Word use in first-person accounts of schizophrenia.

BACKGROUND: Language use is often disrupted in patients with schizophrenia; novel computational approaches may provide new insights. AIMS: To test word use patterns as markers of the perceptual, cognitive and social experiences characteristic of schizophrenia. METHOD: Word counting software was applied to first-person accounts of schizophrenia and mood disorder. RESULTS: More third-person plural pronouns ('they') and fewer first-person singular pronouns ('I') were used in schizophrenia than mood disorder accounts. Schizophrenia accounts included fewer words related to the body and ingestion, and more related to religion. Perceptual and causal language were negatively correlated in schizophrenia accounts but positively correlated in mood disorder accounts. CONCLUSIONS: Differences in pronouns suggest decreased self-focus or perhaps even an understanding of self as other in schizophrenia. Differences in how perceptual and causal words are correlated suggest that long-held delusions represent a decreased coupling of explanations with sensory experience over time.

Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics.

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is reduced by anti-inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. OBJECTIVE: We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. METHODS: This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12-weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). RESULTS: A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (≥ 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma.

Prevalence and impact of rhinitis in asthma. SACRA, a cross-sectional nation-wide study in Japan.

BACKGROUND: Asthma and rhinitis are common co-morbidities everywhere in the world but nation-wide studies assessing rhinitis in asthmatics using questionnaires based on guidelines are not available. OBJECTIVE: To assess the prevalence, classification, and severity of rhinitis using the Allergic Rhinitis and its Impact on Asthma (ARIA) criteria in Japanese patients with diagnosed and treated asthma. METHODS: The study was performed from March to August 2009. Patients in physicians' waiting rooms, or physicians themselves, filled out questionnaires on rhinitis and asthma based on ARIA and Global Initiative for Asthma (GINA) diagnostic guides. The patients answered questions on the severity of the diseases and a Visual Analog Scale. Their physicians made the diagnosis of rhinitis. RESULTS: In this study, 1910 physicians enrolled 29,518 asthmatics; 15,051 (51.0%) questionnaires were administered by physician, and 26,680 (90.4%) patients were evaluable. Self- and physician-administered questionnaires gave similar results. Rhinitis was diagnosed in 68.5% of patients with self-administered questionnaires and 66.2% with physician-administered questionnaires. In this study, 994 (7.6%) patients with self-administered and 561 (5.2%) patients with physician-administered questionnaires indicated rhinitis symptoms on the questionnaires without a physician's diagnosis of rhinitis. Most patients with the physician's diagnosis of rhinitis had moderate/severe rhinitis. Asthma control was significantly impaired in patients with a physician's diagnosis of rhinitis for all GINA clinical criteria except exacerbations. There were significantly more patients with uncontrolled asthma as defined by GINA in those with a physician's diagnosis of rhinitis (25.4% and 29.7%) by comparison with those without rhinitis (18.0% and 22.8%). CONCLUSION: Rhinitis is common in asthma and impairs asthma control.

Effect of oxaliplatin-based chemotherapy on chemosensitivity in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: proof-of-concept study.

BACKGROUND: Chemosensitivity testing, including collagen gel droplet-embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision-making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer. METHODS: All patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease-free (DFS) survival. RESULTS: Of 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin-based regimen. Mean(s.d.) follow-up was 23·4(22·9) months. The median overall survival of all patients was 19·0 (i.q.r. 5·7-36·1) months, with a progression-free survival time of 10·1 (4·5-17·0) months. Patients who received oxaliplatin-based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin-based NACT (P = 0·046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18·8 versus 18·1 months; P = 0·835). The choice of HIPEC agents in patients who received oxaliplatin-based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20·6 (10·9-24·8) versus 19·0 (10·5-34·6) months, P = 0·811; DFS 6·6 (2·8-25·7) versus 9·3 (4·1-13·9) months, P = 0·191). CONCLUSION: Patients who had oxaliplatin-based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation.

3-Nitrotyrosine inhibits fibroblast-mediated collagen gel contraction and chemotaxis.

