Background . Patients with recurrent low grade cytological abnormalities are at increased risk for high grade lesions. We wanted to see whether these patients could be identified by HPV DNA and pap tests. Methods . A prospective study of 663 patients referred for a colposcopy on the basis of ASC‐US or LSIL cytology. High‐risk HPV DNA positivity and cytology were compared with histology. Results . In total 65.6% samples were positive for HC2, and the overall proportion of CIN2+ lesions was 14.6%. No CIN2+ lesions were found in patients testing HC2−, pap−. There were 5/97 (5.2%) high grade lesions, which were HC2‐negative but pap‐positive, including 1 cervical adenocarcinoma in situ . The corresponding histological sections were all positive for p16INK in immunostaining. In further analysis by PCR, 3 samples were positive for HPV DNA. High‐risk HPV type 67, which is not included in the HC2 probe cocktail, was found in 1 case, and 2 cases were HPV positive but could not be typed. One CIN3 and one AIS remained HPV negative. In these 5 cases, the concomitant pap smear showed ASC‐US×1, LSIL×1, HSIL×2 and AGC×1. During 6‐month follow‐up, a relatively high number of CIN2+ (28/557, 5.0%) emerged from the non‐CIN–CIN1 group. Conclusions . The HC2 test or pap test alone were not sensitive enough to detect all CIN2+ lesions. A relatively high number of CIN2+ cases emerged from the non‐CIN–CIN1 group after 6 months. Adequate follow‐up of patients with mild cytological abnormalities, including a repeat pap smear taken during colposcopy and control at 6 months is underscored. Combination of hrHPV DNA and pap test should be considered, since it had high negative predictive value.

Addition of rituximab (R) to chemotherapy (immunochemotherapy) has significantly improved the outcome of B-cell lymphoma patients. However, responses are still unpredictable due to heterogeneous nature of these diseases. The aim of this study was to determine if differences in gene expression in follicular lymphoma (FL) and mantle cell lymphoma (MCL) tissue correlate with outcome in response to immunochemotherapy. 24 FL and 15 MCL patients were classified into complete (CR) or other responders after immunochemotherapy, and genes capable of separating the groups were identified using oligonucleotide-based microarray and supervised learning technique. One of the transcripts associated with increased CR rates in FL was signal transducer and activator of transcription 5a (STAT5a), a transcription factor and a mediator of cellular responses after cytokine stimulation. According to Kaplan Meier estimates, high STAT5a mRNA levels were associated with better progression free survival (PFS). Immunohistochemical analyses of FL samples demonstrated that predominant STAT5a activity localized to resident T-lymphocytes but only 20% of the samples were STAT5a positive. In a validation set of 79 FL patients, a better PFS was observed among patients with high STAT5a protein expression. In contrast, high STAT5a mRNA and protein levels were associated with poor outcome in MCL patients. In the MCL tissue, STAT5a expression localized to nonmalignant T-lymphocytes but also to tumor cells. In comparison to FL, T-lymphocytes were more uniformly positive for STAT5a. In sum, the data show that nonmalignant tumor cells have a profound prognostic impact both in FL and MCL, but also suggest that depending on the lymphoma subtype, the activity of a certain signaling pathway can have either positive or negative consequences on the survival of immunochemotherapy-treated lymphoma patients.

Human NK cells are sensitive to the exogenous toxic compound valinomycin. This toxin, produced by Streptomyces griseus in moisture damaged buildings, induces apoptosis by dissipating the membrane potential in mitochondria. In this paper, we show that valinomycin-induced apoptosis involves two different pathways in human NK cells: the predominant one is caspase-3 independent and the other caspase-3 dependent. Resting human NK cells were found to contain high amounts of active caspase-3 as compared to the T cells in which high caspase-3 activity has been shown only after stimulation. Exposure to valinomycin did not alter the caspase-3 activity of human NK cells but induced nucleosomal fragmentation of DNA. General caspase inhibitor, Z-VAD-FMK, inhibited completely the caspase-3 activity, reduced DNA cleavage but did not prevent the spontaneous or valinomycin-induced apoptosis of NK cells. The endogenous high caspase-3 had only a slight effect on the major functions of human NK cells, i.e. cytotoxicity or γ-IFN production, giving us a reason to suspect that the biological role of caspase-3 in NK cells could be the elimination of potentially harmful NK clones through apoptosis.

