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Biomedical subjects

M Colonna

Publications and source records attributed to M Colonna.

At least 55 records · Page 3Linked to original sources
PubMed2000

National cancer prevalence estimation in France.

In France, as in several other European countries, prevalence has to be estimated from the modelling of 2 of the 3 basic epidemiological measures of incidence, mortality, and survival. Since, in these countries, follow-up of cancer patients is only made in a few registries, we explored the feasibility of estimating prevalence in the absence of follow-up data. The method, which used only incidence and mortality, was validated on Danish data and applied to France. For this latter country, the estimation procedure is based on the recorded mortality data and an estimate of incidence for the entire country. It is applied to selected sites of cancer, which account for 80% of the estimated incidence. In 1992, the prevalence of patients who had such a diagnosis amounts to 538,000 women and 424, 000 men. The most frequent cancer sites are head and neck, breast, and large bowel. Most of the cancer sites present an increase in prevalence proportion between 1987 and 1992. The larger increases concern breast and prostate cancer.

Adult↗
PubMed2000

Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes.

We have identified new activating receptors of the Ig superfamily expressed on human myeloid cells, called TREM (triggering receptor expressed on myeloid cells). TREM-1 is selectively expressed on blood neutrophils and a subset of monocytes and is up-regulated by bacterial LPS. Engagement of TREM-1 triggers secretion of IL-8, monocyte chemotactic protein-1, and TNF-alpha and induces neutrophil degranulation. Intracellularly, TREM-1 induces Ca2+ mobilization and tyrosine phosphorylation of extracellular signal-related kinase 1 (ERK1), ERK2 and phospholipase C-gamma. To mediate activation, TREM-1 associates with the transmembrane adapter molecule DAP12. Thus, TREM-1 mediates activation of neutrophil and monocytes, and may have a predominant role in inflammatory responses.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Combined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a feasibility study.

PURPOSE: To evaluate a cisplatin-containing chemoradiotherapy (CRT) regimen followed by chemotherapy for unresectable (locally advanced group, n = 32) and resected (adjuvant group, n = 10) pancreatic adenocarcinoma. The quality of palliation and percentage of secondary resections were also studied for unresectable disease. METHODS AND MATERIALS: The protocol comprised CRT (45 Gy over 5 weeks), combined with 5-fluorouracil and cisplatin during the first and fifth weeks, followed, 3 weeks later, by 4 cycles of the same chemotherapy plus leucovorin. RESULTS: All patients completed CRT but only 50% of each group finished the entire protocol. Gastrointestinal toxicity and weight loss were the major side effects during CRT. Enhanced hematological toxicity limited the post-CRT chemotherapy. For the locally advanced group, median survival was 9 months; 1- and 2-year survival rates were 31 and 12. 5%, respectively. The overall response rate was 16% and 50% had stable disease. A lasting palliative effect defined as improved performance status and decreased analgesic consumption, was recorded for 43% of the patients. Only three secondary resections have been performed. For the adjuvant group, median survival was 17 months. CONCLUSIONS: Although toxic in advanced disease, this regimen significantly lowered pain and analgesic consumption, but had poor impact on secondary resectability. In an adjuvant setting, although equally toxic, this series was too small to allow conclusions to be drawn.

Adenocarcinoma↗
PubMed2000

Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells.

Signal-regulatory proteins (SIRPs) are cell-surface glycoproteins expressed on myeloid and neural cells that have been shown to recruit SH2 domain-containing protein phosphatase 1 (SHP-1) and SHP-2 and to regulate receptor tyrosine kinase-coupled signaling. One SIRP of unknown function, designated SIRP beta 1, contains a short cytoplasmic domain that lacks sequence motifs capable of recruiting SHP-1 and SHP-2. Using a SIRP-specific mAb, we show that SIRP beta 1 is expressed in monocytes and dendritic cells and associates with the signal transduction molecule DAP12. SIRP beta 1/DAP12 complex formation was required for efficient cell-surface expression of SIRP beta 1. Stimulation of this complex induced tyrosine phosphorylation, mitogen-activated protein kinase activation, and cellular activation. Thus, SIRP beta 1 is a new DAP12-associated receptor involved in the activation of myeloid cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Molecular characterization of two novel C-type lectin-like receptors, one of which is selectively expressed in human dendritic cells.