Reactive nitrogen species induce tissue inflammation and nitrate tyrosine residues of various kinds of proteins. Recent studies have established that the free amino acid form of 3-nitrotyrosine induces cytotoxity and growth inhibition and alters the cellular function in cultured cells. The aim of this study was to evaluate whether 3-nitrotyrosine could affect tissue remodelling in fibroblasts. To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the fibroblast-mediated contraction of floating gels and chemotaxis towards fibronectin. In addition, the ability of fibroblasts to release fibronectin, transforming growth factor (TGF)-beta1, fibronectin and vascular endothelial growth factor (VEGF) was assessed. 3-Nitrotyrosine significantly inhibited gel contraction (p<0.01) compared with control and this inhibition was abolished by nitric oxide synthase (NOS) inhibitor. 3-Nitrotyrosine did not affect TGF-beta1 and VEGF but significantly decreased fibronectin release (p<0.01) into the media. 3-Nitrotyrosine significantly inhibited chemotaxis towards fibronectin through suppression of alpha(5)beta(1) integrin expression (p<0.01). NOS inhibitor also reversed 3-nitrotyrosine-inhibited chemotaxis (p<0.01). Finally, 3-nitrotyrosine enhanced the expression of the inducible type of NOS (p<0.01) and nitric oxide release (p<0.01) through nuclear factor-kappaB activation. These results suggest that the free amino acid form of 3-nitrotyrosine can affect the tissue repair process by modulating nitric oxide production.

Matrix metalloproteinase 2 improves the transplanted adipocyte survival in mice.

BACKGROUND: Fat tissue is a common material for autologous transplantation in plastic and reconstructive surgery. Basic fibroblast growth factor (bFGF) ameliorates the fat graft survival. A transplantation model has shown the gene expression of matrix metalloproteinases (MMPs) to increase in adipocytes. The aim of this study is to investigate the role of MMPs in the amelioration of survival by bFGF. MATERIALS AND METHODS: 3T3-L1 adipocytes were incubated with or without 10 microg mL(-1) bFGF for 8 h in the presence or absence of the MMP inhibitor GM6001, vascular endothelial growth factor (VEGF), MMP-2 or anti-bFGF antibody to study the effect of bFGF on MMP-2 mRNA expression, MMP-2 activity, fat accumulation or 2-deoxyglucose uptake. Collagen sheets containing l x l0(7) adipocytes with or without bFGF in the presence or absence of GM6001 were subcutaneously transplanted into mice, and the appearance, histology, mRNA expression and fat accumulation of the grafts were analysed 4 weeks after transplantation. RESULTS: The MMP-2 expression was drastically induced by bFGF among MMPs in 3T3-L1 adipocytes. MMP-2 accelerated fat accumulation, peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA expression, and glucose uptake to an extent similar to those induced by bFGF, respectively. The bFGF-induced increases were inhibited by the blocking of MMP-2. The transplantation of adipocytes into mice showed that bFGF ameliorates the appearance and fat accumulation, as well as mRNA expression in grafts. These effects were almost or partly inhibited by a MMP blockade. CONCLUSIONS: MMP-2 may be involved in the mechanism by which bFGF ameliorates the survival of fat grafts.

Neuropsychological impairment and decreased regional cerebral blood flow by interferon treatment in patients with chronic hepatitis: a preliminary study.

It is well known that interferon (IFN) has various side effects including neuropsychiatric complications such as depression. We examined the relationship between neuropsychological impairment and regional cerebral blood flow (CBF) in chronic hepatitis patients treated with and without IFN-alpha. Eight patients with chronic hepatitis participated in this study. Four patients were treated with IFN-alpha (IFN group) and 4 patients were not treated (control group). The entire IFN group and half of the control group were diagnosed with hepatitis C and the rests of the control group had hepatitis B. Neuropsychological tests were conducted. The Self-Rating Depression Scale and the State-Trait Anxiety Inventory were also completed by the subjects. In addition, cerebral single photon emission computed tomography (SPECT; 3DSRT) was performed in all patients. Neuropsychological tests and SPECT were performed in the IFN group 2 months after starting IFN treatment and in the control group 2 months after starting follow-up. A significant reduction of regional CBF in the IFN group was observed in two cerebral regions (lt-angular and lt-temporal region) (P < 0.05), which have reported associations with memory and language function. In addition, the Auditory-Verbal Learning Test (AVLT), a measure of memory function, showed a decreased tendency in the IFN group. A decrease of regional CBF by IFN treatment was shown, suggesting that a decrease of regional CBF may contribute to the neuropsychological impairment by IFN treatment.