A pulp suspension flowing in a pipe has a tendency to form a profile: The properties of the pulp vary significantly in a cross-section of the flow. This causes problems both in online-measurements and sampling. The importance of representative sampling is further emphasized by the fact that samples taken are often used as reference in calibration of measurement instruments. The problem of representative sampling and the variation of quality in a pulp flow were studied using equipment with which it was possible to take samples from different depths in the flow and thus determine the variations. Experimental testing was conducted in different process conditions and with different pulp types. The results of the tests showed that the quality variations in a pulp flow were more profound than initially thought: Several pulp properties have significant profiles within the flow that depend on the type of the pulp and the flow conditions. The variation of pulp properties is large enough to somewhat affect all measurements made from the flow in question. The findings of the study suggest new guidelines for sampling and installing instrumentation when a pulp suspension flow is measured.

SUMMARYThe lipophilic toxin, cereulide, emitted by emetic food poisoning causing strains of Bacillus cereus, is a powerful mitochondria toxin. It is highly lipophilic and rapidly absorbed from the gut into the bloodstream. We tested how this toxin influences natural killer (NK) cells, which are important effectors in defence against infections and malignancy. Cereulide inhibited cytotoxicity and cytokine production of natural killer cells, caused swelling of natural killer cell mitochondria, and eventually induced natural killer cell apoptosis. The suppressive effect on cytotoxicity was fast and toxic concentration low, 20–30 μg/l. As the emesis causing concentration of cereulide is around 10 μg/kg of total body mass, our results suggest that emesis causing or even lower doses of cereulide may also have a systemic natural killer cell suppressive effect.

IFN-gamma a product of NK and T cells, is a key cytokine contributing innate and adaptive immunity. IFN-gamma production is induced via direct cell-cell contacts with APC and IFN-gamma -producing cells or by cytokines, During microbial infections macrophage-derived IFN-alpha, IL-12, and IL-18 enhance IFN-gamma production and Th1 response Here we show that IFN-a in combination with IL-18 very efficiently induces IFN-gamma expression also in primary, nonactivated NK cells and in. NK-92 cell line. Comparison of the kinetics of IFN-gamma mRNA expression in nonactivated NK cells, NK-92 cells and activated T cells stimulated with IFN-alpha or IL-12 revealed that, although both of these cytokines directly up-regulate IFN-gamma mRNA expression, its levels remain elevated much longer with IL-12 stimulation. in both NK cells and T cells, Stat4 is known to be critical in IL-12 and IFN-alpha signaling. We show that Stat4 activation is transient in cells: stimulated with IFN-cc, whereas IL-12 induces more long-lasting activation of the transcription factor. This prolonged activation of IFN-gamma gene by IL-12 may result in more efficient IFN-gamma production. compared: to that of IFN-alpha. Our results demonstrate that IFN-alpha and IL-48 are important innate cytokines in inducing NK cell. IFN-gamma production.

The incidence of diabetes is increased in patients with pancreatic cancer, but the mechanisms underlying this association are not clear. Alterations in [beta ]-cell function, such as formation of amyloid from excessive production of amylin and reduced expression of GLUT2, have been suggested to be possible mechanisms. We compared in vivo secretory responses of amylin and insulin (n = 37) and expression of GLUT2 in pancreata (n = 10) obtained at surgery between diabetic and nondiabetic patients with and without pancreatic tumors. Fourteen had pancreatic adenocarcinoma, 7 had diabetes (duration 6 [plusmn] 3 years) and a pancreatic tumor, 8 had type 2 diabetes (duration 6 [plusmn] 2 years), and 8 were normal subjects. First (0 to 10 minutes) and second (10 to 120 minutes) phase insulin and amylin secretion were characterized using the hyperglycemic clamp technique. Both amylin and insulin concentrations followed a biphasic pattern in nondiabetic subjects. In nondiabetic patients with pancreatic cancer, total, as well as nonglycosylated amylin concentrations, were increased compared with nondiabetic subjects without pancreatic cancer. Both first- and second-phase plasma amylin and serum immunoreactive insulin concentrations were low in all patients with diabetes, ie, both in type 2 diabetes and in those patients with diabetes and pancreatic tumors. At surgery, specimens were obtained for characterization of GLUT2 expression in [beta ] cells, which was unaltered in nondiabetic (n = 7) and diabetic (n = 3) patients. Amyloid staining was similarly negative in diabetic and nondiabetic pancreata independent of pancreatic carcinoma. In conclusion, plasma amylin, but not insulin concentrations, are increased in nondiabetic patients with pancreatic cancer, but low in all patients with diabetes. These data support the potential of using an increase in the ratio of circulating amylin to insulin as a marker for pancreatic cancer in nondiabetic patients.

