Regional mapping of RBP4 to 10q23→q24 and RBP1 to 3q21→q22 in man

The human gene coding for RBP4 has been assigned to 10q2324 using a panel of somatic cell hybrids and in situ hybridization experiments. The mapping of the human RBP1, previously assigned by our group to chromosome 3 using a panel of somatic cell hybrids, was restricted to the region 3q2122 using in situ experiments and Southern blots of genomic DNA from a hybrid retaining a portion of chromosome 3.R.F. is recipient of a Research Grant from A.I.R.C.     

Expression of cyclooxygenase-2 in osteosarcoma of bone.

Several studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in human malignancies, where it produces high levels of prostaglandins and contributes to tumor growth. In this study we have analyzed the expression of COX-2 in a series of 48 skeletal osteosarcomas of different subtypes by immunohistochemistry. In addition, we examined the effects of the specific COX-2 inhibitor Celecoxib on the growth of the human osteosarcoma cell line SaOS-2. Immunoreactivity for COX-2 was observed in 39 out of 48 tumors (81.2%), 30 (76.9%) of which showed a moderate or diffuse immunostaining. Considering the group of 42 primary osteosarcomas, COX-2 immunoreactivity was significantly higher in high grade osteosarcomas, where moderate or diffuse expression was detected in 23 out of 32 cases (71.8%), than in low grade osteosarcomas, where moderate or diffuse expression was detected in 2 out of 10 cases (20%) (P = 0.008, Fisher exact test). In addition, low COX-2 expression was always associated with a good response to chemotherapy (5 out of 5 cases), whereas moderate or diffuse COX-2 expression was associated with a good response in 11 out of 20 cases (55%) (P = 0.12, Fisher exact test). In SaOS-2 osteosarcoma cells, which express COX-2, treatment with Celecoxib determined inhibition of cell proliferation and induction of apoptosis. These results indicate that COX-2 is expressed at high levels in high grade osteosarcomas and support the use of COX-2 inhibitors to improve both the tumor response to chemotherapy and the outcome of osteosarcoma patients.     

Protein kinase A activity in platelets from patients with bipolar disorder

BACKGROUND: Abnormal levels of protein kinase A (PKA) were found in patients with bipolar disorder (BD). Since altered levels are generally accompanied by functional modifications, the purpose of this study was to investigate PKA activity in patients with BD. METHODS: PKA activity was assessed in platelets from 20 drug-free bipolar patients and 19 controls. RESULTS: The cAMP-stimulated PKA activity was significantly increased in bipolar patients compared with controls. LIMITATIONS: This study made use of platelets, which may not fully represent changes occurring in specific brain regions. CONCLUSION: This study adds to the growing evidence suggesting that abnormalities of PKA are associated with BD.     

Regulatory effects of osteoprotegerin on cellular and humoral immune responses

The interaction between receptor activator of nuclear factor-kappaB ligand (RANKL) and RANK has been reported to regulate immunity in addition to bone metabolism. The aim of this study was to determine if osteoprotegerin (OPG), an inhibitor of the RANKL-RANK interaction and possibly a new drug against osteoporosis, would adversely affect immunity. OPG was used to treat mice developing different models of cellular and humoral immune responses and also in vitro in T and B cell assays. In mice, OPG does not affect cell-mediated reactions such as contact hypersensitivity to the hapten oxazolone and liver damage, granuloma formation, and infectious load induced by mycobacterial infection. However, OPG increases humoral reactions such as the production of IgM, IgG, and IgE against the T cell dependent antigen keyhole limpet hemocyanin and the production of IgM against the T cell independent antigen Pneumovax. In vitro, OPG modestly co-stimulates T cells but does not affect the proliferation of B cells. OPG has modest immunoregulatory effects that seem to be confined to the humoral response to specific antigens.     

Analysis of 4-nitroquinoline-1-oxide induced mutations at the hprt locus in mammalian cells: possible involvement of preferential DNA repair

Mutation spectra induced by 4-nitroquinoline 1-oxide (4NQO)at the hprt locus for both normal (AA8) and 4NQO-sensitive (UV5)Chinese hamster ovary cells were determined to investigate theeffect of DNA repair on the nature of induced mutations. TheUV5 cell line is three times more sensitive to 4NQO than theAA8 parental cell line. In UV5 cells, the dGuo-N2-AQO adduct,which is considered to be the most toxic and mutagenic adductin Escherichia coli, is poorly repaired. The molecular natureof 30hprt mutants isolated from AA8 and 20 isolated from UV5cells was determined by sequence analysis of in vitro amplifiedhprtcDNA. Both similarities and differences emerged. In bothcell lines we found that (i) 4NQO is basically a base substitutionmutagen acting almost exclusively at G residues and (ii) G transversionsare prevalent over G transitions in both cell lines, independentlyfrom the ability to repair dGuo-N2-AQO. A high proportion (13/25)of splice mutations was observed in AA8 cells, statisticallydifferent (P < 0.04, Fisher‘s exact test) from theincidence of splice mutants in UV5 cells (4/20). In AA8 mutants,all but two of the point mutations were due to lesions localizedon the non-transcribed strand, suggesting preferential repairof the transcribed strand. Compared with AA8, the proportionof mutants due to lesions present on the transcribed strandwas higher in UV5 cells, as expected if a preferential repairmechanism was impaired in the sensitive cell line. Our dataare consistent with the molecular defect in DNA repair recentlycharacterized in UV5. ³To whom correspondence should be addressed     

Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer.

Down-regulation of expression of MHC alleles, as well as tumor-specific antigens, is observed frequently during tumor progression, resulting in an impairment of MHC-restricted, alphabeta-T-cell-mediated, tumor-specific immunity. Given the unique set of antigens recognized and the lack of requirement for classical antigen-presenting molecules, gammadelta T cells might, therefore, represent a nonredundant system in anticancer surveillance, as proposed for the immune response against pathogens. Evidence that gammadelta and alphabeta T cells make distinct contributions to anticancer surveillance has been provided recently in mice. Here, we discuss the potential role played by resident Vdelta1(+) and circulating Vdelta2(+) T cells in the defense against solid tumors and hematological malignancies.     

Tuning of innate immunity and polarized responses by decoy receptors

After the identification of the interleukin (IL)-1 type II receptor as the prototype, decoy receptors have been identified for a number of members of the IL-1/IL-18, TNF, IL-10 and IL-13 receptor families. Moreover, the silent receptor D6 is a promiscuous decoy and scavenger receptor of inflammatory chemokines. The IL-1 decoy receptor is regulated by pro- and anti-inflammatory signals and its levels may serve as a readout of the activation of anti-inflammatory pathways, for instance by glucocorticoid hormones. Decoy receptors represent a strategy to tune inflammatory and polarized adaptive responses.     

Expression and function of NKRP1A molecule on human monocytes and dendritic cells

In this study, we analyzed the expression and function of the lymphocyte surface lectin NKRP1A on peripheral blood monocytes (Mo) or Mo and dendritic cells (DC) derived from thymic and bone marrow precursors. De novo expression of NKRP1A and CD14 molecules was detected upon culture of CD2^? CD3^? CD14^? CD16^? CD1a^? NKRP1A^? immature thymic precursors for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Under these culture conditions, by day 21, a fraction of cells had lost CD14 and acquired both CD80 (B7.1) and CD86 (B7.2) molecules. These cells displayed a DC-like morphology and were surface NKRP1A positive. CD34⁺ NKRP1A^? CD14^? precursors, isolated from bone marrow and cultured in the presence of GM-CSF, also expressed both NKRP1A and CD14: these antigens were newly expressed on about one third of cells which had lost the CD34 precursor marker. In addition, NKRP1A was constitutively present on resting CD14⁺ peripheral blood Mo. When these cells were cultured in the presence of GM-CSF, the resulting DC population retained the expression of NKRP1A and acquired CD80, while they lost the CD14 antigen. Functional analysis revealed that the engagement of NKRP1A molecule leads to a strong intracellular calcium ([Ca²⁺]_i) increase both in resting peripheral blood Mo and in vitro-derived DC. [Ca²⁺]_i increase was mainly due to extracellular calcium influx, as it was completely abrogated by the addition of EGTA. More importantly, the engagement of the NKRP1A molecule induced interleukin (IL)-1β and IL-12 production by resting Mo and DC, respectively. Altogether these data indicate that NKRP1A lectin is present at the surface of Mo and DC and may play a relevant role in the activation and function of both cell types.     

Estimation of poly (C) avid serum ribonuclease in hepatoma patients

Human poly (C) avid serum ribonuclease (RNase) differs in physico-chemical, electrophoretic, and catalytic properties from ribonuclease activity encountered in liver preparations. The first is reported as "secretory type", the latter, because it is undetectable in body fluids, as "nonsecretory type". We determined RNase activity in 11 hepatoma patients. A statistical difference from a normal control of corresponding age was encountered in both age groups investigated (51-60 years, P less than 0.05; 61-70 years, P less than 0.01). The circumstances mentioned above make the tumor itself unlikely to be the source of RNase elevation. Besides a diminished synthesis of RNase inhibitor by hepatoma cells, tumor-derived polyamines could contribute to enhanced RNase activity. The influence of polyamines on RNase activity has already been demonstrated by in vitro experiments. Simultaneous estimation of polyamines and RNase is required to elucidate in vivo circumstances.