Correlation of serum pepsinogens and gross appearances combined with histology in early gastric cancer.

The correlation between serum pepsinogen (PG) levels and the gross types was investigated in 128 consecutive patients with early gastric cancer. Although there was no significant difference in age, gender, cancer location, or cancer depth among gross appearances, the distribution of histological type was significantly different between polypoid and depressed cancers: all polypoid cancers except one were intestinal type, whereas nearly a third of depressed cancers were diffuse type. All the patients in whom Helicobacter pylori status was investigated had Helicobacterpylori infection. Combination of gross appearances and histology (polypoid cancer with intestinal type, depressed cancer with intestinal type and depressed cancer with diffuse type) showed a clear difference in distribution of serum PG levels and a ratio between levels of PG I and PG II (I/II ratio). In polypoid cancer with intestinal type, a PG I level and a I/II ratio were significantly lower than those of the others. In depressed cancer with diffuse type, PG I and PG II levels were significantly higher. These findings revealed that backgrounds such as intragastric acidity and extent of gastric atrophy might differ among early gastric cancers with different morphology and histology.

Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase.

TNP470, a derivative of fumagillin, suppressed in vivo growth of human PLC/PRF/5 hepatoma and ameliorated cachexia of hepatoma-bearing mice. These in vivo effects were associated with reductions in microvessel and macrophage counts. In in vitro experiments, TNP470 inhibited the growth and migration of human hepatoma and bovine vascular endothelial (VE) cells. TNP470 did not inhibit the production of VE growth factor by the hepatoma, which suggests that this compound acts directly on VE cells in vivo. In contrast, TNP470 inhibited the production of leukemia inhibitory factor, which may be related to the amelioration of cancer cachexia. TNP470 induced apoptosis and enhanced the expression of beta-galactosidase, a biomarker of senescence, which was partly mimicked by a nitric oxide (NO) donor S-nitroso-N-acetyl penicillamin. TNP470 inhibited myristoylation and membrane translocation of NO synthase and increased the cellular content of NO synthase and production of NO. Therefore, it is suggested that the actions of TNP470 are mediated, at least in part, through the inhibition of membrane translocation of biologically active proteins.

DNA methylation and expression of the rat pepsinogen gene in embryonic, adult, and neoplastic tissues.

The relationship between methylation and expression of rat pepsinogen 1 (Pg1) genes was investigated in various tissues. On Northern blotting with a Pg1 complementary DNA probe, Pg1 mRNA was detected only in the glandular stomach of normal rats. Methylation analysis with Msp1/HpaII and Hha1 revealed tissue specific methylation patterns of Pg1 genes with less methylated in the stomach than in other normal tissues not expressing the genes. During stomach development, there was a progressive increase in the Pg1 mRNA level that almost coincided with change in the mucosal pepsinogen level and progressive demethylation after the onset of transcription. Thus, there was an inverse correlation between methylation and expression of Pg1 genes, suggesting a role of DNA methylation in Pg1 gene regulation during normal differentiation, although not its primary role in gene activation. There was no detectable Pg1 mRNA in either primary or transplanted stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine. The methylation patterns of Pg1 genes were different from those of normal tissues that expressed the gene and of those that did not and no simple correlation was observed between methylation and expression of Pg1 genes. This result is consistent with a previous finding that DNA methylation is deranged in tumor cells.

Differentially expressed MHC class II-associated invariant chain in rat stomach pyloric mucosa with N-methyl-N-nitro-nitrosoguanidine exposure.

Administration of N-methyl-N'-nitro-N-nitrosoguanidine, a glandular stomach carcinogen, at the concentration of 100 microg/ml in drinking water for 8 days induced the appearance of a MHC class II-associated invariant chain in the target organ of stomach pyloric mucosa of male Lewis rats. The up-regulation of the MHC class II-associated invariant chain was revealed by fluorescent differential display analysis, reverse transcription-PCR, Northern blot, and histochemical staining. The appearance of MHC class II and MHC class I was also demonstrated by reverse transcription-PCR and Northern blot. The results suggest the involvement of MHC-controlled immune reactions in chemically-induced stomach carcinogenesis.