Three consecutive patients with no apparent immunodeficiency who had frequent intraoral herpes simplex type 1 recurrences, a rare complication of herpes simplex virus infection, were found to have a total deficiency of either the A or B isotype of the complement component C4 and to be homozygous for the studied HLA antigens. A combination of HLA homozygosity, which may lead to impaired T cell recognition of viral peptides, and deficiency in the classical complement pathway, which can compromise virus neutralization, may predispose to severe and frequent herpes simplex virus infections.

Conference Abstract| October 01 2000 IFN-α and IL-12 differentially regulate IFN-γ gene expression in human NK and T cells S. Matikainen; S. Matikainen 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar A. Paananen; A. Paananen 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar M. Miettinen; M. Miettinen 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar M. Kurimoto; M. Kurimoto 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar T. Timonen; T. Timonen 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar I. Julkunen; I. Julkunen 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar T. Sareneva T. Sareneva 1National Public Health Institute, FIN-00300 Helsinki, Finland2Haartman Institute, FIN-00014 University of Helsinki, Finland3Fujisaki Institute, Hayashibara Biochemical Laboratories, Fujisaki, Okayama 702–2006, Japan Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2000) 28 (5): A257. https://doi.org/10.1042/bst028a257c Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation S. Matikainen, A. Paananen, M. Miettinen, M. Kurimoto, T. Timonen, I. Julkunen, T. Sareneva; IFN-α and IL-12 differentially regulate IFN-γ gene expression in human NK and T cells. Biochem Soc Trans 1 October 2000; 28 (5): A257. doi: https://doi.org/10.1042/bst028a257c Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2000 Biochemical Society2000 Article PDF first page preview Close Modal You do not currently have access to this content.

ABSTRACTStreptomyces griseusstrains isolated from indoor dust have been shown to synthesize valinomycin. In this report, we show that human peripheral blood lymphocytes treated with small doses (30 ng ml−1) of pure valinomycin or high-pressure liquid chromatography-pure valinomycin fromS. griseusquickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml−1) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml−1dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte-macrophage colony-stimulating factor and gamma interferon (IFN-γ) production by NK cells. However, IFN-γ production induced by a combination of IL-15 and IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect of the cytokine combination against valinomycin. Thus, valinomycin in very small doses may profoundly alter the immune response by reducing NK cell cytotoxicity and cytokine production.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles1,2,3. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland4 and Japan, with an estimated population prevalence of 2×10−6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein7 (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells8. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules7,9. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.

Purpose: To study short-term events in the mechanism of action of BCG with an emphasis on the interaction between BCG and T24 cell line cells.Materials and Methods: Peripheral blood mononuclear cells (PBMNC) or/and several tumor cell lines were incubated with BCG (Oncotice) using various clinical and subclinical BCG concentrations.Results: 3 h BCG incubation of PBMNC at 10(7) - 5*10(5) CFU/ml., followed by a 4 h cytotoxicity test, resulted in a significant augmentation of cytotoxicity of PBMNC against T24 cells, and the augmentation was almost significant at 10(5) CFU/ml. Overnight BCG incubation of PBMNC further augmented that cytotoxicity at all concentrations down to 10(4) CFU/ml, The minimum overall time (incubation with BCG + cytotoxicity test), where stimulation of PBMNC could be detected, was only 4 h. The BCG enhanced cytotoxicity of PEMNC could be demonstrated against all the tested cell line cells in a 4 h cytotoxicity test by using a preceding overnight BCG incubation of PBMNC, and against the majority of the cell lines by using a preceding 3 h BCG incubation of PBMNC. No convincing evidence was obtained to support the hypothesis that BCG should be first processed by T24 cells to make these cells more susceptible to cell mediated lysis by PBMNC.Conclusions: Clinical and subclinical concentrations of BCG are directly stimulatory to PBMNC, which become, in a minimum time of a few hours, more capable of killing tumor cells, without a need for preceding interaction between. BCG and tumor cells.

The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat fibroblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of efficiently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing fibroblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target fibroblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein E1B19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing fibroblasts were more sensitive to the cytolytic effects of isolated NK cell-derived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.