We have identified two human C-type lectin-like receptors, CLEC-1 and CLEC-2. Both display a single carbohydrate recognition domain and a cytoplasmic tyrosine-based motif. They are homologous to the NK cell receptors NKG2s and CD94 and also to the oxidized low-density lipoprotein receptor 1. CLEC-1 and CLEC-2 are preferentially transcribed in dendritic cells (DC) and in the liver, respectively. Following transient transfection in COS cells, CLEC-1 is expressed intracellularly, perhaps requiring an associated chain to reach the cell surface. CLEC-2 is expressed on the surface of transfected cells as a protein of approximately 33 kDa. CLEC-1 and CLEC-2 genes map to human chromosome 12, most likely in linkage with the NK gene complex (NKC). Thus, the NKC may encode C-type lectin-like receptors expressed not only in NK cells but also in other cells, and at least one of these is of potential importance in regulating DC function.

Amino Acid Sequence↗
PubMed2000

Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity.

Patients with the X-linked lymphoproliferative disorder (XLPD) are unable to control Epstein-Barr virus (EBV)-induced infections and lymphoproliferation. This disease is caused by a deficit of SAP, an adapter protein involved in the signal transduction of several cell surface receptors of the CD2 superfamily. One of these receptors, called 2B4, is expressed on NK cells, cytotoxic T cells and myeloid cells and activates NK cell cytotoxicity. Here we show that XLPD patients have a defect of 2B4 receptor-mediated NK cell cytotoxicity. This defect may contribute to the pathogenesis of XLPD by reducing NK cell lysis of EBV-infected B cells.

Antigens, CD↗
PubMed2000

2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism.

2B4 is a cell surface glycoprotein of the Ig-superfamily structurally related to CD2-like molecules such as CD2, CD48, CD58, CD84, Ly-9, and SLAM. Engagement of 2B4 on NK cells with specific antibodies or with its ligand CD48 enhances NK cell-mediated cytotoxicity. 2B4 is also expressed on both CD8+ T cells and myeloid cells, but its function in these cells remains unknown. Signal transduction through 2B4 involves recruitment of the SH2-containing adapter molecule SAP to cytoplasmic tyrosines. SAP is deficient in patients affected by X-linked lymphoproliferative disorder (XLP), which is triggered following EBV infection. Thus, an interruption of signaling through 2B4 and related molecules may impair NK cell recognition of virally infected cells and contribute to XLP.

Antigens, CD↗
PubMed2000

Fast growing cervical carcinomas. A retrospective analysis of 20 IB-IIB FIGO.

INTRODUCTION: Fast growing cervix carcinomas have a pejorative outcome: they may occur quickly after cervical smears qualified as normal - within an interval from 12 to 18 months in women less than 50 years old, and involveing the endocervix. This retrospective analysis is aimed at assessing 5-year outcomes. MATERIALS AND METHODS: Twenty cases of fast-growing cancer of the uterine cervix classified according to the FIGO clinical staging system as IB (n=14), IIA (3), and IIB (3), have been reviewed and compared to a cohort of 160 cases not having this feature. As regard to fast-growing carcinoma, the median age was 41 years (range 25-50), and the median follow-up 22 months (8-213) as compared to 54 years (27-79) and 80 months (5-199) for the reference cohort. The comparison of the two cohorts shows only a difference of breakdown which concerns the histological pelvic lymph nodes status (P<0.05), more often positive in fast-growing forms. The treatment policy was equally distributed between a radio-surgical approach, cesium 137 intracavitary irradiation followed by radical hysterectomy and lymphadenectomy, or a definitive irradiation with pelvic external irradiation followed by cesium 137 intracavitary irradiation. RESULTS: Thirteen deaths are reported in the fast-growing series instead of 54 in the other series. The 5-year overall survival is, respectively, 34 (13-55) vs. 74% (68-82) (P<0.001), the loco-regional-free survival 58 (33-84) vs. 85% (79-81) (P<0.001), the 5-year metastasis-free survival 61 (38-84) vs. 84% (78-90) (P=0. 004). CONCLUSION: These poor results emphasize the need to intensify loco-regional therapy with a concurrent cisplatin-based chemotherapy within the framework of a multidisciplinary approach.

Adult↗
PubMed2000

Human inhibitory and activating Ig-like receptors which modulate the function of myeloid cells.

There is increasing evidence that myeloid cells express several receptor families, which include both inhibitory and stimulatory isoforms. The expression of receptor isoforms with similar specificities but opposite functions on the same cell is intriguing. What might be the interplay between these receptors? Some clues to the answer to this question may come from recent studies on two myeloid receptor families: the ILT/LIR/MIR (immunoglobulin-like transcript/leukocyte Ig-like receptor/monocyte/macrophage Ig-like receptor) and the SIRP (signal-regulatory protein).

Animals↗
PubMed2000

Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization.