Involvement of dendritic cell response to resistance of stomach carcinogenesis caused by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

The involvement of immune response in the resistance of chemically induced stomach cancer was studied in a resistant rat strain (Buffalo) and a sensitive rat strain (ACI). Groups of 10 male Buffalo and ACI rats, 6 weeks of age, were given drinking water with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; 100 mg/l) for 14 days. Total RNA was isolated from the stomach pyloric mucosa from five rats, and cDNA was prepared with reverse transcriptase. Tissue sections of the stomach pyloric mucosa from five rats were stained with antibodies recognizing molecules expressed by various immune cells. Reverse transcription-PCR (RT-PCR), competitive RT-PCR, and Northern blot demonstrated that the expression of MHC class II group genes [MHC class II, MHC class II-associated invariant chain (Ii), CD4 and IgM (B cell marker)], MHC class I group genes (MHC class I and CD8), B7-1 (costimulator on dendritic cells), and CD28 (receptor to B7 on T cells) in the pyloric mucosa was elevated by MNNG in both rat strains but was elevated to a 4-7-fold greater extent in Buffalo rats than in ACI rats. These genes were scarcely expressed in control rats. Histochemical antibody staining after MNNG exposure showed a greater number of cells stained with monoclonal antibody to Ii, OX-62 (dendritic cell marker), and ED-1 (dendritic cell and macrophage common marker) in the interstitial tissue of the pyloric mucosa of Buffalo rats compared with ACI rats. Cell proliferation, as measured by 5-bromo-2-deoxyuridine (BrdUrd)-labeling indices, revealed the presence of BrdUrd-labeled cells only among epithelial cells in the proliferative zone; cells in the interstitial tissue were not labeled with BrdUrd. The results suggest the involvement of dendritic cell response in the resistance to the MNNG induction of stomach carcinogenesis in rats.

Should total gastrectomy and total colectomy be considered for selected patients with severe tumor burden of pseudomyxoma peritonei in cytoreductive surgery?

BACKGROUND: This study aims to evaluate the safety and efficacy of cytoreductive surgery (CRS) including total gastrectomy and total colectomy in selected pseudomyxoma peritonei (PMP) patients with entire stomach and colon covered by mucinous tumor. METHODS: A total of 48 patients received this extensive treatment between January 2006 and January 2014. The main focus of this study was survival after CRS as well as perioperative morbidity and mortality. RESULTS: Twenty-eight patients were male, and median age was 52.5 years. Median peritoneal cancer index was 33. Complete cytoreduction was achieved in all 48 patients, and 26 patients received hyperthermic intraperitoneal chemotherapy (HIPEC). Until last follow-up, the estimated median survival after CRS was 54.0 months (95% CI 36.5-71.6 months). The 1-, 2-, 3-, and 5-year survival rates were 91.7%, 81.3%, 70.1%, and 48.6%, respectively. Histology was significantly associated with survival (P = 0.020). The median disease-free survival was 32.0 (95% CI 25.7-38.3) months. HIPEC (P = 0.048) and histology (P = 0.002) was significantly associated with disease-free survival after CRS. Overall Grade 3-5 complications occurred in 18 (37.5%) patients with mortality of 2.1%. For patients who received surgery over 6 months, they could gradually have an acceptable quality-of-life similar as other patients receiving ordinary CRS and HIPEC. CONCLUSION: CRS including total gastrectomy and total colectomy can be performed in experienced specialized institutions as a feasible option to achieve complete cytoreduction with acceptable safety in selected PMP patients with stomach and colon covered by mucinous tumor. Perioperative management should be carried out cautiously to decrease and avoid complications.

Kinetics of v-src-induced epithelial-mesenchymal transition in developing glandular stomach.

