongly in the highly metastatic cell line is hamster oxysterol binding protein‐related protein (ORP)‐5. The aim of the present study was to clarify the relationship between ORP5 and invasion and poor prognosis of human pancreatic cancer. Invasion assays were carried out in both hamster and human pancreatic cancer cells by suppressing the ORP5 gene with short interfering RNA or inducing its expression by introducing an expression vector. To evaluate the relationship between ORP5 and the characteristics of human pancreatic cancer, 56 pancreatic cancer tissue specimens were analyzed and the ORP5 expression in each pancreatic cancer tissue specimen was analyzed by immunohistochemistry. In both the hamster and human pancreatic cancer cells, suppression of ORP5 significantly reduced the invasion rate of the cells and induction of ORP5 significantly enhanced the invasion rate of the cells. In the clinical sample, the median survival times of the patients with ORP5‐positive (n = 33) and ORP5‐negative (n = 23) cancer were 8.3 and 17.2 months, respectively (P = 0.02). Also, the 1‐year survival rates of patients with ORP5‐positive and ORP5‐negative cancer were 36.4 and 73.9%, respectively (P = 0.005). The ORP5 expression level was related to both invasion and poor prognosis in human pancreatic cancer. These findings suggest that the expression of ORP5 may induce cancer cell invasion, resulting in the poor prognosis of pancreatic cancer. (Cancer Sci 2008; 99: 2387–2394)     

A case report of advanced gastric cancer responding to TS-1, a novel oral fluorouracil derivative

TS-1 is a new, oral anticancer agent composed of two modulators, gimeracil (CDHP) and oteracil potassium (Oxo) are mixed with tegafur in a ratio of 1:0.4:1. We report one case of advanced gastric cancer with lung and lymph node metastases that completely responded to TS-1. A 71-year-old woman was admitted to our hospital because of breathlessness. A diagnosis of advanced gastric cancer with extensive lymph node metastases and multiple pulmonary metastases was made. One hundred mg/body/day of TS-1 was orally administrated for 4 weeks. A partial response (PR) was obtained after the first course with regression of multiple pulmonary metastases. After 1 drug-free week, the second course was administered with 120 mg/body/day of TS-1 for 4 weeks. After two courses, the primary tumor was reduced to an ulcer scar with pathological confirmation of a complete disappearance of the cancer tissue. Moreover, computed tomography (CT) showed a complete regression of the extensive lymph node and diffuse lung metastases, for a complete response (CR). The serum level of CEA was reduced from 172.7 ng/ml to 8.1 ng/ml after TS-1 treatment. As for adverse events, only pigmentation of the skin and Grade 2 oral aphta were observed.     

Molecular Analysis of edicinally-Used Chinese and Japanese Curcuma Based on 18S rRNA Gene and trnK Gene Sequences

ＧｅｎｕｓＣｕｒｃｕｍａｏｆｔｈｅｆａｍｉｌｙＺｉｎｇｉｂｅｒａｃｅａｅｃｏｎｓｉｓｔｓｏｆａｂｏｕｔ 70ｓｐｅｃｉｅｓｉｎｔｈｅｗｏｒｌｄ ,ｏｆｗｈｉｃｈｍｏｒｅｔｈａｎｔｅｎａｒｅｄｉｓｔｒｉｂｕｔｅｄｏｒｃｕｌｔｉｖａｔｅｄｉｎＣｈｉｎａ[1] ａｎｄＪａｐａｎ[2 ] .ＳｅｖｅｒａｌｈｅｒｂａｌｄｒｕｇｓｕｓｅｄｆｒｅｑｕｅｎｔｌｙａｒｅｄｅｒｉｖｅｄｆｒｏｍｔｈｅＣｕｒｃｕｍａｓｐｅｃｉｅｓ.ＩｎＣｈｉｎａ ,“Ｊｉａｎｇｈｕａｎｇ”ｆｒｏｍｔｈｅｒｈｉ ｚｏｍｅｏｆＣｕｒｃｕｍａｌｏｎｇａ ,“Ｐｉａｎｊｉａｎｇｈｕａｎｇ”ｆｒｏｍｔｈｅｓｌｉｃｅｄｒｈｉｚｏｍｅｏｆＣ .ｗｅｎｙｕｊｉｎ ,“Ｅｚｈｕ”ｆｒｏｍｔｈｅｒｈｉｚｏｍｅｓｏｆＣ .ｐｈａｅｏｃａｕｌｉｓ,Ｃ .ｗｅｎｙｕｊｉｎｏｒＣ .ｋｗａｎｇｓｉｅｎｓｉｓ,ａｎｄ“Ｙｕｊｉｎ”ｆｒｏｍｔｈｅｔｕｂｅｒｓｏｆＣ .ｗｅｎｙｕｊｉｎ ,Ｃ .ｌｏｎｇａ ,Ｃ .ｋｗａｎｇｓｉｅｎｓｉｓｏｒＣ .ｐｈａｅｏｃａｕｌｉｓａｒｅｉｎｕｓｅ .[3] ＩｎＪａｐａｎ ,“Ｇａｊｕｔｓｕ”ｆｒｏｍｔｈｅｒｈｉｚｏｍｅｏｆＣ .ｚｅｄｏａｒ...     