Plasmacytoid dendritic cells (PDCs) are a subset of dendritic cells present in human blood and inflamed lymph nodes. Here we show that blood PDCs, when stimulated with influenza virus and CD40L in vitro, undergo a maturation process characterized by up-regulation of major histocompatibility complex proteins and adhesion and costimulatory molecules. In addition, PDCs down-regulate CXCR3 and L-selectin, which mediate migration and homing of these cells into the lymph node. Mature PDCs efficiently stimulate T cells and drive a potent TH1 polarization in vitro, which is mediated by the synergistic effect of interleukin 12 and type 1 interferon. In vivo, mature PDCs are found in secondary lymphoid organs, where they represent the principal source of type 1 interferon during inflammation. Thus, PDCs probably participate in antiviral and pro-inflammatory responses, rather than in TH2 polarization and tolerance induction.

Antigen Presentation↗
PubMed2000

Natural killer-type receptors for HLA class I antigens are clonally expressed in lymphoproliferative disorders of natural killer and T-cell type.

In recent years, natural killer (NK) cells, as well as subpopulations of T cells, have been found to express diverse NK receptors (NKRs) for HLA class I molecules. We have characterized NKR phenotypes in lymphoproliferative disorders of NK or T-cell type. Peripheral blood of patients with lymphoproliferative disorders (n = 9) was analysed by multiparametric immunofluorescence flow cytometry with eight different antibodies against NKRs. Abnormal neoplastic cell populations from different types of NK or T-cell lymphoproliferative disorders lacked diversity in their NKR repertoires, i.e. all or none of the abnormal cells expressed individual NKRs and this expression occurred at single levels of intensity. This pattern of expression was specific for lymphoproliferative disorders as these resticted NKR repertoires were not found either in healthy donors (n = 9) or in patients with viral or autoimmune disease (n = 5). We conclude that NKRs are clonally expressed in lymphoproliferative disorders of NK or T-cell origin. NKR repertoires may represent a novel tool in diagnosing clonal disorders of NK and T-cell type.

CD3 Complex↗
PubMed1999

Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules.

BACKGROUND: Granulomatous syndromes, such as Wegener's granulomatosis, are defined according to complex criteria, but the underlying cause is rarely identified. We present evidence for a new aetiology for chronic granulomatous lesions associated with a recessive genetic defect, which is linked to the human leucocyte antigen (HLA) locus. METHODS: Five adults with necrotising granulomatous lesions in the upper respiratory tract and skin, associated with recurrent bacterial respiratory infections and skin vasculitis, were identified. A diagnosis of Wegener's granulomatosis was considered in all of them, but abandoned because of an incompatible disease course and resistance to immunosuppressive treatments. Peripheral-blood samples were taken and analysed by immunohistochemistry and fluorescent-activated-cell-sorter analysis. Since all five patients were homozygous for the HLA locus, we looked for genetic defects located within the HLA-locus with PCR and restriction fragment length polymorphism. FINDINGS: A severe decrease in cell-surface expression of HLA class-I molecule was seen in all patients. Defective expression of the transporter associated with antigen presentation (TAP) genes was responsible for the HLA class-I down-regulation, and in two patients we identified a mutation in the TAP2 gene responsible for the defective expression of the TAP complex. We showed the presence of autoreactive natural killer (NK) cells and gammadelta T lymphocytes in the peripheral blood cells of two patients. Correction of the genetic defect in vitro restored normal expression of HLA class-I molecules and prevented self-reactivity in the patients' cells. Histology of granulomatous lesions showed the presence of a large proportion of activated NK cells. INTERPRETATION: Our findings define the cause and pathogenesis of a new syndrome that affects patients with a defective surface expression of HLA class-I molecules. The syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a better understanding of the cause and pathogenesis of a disease.

ATP-Binding Cassette Transporters↗
PubMed1999

Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties.

Transmembrane adapter proteins are a class of molecules that mediate signals from an extracellular receptor to the cytoplasm of the cell. We have cloned a novel transmembrane adapter protein called KAP10, a approximately 10-kDa protein that is encoded within 100 bp of the DAP12 locus on human chromosome 19. KAP10 is predominantly expressed in immune cells, including NK cells, T cells, and monocytes. We show that KAP10, unlike other transmembrane adapter proteins, binds phosphatidylinositol-3 kinase following phosphorylation of a cytoplasmic YINM motif, which results in activation of Akt. In addition, we identify KAP10 as being able to bind the adapter protein Grb2. Based on our data, we suggest that this molecule is involved in stimulation and costimulation in cells of both myeloid and lymphoid origin.

Adaptor Proteins, Signal Transducing↗