The oncogene function in primary epithelial cells is largely unclear. Recombination organ cultures in combination with the stable and transient gene transfer techniques by retrovirus and electroporation, respectively, enable us to transfer oncogenes specifically into primary epithelial cells of the developing avian glandular stomach (proventriculus). In this system, the epithelium and mesenchyme are mutually dependent on each other for their growth and differentiation. We report here that either stable or transient expression of v-src in the epithelium causes budding and migration of epithelial cells into mesenchyme. In response to the transient expression of v-Src or a constitutive active mutant of MEK, we observed immediate downregulation of the Sonic hedgehog gene and subsequent elimination of E-cadherine expression in migrating cells, suggesting the involvement of MAP kinase signaling pathway in these processes. v-src-expressing cells that were retained in the epithelium underwent apoptosis (anoikis) and detached from the culture. Continuous expression of v-src by, for example, Rous sarcoma virus (RSV) was required for the epithelial cells to acquire the ability to express type I collagen and fibronectin genes (mesenchymal markers), and finally to establish the epithelial-mesenchymal transition. These observations would partly explain why RSV does not apparently cause carcinoma formation, but induces sarcomas exclusively.

Induction of two K+ currents by complement component C5a in mouse macrophages.

Puff application of complement component C5a (5 x 10(-8) M) onto peritoneal macrophages from thioglycollate-stimulated mice induced two kinds of outward current at a holding potential of -68 mV, a slowly-rising sustained outward current and a spike-like transient outward current. Quinidine (2 x 10(-4) M) and tetraethylammonium (10(-2) M) partially suppressed both types of outward current. Charybdotoxin (2 x 10(-6) M) markedly suppressed the spike-like outward current. Reversal potentials in bath solutions of different external K+ concentrations were dependent only on K+ concentrations. The transient current was not suppressed in Ca(2+)-free EGTA-containing solution, but was completely abolished in BAPTA-containing solution. One kind of single channel responding to C5a, which has a single-channel conductance of 29 pS, was recorded from cell-attached patches. These results suggest that C5a activates a Ca(2+)-dependent and another type of K+ current.

Partial purification and characterization of glycylprolyl dipeptidyl aminopeptidase in porcine pancreas.

This study reports the presence of glycylprolyl dipeptidyl aminopeptidase in porcine pancreas, and its partial purification and some properties. Crude enzyme preparation was obtained by extraction from acetone-dried powder of the pancreas at pH 7.6. For solubilization of enzyme, freezing and thawing were carried out. Crude enzyme extract was fractionated with ammonium sulfate precipitation, gel filtration on Sephadex G-200 column and ion-exchange chromatography on DEAE-cellulose. Partially purified enzyme showed 2897-folds purification. The enzyme activity on polyacrylamide gel electrophoresis showed good agreement with a main protein band stained with Coomassie brilliant blue. Molecular weight of this enzyme from the pancreas was estimated to be 300000 by gel filtration on Sephacryl S-300 column. Optimum pH was between 8.5 and 9.0, and Km value for glycylproline-p-nitroanilide tosilate was 0.33 mM. This enzyme from the pancreas was a serine enzyme and was relatively stable to heat at 60 degrees C for 10 min.

Linkage disequilibrium in isolated populations of Drosophila melanogaster.

In order to test the interaction effect of overdominance and random genetic drift on the formation of linkage disequilibria under the condition of multiplicative gene action, linkage disequilibria between isozyme genes, inter se, and between polymorphic inversions and isozyme genes were tested for the second chromosomes of Drosophila melanogaster sampled from two isolated Pacific islands and one locality of the northern district of the mainlands of Japan. The effective sizes of these populations were known to be approximately 3,000 to 6,000 on the basis of the allelism rate of lethal chromosomes and their frequencies. The following results were obtained: (1) No linkage disequilibrium considered to be induced by epistasis, including the interaction between overdominance and random genetic drift, was detected. (2) Nonrandom association between polymorphic inversions and isozyme genes that are included in the inversions or located in the adjacent region outside the inversions was detected. (3) On the basis of the comparison of chi (2) values, indicating the magnitudes of linkage disequilibrium, between the present isolated populations and the Raleigh, N.C., population (Mukai et al. 1974, 1977), the characteristics of the isolated populations and the nature of these linkage disequilibria are discussed.

Changes in serum and red blood cell membrane lipids in patients treated with interferon ribavirin for chronic hepatitis C.

