Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions.

PURPOSE: Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of TR in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma. EXPERIMENTAL DESIGN: We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+CD4+CD25+ TR in the CD4+ T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions. RESULTS: The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P<0.0001). The increased prevalence of T(R) was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of T(R), and this was independent of other survival factors (P<0.0001). Infiltration of intraepithelial CD8+TIA-1+ cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of TR increased significantly during the progression of premalignant lesions. CONCLUSIONS: T(R) play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.     

Influence of chorioamnionitis on survival and morbidity in singletons live-born at < 32 weeks of gestation

BACKGROUND: Chorioamnionitis (CAM) may accelerate lung maturation in fetuses. It is possible that CAM prevents infant death after live birth. METHODS: A retrospective study of live-born singletons at < 32 weeks of gestation between 1993 and 1997. Perinatal risk factors for adverse outcomes were analyzed using a logistic regression model, with special reference to the presence of histologically confirmed CAM. Adverse outcomes included infant death before 1 year of age, and survival with cerebral palsy and/or mental retardation. RESULTS: A total of 81 infants, weighing 1181 +/- 426 g, were born at 28.1 +/- 2.3 weeks of gestation. Of those, 15 (19%) died before 1 year of age, while 16 (20%) infants developed major handicaps by 1.5 years of age (six with cerebral palsy, eight with mental retardation, and two with both cerebral palsy and mental retardation). CAM, present in 44 women, was significantly associated with a reduced risk of death after live birth, with an odds ratio of 0.11 (p = 0.01). Only the presence of such intracranial lesions as periventricular leukomalacia and intraventricular hemorrhage were significantly associated with an increased risk of major handicaps (odds ratio of 11.0, p = 0.04). Adverse outcomes occurred in a similar proportion of infants in groups without CAM (14/37) and with CAM (17/44). However, among infants with adverse outcomes, the number of deaths was significantly higher in the group without CAM (10/14) vs. with CAM (5/12) (p < 0.05). CONCLUSIONS: The presence of CAM may somehow prevent infant death after live birth. Larger studies are required to confirm this phenomenon.     

Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist,in healthy subjects

Summary The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n=6), or 100 mg (n=6) or placebo (n=3) once daily for 7 consecutive days.In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg dl^–1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged.In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg·dl^–1) and last administrations (4.42 mg·dl^–1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576).The findings suggest that DuP-753 posesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.     

Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas

Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs. The aim of the present study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during pancreatic carcinogenesis. Immunohistochemical analysis of DNMT1 in 48 peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (DE), 54 peripheral pancreatic duct epithelia with an inflammatory background (DEI), 188 pancreatic intraepithelial neoplasias (PanIN), and 220 areas of invasive ductal carcinoma from surgical specimens resected from 100 patients, was carried out. The average incidence of DNMT1 immunoreactivity increased progressively from DE to DEI (P = 0.003), from DE and DEI to PanIN (P < 0.0001), among PanIN with different grades of dysplasia (from PanIN I to PanIN II, P = 0.0012), from PanIN to invasive ductal carcinomas (P < 0.0001) and among invasive ductal carcinomas with different grades of histological differentiation (from well or moderately to poorly differentiated adenocarcinomas, P < 0.0001). High-level DNMT1 protein expression in invasive ductal carcinomas was correlated significantly with an advanced t category (P = 0.0224) and an advanced stage (P = 0.0294). Moreover, patients with invasive ductal carcinomas showing high-level DNMT1 protein expression had a poorer outcome (P = 0.0469). These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis.     

A specific COX-2 inhibitor attenuates cell infiltration but does not prolong graft survival in murine cardiac transplantation

COX-2 is a key factor in the progression of inflammation, the effects of a specific COX-2 inhibitor in cardiac transplantation have not yet been elucidated. To test the hypothesis that a COX-2 inhibitor can alter cardiac rejection, we analyzed graft survival using totally allomismatched grafts. Although the COX-2 inhibitor attenuated myocardial cell infiltration, the inhibitor did not prolong survival. We conclude that the COX-2 inhibition may have potential for the suppression of inflammation in cardiac allografts.     

Hepatic Resection for Metastatic Breast Cancer: Prognostic Analysis of 34 Patients

Liver metastasis of breast cancer is considered a generalized disease, and surgical treatment is rarely discussed. Thirty-four patients who underwent 35 hepatectomies for liver metastases of breast cancer between 1985 and 2003 were analyzed. The median interval between the breast surgery and relapse in the liver was 1.9 years (0–20 years). The liver was the first site of recurrence in 25 patients. Fifteen clinicopathologic factors were evaluated using univariate and multivariate analyses to predict survival after hepatic resection. No patients died because of the surgery. The median survival was 36 months (1 month to 20 years). The overall and disease-free 5-year survival rates after hepatectomy for breast metastases were 21% and 16%, respectively. Four patients survived more than 5 years. The presence of extrahepatic recurrence prior to hepatectomy was the only significant prognostic factor according to the analyses, and the 5-year survival rate of patients without extrahepatic disease was 31%. No patient who had hilar lymph node metastasis survived more than 5 years. In the absence of extrahepatic recurrence, surgical resection of liver metastasis from breast cancer can offer an acceptable prognosis and should not be avoided in selected patients.     

