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Biomedical subjects

J Michel

Publications and source records attributed to J Michel.

At least 55 records · Page 3Linked to original sources
PubMed1999

CD137 induces proliferation and endomitosis in monocytes.

Peripheral monocytes are short-lived and are replenished from hematopoietic stem cells whose proliferation is believed to be confined to the bone marrow. Human peripheral monocytes are assumed not to be able to proliferate. In this study we show that CD137 (ILA/4-1BB), a member of the tumor necrosis factor receptor family, induces a widespread and profound proliferation of human peripheral monocytes. Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are essential, but not sufficient for proliferation. Additional soluble autocrine factors induced by CD137 are required. Induction of proliferation is mediated via reverse signaling through a CD137 ligand, expressed constitutively by peripheral monocytes. The ability of CD137 to induce proliferation in human peripheral monocytes is not shared by any other known molecule.

Antigens, CD↗
PubMed1999

Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3gamma4.

Murine anti-CD3 (OKT3, Muromonab-CD3) is a potent human T-lymphocyte mitogen. A previous clinical Phase I trial examined OKT3 as an immunomodulator for the treatment of cancer. However, the murine monoclonal antibody triggered a potent humoral response that neutralized the antibody activity during subsequent administration. Thus, a "humanized" form of OKT3 (hOKT3gamma4) was developed to minimize immunogenicity. The genetically engineered human anti-CD3 retained its binding activity and effectively activated T cells in vitro. Therefore, we evaluated the safety and activity of hOKT3gamma4 in a Phase I clinical trial. hOKT3gamma4 was administered as a 10-min i.v. infusion every 2 weeks for three injections (one course of therapy). Six dose levels ranging from 50 to 1600 microg/injection were evaluated. Headache and fever were common, transient toxicities but were not dose limiting. The dose-limiting toxicities were rigors and dyspnea at the 1600-microg dose level, which defined 800 microg as the maximally tolerated dose in this trial. A dose-dependent in vivo T-lymphocyte activation was produced by this treatment, and the most significant T-lymphocyte activation occurred in patients treated at the two highest dose levels (800 and 1600 microg). Persistent CD3 modulation occurred after administration of 1600 microg of hOKT3gamma4. Anti-idiotypic antibodies were detected in only 6 of 24 patients after multiple injections and were not associated with attenuation of T-lymphocyte activation. Malignant ascites resolved in three patients, one each with peritoneal mesothelioma, pancreatic adenocarcinoma, and ovarian adenocarcinoma. hOKT3gamma4 can induce T-lymphocyte activation in patients with cancer, and the immunogenicity of the "humanized" antibody is sufficiently reduced relative to its murine "parent" to permit immunostimulation by repetitive i.v. administration. The therapeutic potential of biweekly i.v. hOKT3gamma4 at a dose of 800 microg should be further evaluated.

Adjuvants, Immunologic↗
PubMed1999

Paragenetic suppressors of suppressor genes--a new class of oncodeterminants.

Impairment or loss of suppressor genes is a common event permitting the oncogene/suppressor gene machinery to develop neoplasia. Following prenatal treatment with X-rays and UV-B, we detected a new class of oncodeterminants that could not be specified as genes. This points to paragenetic elements that suppress suppressorgenes and thus provoke melanoma at earlier ages of onset as expected, with increased severity and increased number of incidences in successive generations, in the absence of further treatment. These elements were isolated from a xiphophorine DNA library by endogenously labeled long terminal repeats (LTR) of a xiphophorine retrovirus, and were characterized as retrotransposons by Southern and Northern blotting and reverse transcription/polymerase chain reaction and transient transfection studies, in situ hybridization, and sequencing. They appear in multiple copies in the telomeric chromosome regions, where they can extend. Three open reading frames (ORF) are flanked by LTR that contain genetically active regulatory elements, and are inducible by UV-B. ORF 3 shows nests of CG dinucleotides and CGG trinucleotides, which are reminiscent of CGG nests predisposing subjects to anticipation of certain human diseases involving tumor generation. Genetic anticipation as defined by Nettleship (1909) or Warren (1996) including an increase of neoplasia might represent an acquired genetic load in preceding generations, which might provide a lead to a molecular understanding of the worldwide increase of incidences of human tumor.

Animals↗
PubMed1999

Assessment of bone response to systemic therapy in an EORTC trial: preliminary experience with the use of collagen cross-link excretion. European Organization for Research and Treatment of Cancer.

This study was designed to evaluate new bone resorption and tumour markers as possible alternatives to serial plain radiographs for the assessment of response to treatment. Thirty-seven patients with newly diagnosed bone metastases from breast cancer, randomized to receive oral pamidronate or placebo tablets in addition to anticancer treatment within the context of a multicentre EORTC trial, who were both assessable for radiographic response in bone and had serum and urine samples collected for more than 1 month were studied. The markers of bone metabolism measured included urinary calcium (uCa), hydroxyproline (hyp), the N-telopeptide cross-links of type I collagen (NTx) and total alkaline phosphatase. The tumour markers measured were CA15-3 and cancer-associated serum antigen (CASA). Before treatment, levels of Ntx, uCa and Hyp were elevated in 41%, 24% and 28% respectively, and CA15-3 and CASA increased in 69% and 50%. For assessment of response and identification of progression, Ntx was the most useful bone marker. All markers behaved similarly in no change (NC) and partial response (PR) patients. There was a significant difference (P < or = 0.05) in Ntx levels (compared to baseline) at 1 and 4 months and in CA15-3/CASA at 4 months between patients with PR or NC and those with progressive disease (PD), and at 4 months between those with time to progression (TP) > 7 and those with TP < or = 7 months. The diagnostic efficiency (DE) for prediction of PD following a > 50% increase in Ntx or CA15-3 was 78% and 62% respectively. An algorithm to predict response to therapy has been developed for future prospective evaluation.