One of the side effects by interferon ribavirin (I/R) treatment is haemolytic anemia, causing some patients to discontinue I/R treatment. The exact mechanism of I/R-induced anemia is unknown. The aim of this study is to evaluate the effects of I/R treatment on the serum lipid and red blood cell (RBC) membrane lipid profiles of patients with chronic hepatitis C (CHC) and the association between changes of RBC membrane lipids and haemolytic anemia by I/R treatment. Fourteen patients with CHC were treated with I/R and their serum lipid profiles were studied. In addition, in seven of the 14 patients, the RBC membrane lipid profiles were analysed. In the RBC membrane lipid composition, the total cholesterol, total phospholipids and cholesterol/phospholipids (C/PL) ratio were significantly increased. Phosphatidylcholine (PC) and the phosphatidylcholine/ sphingomyelin (PC/SM) ratio were significantly decreased and other phospholipid fractions were significantly increased. Changes in the serum lipids and RBC membrane lipid profiles of patients with CHC treated with I/R were shown. Especially, a decrease in the RBC deformability and membrane fluidity by changes in these RBC membrane lipids was supposed and it is suggested that those changes may result in haemolytic anemia by I/R treatment.

Autologous dendritic cells or cells expressing both B7-1 and MUC1 can rescue tumor-specific cytotoxic T lymphocytes from MUC1-mediated apoptotic cell death.

We attempted to induce MUC1-specific cytotoxic T lymphocytes (CTLs) by mixed-lymphocyte tumor cell culture (MLTC) using two allogeneic MUC1-positive cancer cell lines, T-47D and MCF7. The induced CTLs exhibited MUC1-specific cytotoxicity 16 days after the initial stimulation. However, these CTLs underwent apoptotic death within 16 days. To examine whether the B7-1 molecule is required for the expansion of the responder cells, a B7-1(+)/MUC1(-) cell line was transfected with MUC1 cDNA, and the resulting transfectant was employed as a stimulator in an autologous MLTC. The CTLs exhibited MUC1 specificity but also continued to propagate. In parallel, autologous dendritic cells (DCs) were added to an MLTC containing peripheral blood lymphocytes (PBLs) and the allogeneic MUC1-positive stimulators. The CTLs demonstrated MUC1 specificity and their number increased. This suggests that the B7-1 molecule is required for rescuing CTLs from MUC1-mediated apoptotic death, but not for the induction of MUC1-specific responsiveness. This strategy to obtain the CTLs efficiently may be useful for adoptive immunotherapy against cancer.

Possible involvement of urokinase-type plasminogen activator release from human peripheral blood lymphocytes in the pathophysiology of chronic allograft nephropathy.

BACKGROUND: Little is known of the fibrinolytic host immune mechanisms responsible for induction of chronic allograft nephropathy (CAN), defined as a loss in glomerular filtration rate (GFR) caused by tubular atrophy and interstitial fibrosis, often with fibrous intimal thickening in the small arteries. However, chronic rejection has been reported to be associated with decreased activity of the fibrinolytic system. In our previous study, [Deamino-Cys1, D-Arg8]-vasopressin (dDAVP) induced urokinase-type plasminogen activator (uPA) release from human peripheral T lymphocytes via arginine vasopressin (AVP) V2-receptor-mediated reaction enhanced by an AVP V1-receptor antagonist. Therefore, we examined the level of uPA released from peripheral T lymphocytes by AVP in transplant patients with CAN in comparison with control groups. PATIENTS AND METHODS: In this study, we evaluated in vitro uPA releasing activity of lymphocytes obtained from renal allograft patients with well-functioning grafts (n = 9), CAN (n = 5), or acute rejection episodes (n = 5) compared with lymphocytes from healthy volunteers with normal renal function (n = 12) or patients with renal insufficiency (n = 5). RESULTS: Lymphocytes prepared from patients with chronic allograft nephropathy showed a significantly lower increase in uPA release induced by the combination of the V1-receptor antagonist and dDAVP compared with those from the other groups. CONCLUSION: This finding suggested that a decrease in uPA release from human peripheral blood lymphocytes by AVP-related peptides may be potentially involved in the pathophysiology of CAN.