P-Glycoprotein Is Positively Correlated with p53 Protein Accumulation in Human Colorectal Cancers

To explore the relationship between mutant p53 and Pgp expression, we have examined the levels of both proteins in human colorectal adenocarcinomas. Serial frozen sections of 40 surgical samples were stained with an anti-Pgp (MRK16) and two different anti-p53 protein antibodies (Abs), PAb421 and Pabl80l. Nineteen (47.5%) of 40 samples examined were positive for Pgp, and 18 (45%) of 40 were positive for p53. The samples that stained positively with PAb421 also stained positively with Pahl80l. Pgp expression was detected in 13 (76.5%) of 17 samples that were positive for p53 using PAb421 and in 15 (83.3%) of 18 samples that were positive for p53 using Pabl80. Thus, we found that p53 and Pgp were co-expressed in a significant number of samples ( P < 0.002). There was no relationship between Pgp or p53 protein accumulation and histologic grade or stage. The present results demonstrate that Pgp expression is closely associated with p53 protein accumulation in human colorectal cancers. These data provide evidence to support the idea that mutant p53 activates the MDR1 gene in vivo .     

Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma

Using microarrays, we have screened for genes reactivated by drugs that modify epigenetic mechanisms in pancreatic cancer cells. One of the genes identified was tissue factor pathway inhibitor 2 (TFPI-2), which encodes for a broad-spectrum serine proteinase inhibitor that negatively regulates the extracellular matrix degradation, an essential step in tumor invasion and metastasis. We therefore investigated the expression and methylation patterns of the TFPI-2 gene in pancreatic adenocarcinoma, and determined its role in tumor growth and invasion. In contrast to its abundant expression in normal pancreas, TFPI-2 mRNA was undetectable in a high fraction of pancreatic cancer cell lines and in primary pancreatic ductal neoplasms (IPMNs). Loss of TFPI-2 expression was associated with aberrant hypermethylation of its promoter CpG island. Treatment with the phorbol ester (PMA), known to stimulate the TFPI-2 promoter activity, augmented the TFPI-2 expression in cell lines with unmethylated or partially methylated TFPI-2, but failed to induce the expression in cell lines that harbored fully methylated TFPI-2. Aberrant methylation of TFPI-2 was also detected in 73% (102/140) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas, was more likely in older patients with pancreatic cancer, and significantly correlated with progression of IPMNs (P=0.0002). Restored expression of the TFPI-2 gene in nonexpressing pancreatic cancer cells resulted in marked suppression in their proliferation, migration, and invasive potential in vitro. We thus conclude that epigenetic inactivation of TFPI-2 is a common mechanism that contributes to the aggressive phenotype of pancreatic ductal adenocarcinoma.     

Glucose transporter-1 expression in the thyroid gland: clinicopathological significance for papillary carcinoma

Glucose transporter-1 (GLUT-1) expression was immunohistochemically analysed in a total of 268 cases of thyroid gland disease, including 129 cases of papillary carcinoma (PC), 60 cases of follicular carcinoma (FC), 57 cases of follicular adenoma, and 22 cases of adenomatous goitre. Seventy-one percent (91/129) of PC cases showed GLUT-1 expression, semi-quantitatively evaluated as: +, 21 cases (16%); 2+, 37 cases (29%); 3+, 33 cases (26%); and negative, 38 cases (29%). These positive cases were divided into two groups: 'membrane-like' pattern in 24 cases (19%), and 'cytoplasm-predominance' pattern in 67 cases (52%). GLUT-1 expression was observed in 5% (3/60) of FC cases, but all follicular adenomas and adenomatous goitres were negative for GLUT-1 (PC vs. FC, p<0.0001). Membrane-like expression was observed more frequently in non-organ-confined PCs (pT4) than in organ-confined PCs (pT1, 2, and 3) (p=0.0056). Seventy-five percent (18/24) of PC cases showing membrane-like expression were non-organ-confined. The membrane-like pattern was observed more frequently in PCs with lymph node (LN) metastasis compared to those without (p=0.0036). Ninety-two percent (22/24) of PC cases showing the membrane-like pattern were not organ-confined. Semi-quantitative analysis of glut-1 mRNA by RT-PCR showed a tendency toward higher expression in PCs compared to FCs, follicular adenomas and adenomatous goitres, and the mRNA expression in PCs with a membrane-like pattern was higher than those showing cytoplasm-predominance. We concluded that: 1) GLUT-1 is immunohistochemically useful in distinguishing PC from FC and benign diseases; 2) GLUT-1 may play an important role in the advancement of PC and LN metastasis, and its membrane-like expression is of more clinical significance than the cytoplasm-predominance pattern; and 3) glut-1 mRNA expression corresponds with the immunohistochemical expression profile.     

Altered brain penetration of diclofenac and mefenamic acid, but not acetaminophen, in Shiga-like toxin II-treated mice

It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.     

A case of giant epidermoid cyst occupying the testis

A case of a giant epidermoid cyst of the testis is presented. A 65-year-old man was incidentally pointed out to have left scrotal painless swelling. Physical examination revealed an over hen-egg sized enlargement of the left scrotal contents. Ultrasonography revealed a 7.5 X 5.5 X 4.0 cm solid tumor with heterogeneous echogenicity. No other abnormal findings were observed including tumor markers. Since preoperative examination did not rule out malignancy, we performed left high orchiectomy. Pathological diagnosis was a epidermoid cyst of the testis with a small portion of atrophic testis. Although the preoperative diagnosis of testicular epidermoid cyst is possible, it may be considerably difficult when a giant epidermoid cyst is occupying the testis.