A case presenting concurrence of Marfan syndrome, Basedow's disease and Arg353Gln polymorphism-related factor VII deficiency

We report the case of a 48-year-old Japanese man who suffered from Marfan syndrome with severe aortic regurgitation, mitral regurgitation and rapid atrial fibrillation, which were aggravated by hyperdynamic circulatory conditions associated with coexistent Basedow's disease. Furthermore, concurrence of Arg353Gln polymorphism-related factor VII deficiency was discovered at the preoperative assessments. Both of his two brothers suffered from Marfan syndrome; however they had no findings of Arg353Glu polymorphism-related factor VII deficiency or Basedow's disease. After normalization of thyroid function, he had successfully the operations of Bentall procedure: a composite prosthetic graft: replacement of both the ascending aorta and aortic valve, and mitral valve annuloplasty. No specific therapy such as fresh frozen plasma or factor VII replacement therapy was required. He completely returned to his business work 6 weeks after the operation. Concurrence of Marfan syndrome and factor VII deficiency induced by two-hit genomic abnormalities and furthermore Basedow's disease, which significantly compromised the pathophysiological condition of Marfan syndrome, is extremely rare.     

KiBank: a database for computer-aided drug design based on protein-chemical interaction analysis

KiBank is a database for computer-aided drug design and consists of binding affinities and chemical and target protein structures. Each chemical or protein structure with hydrogen atoms added was optimized by energy minimization and stored in PDB or MDL MOL file format, so that the structural data can be directly used for in silico binding studies. To describe the extent of inhibition, the inhibition constant (K(i)) value is used to simplify comparisons of strengths among chemical-protein bindings. As of April 2004, KiBank contained 142 proteins, over 5000 chemicals, and over 6000 binding affinity values that were published in peer-reviewed journals. The binding affinity values are currently mostly for membrane and nuclear receptors but are soon being expanded to other drug targets. KiBank is updated daily and can be accessed on the Web at http://kibank.iis.u-tokyo.ac.jp/at no charge.     

Protective effect of S-allyl-L-cysteine,a garlic compound,on amyloid beta-protein-induced cell death in nerve growth factor-differentiated PC12 cells

Aged garlic extract (AGE) contains several neuroactive compounds, including S-allyl-L-cysteine (SAC) and allixin. We characterized cell death induced by amyloid beta-protein (Abeta), 4-hydroxynonenal (HNE), tunicamycin, an endoplasmic reticulum (ER) stressor, or trophic factor deprivation, and investigated whether and how SAC could prevent this in nerve growth factor (NGF)-differentiated PC12 cells, a model of neuronal cells. Exposure of the cells to amyloid beta-protein(1-40) (Abeta(1-40)) decreased the extent of [3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction activity and loss of neuronal integrity, but these effects were not prevented by Ac-DEVD-CHO, a caspase-3 inhibitor. Simultaneously applied SAC protected the cells against Abeta-induced cell death in a concentration-dependent manner. It also protected them against tunicamycin-induced neuronal death. In contrast, it afforded no protection against cell death induced by HNE and trophic factor deprivation, which is mediated by a caspase-3-dependent pathway. These results suggest that SAC may selectively protect cell death induced by Abeta and tunicamycin, which may be triggered by ER dysfunction in NGF-differentiated PC12 cells.     

Induction of immunologic tolerance to cardiac allograft by simultaneous blockade of inducible co-stimulator and cytotoxic T-lymphocyte antigen 4 pathway

BACKGROUND: Inducible co-stimulator (ICOS) is one of the most recently described members of the CD28 family, and it plays an important role in immune responses. To investigate the role of ICOS in allograft rejection, the authors studied graft survival after cardiac transplantation in mice. METHODS: Hearts from BALB/c mice were transplanted into C3H/He mice. Immunohistochemical staining and flow cytometry were performed. Monoclonal antibody to ICOS or ICOS-immunoglobulin (Ig) was injected intraperitoneally. The authors performed mixed lymphocyte reaction (MLR). RESULTS: ICOS was expressed strongly by graft-infiltrating cells during rejection of the allograft. Blockade of the ICOS pathway with anti-ICOS antibody and ICOSIg significantly prolonged graft survival time relative to that in untreated mice; however, all cardiac allografts were eventually rejected by a single treatment. Treatment with both ICOSIg and cytotoxic T-lymphocyte antigen 4 (CTLA4) Ig induced not only long-term acceptance of the cardiac allograft but also donor-specific tolerance, which was shown by acceptance of donor but not third-party skin. Graft arterial intimal hyperplasia in these cardiac allografts was remarkably less than that in cardiac allografts treated with tacrolimus. Addition of anti-ICOS antibody or ICOSIg to MLR resulted in inhibition of T-cell proliferation. CONCLUSIONS: Inhibition of T-cell proliferation with ICOSIg and CTLA4Ig was more effective than that with ICOSIg alone. Thus, ICOS appears to be an important regulator of T-cell activation, and may be an effective therapy in clinical cardiac transplantation.