Adult↗
PubMed1999

CD137-induced apoptosis is independent of CD95.

CD95 (APO-1/Fas) and CD137 (ILA/4-1BB) are members of the tumour necrosis factor receptor family, and both are involved in induction of apoptosis in lymphocytes. Contrary to the case of CD95, apoptosis by CD137 is caused by cross-linking of the respective ligand rather than the receptor. Nothing is known so far about the mechanism of CD137-induced cell death. Here, we show that immobilized CD137 protein induces expression of CD95 in resting primary T and B lymphocytes. However, induction of apoptosis by CD137 is independent of CD95, because: (1) antagonistic anti-CD95 antibody fragments do not block CD137-induced apoptosis; and (2) CD137, but not anti-CD95, can induce apoptosis in resting lymphocytes.

Antigens, CD↗
PubMed1999

Comparative responses of genetically lean and fat broiler chickens to dietary threonine concentration.

Genetically lean (LL) or fat (FL) male broiler chicken's were fed on 5 diets containing either 3.80, 4.27, 4.75, 5.22 or 5.70 g true digestible threonine per kg. Threonine deficiency induced a more pronounced reduction in growth in the LL than in the FL but did not influence abdominal fat and breast muscle proportions in either line. Plotting weight gain or protein gain against threonine intake suggests that the requirement of both lines is very similar in terms of mg per g of gain. Thus food intake or appetite should account for differences between genotypes. Requirement for true digestible threonine was estimated as 10.70 mg per g of weight gain or 63.8 mg per g of protein gain, using a linear regression approach. The quadratic polynomial equations suggest that the requirements are 13.9 and 12.4 mg digestible threonine per g of gain for LL and FL respectively.

Adipose Tissue↗
PubMed1999

Management of intraductal papillary mucinous tumours of the pancreas.

OBJECTIVE: To focus attention on the management and outcome of patients with intraductal papillary mucinous tumours of the pancreas. DESIGN: Retrospective study and analysis of published reports. SETTING: University hospital, France. SUBJECTS: 111 patients (101 published cases and our own 10 cases) divided in two groups: the first including malignant tumours (n = 46), and the second group benign or in situ tumours (n = 61). In 4 patients the type of tumour was not known. MAIN OUTCOME MEASURE: Resectability, mortality and recurrence. RESULTS: More men had benign or in situ tumours [48/61 (79%) compared with 28/46 (61%), p = 0.054]. Pancreatitis was more common among benign than malignant tumours [34/61 (58%) compared with 21/46 (46%), p = 0.33]. In group I, 39 patients had diabetes. A total of 107 patients were operated on: pancreaticoduodenectomy (n = 54, 50%), distal pancreatectomy (n = 25, 23%), total pancreatectomy (n = 4,4%), bypass (n = 2,2%). The type of resection was not mentioned in 22 records (21%). Four patients were not operated on because of their poor general condition. The resectability rate was 98% (105/107). Eleven patients had died at the time of publication. Hospital mortality rate was 3% (n = 3), mainly because 2 of the 4 who had total pancreatectomy died. With a median follow-up of 37 months, recurrence was 5% (n = 5). CONCLUSION: Intraductal papillary mucinous tumours of the pancreas are well known distinctive pancreatic tumours that are usually intraductal but may develop into invasive carcinoma. They should be resected, and have a good prognosis and low recurrence rate.

Adult↗
PubMed1999

Response of chick lines selected on carcass quality to dietary lysine supply: live performance and muscle development.

Broiler carcass quality can be improved by conventional selection techniques. In this regard, an experimental "quality" line (QL) was selected for high breast meat yield. We analyzed the effects of this selection on the dietary lysine requirement in chicks from 0 to 3 wk. Control (CL) and QL chicks were provided ad libitum access to isoenergetic diets containing 20% crude protein but differing in their lysine content (0.75, 0.88, 1.01, and 1.13%). Two-way ANOVA showed a significant effect (P < 0.01) of genotype on body weight, growth rate, feed intake, and weight of Pectoralis major and Gastrocnemius muscles. Conversely, the Sartorius muscle weight was not modified (P = 0.21) by genotype. Lysine deficiency markedly reduced body weight, growth rate, and feed intake, and increased feed conversion ratio (P < 0.001). Low dietary levels of lysine also depressed the weight of Gastrocnemius, Sartorius, and P. major (P < 0.001). The body or muscle weight response to diet lysine concentration depended on the line, with QL chicks appearing less sensitive to lysine deficiency. Consequently, their dietary requirements could be lower. Finally, when weight gain and P. major muscle protein deposition were plotted against lysine intake, QL chicks appeared to be more efficient than CL chicks. The underlying mechanisms responsible for this await clarification.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism.

BACKGROUND/AIMS: Alcoholic cirrhosis remains a controversial indication for liver transplantation, mainly because of ethical considerations related to the shortage of donor livers. The aim of this study was to review experience to date, focusing on survival rates and complications, and the effect of alcohol relapse on outcome and alterations in marital and socioprofessional status. METHODS: The results for 53 patients transplanted for alcoholic cirrhosis between 1989 and 1994 were compared with those for 48 patients transplanted for non-alcoholic liver disease. The following variables were analysed: survival, rejection, infection, cancer, retransplantation, employment and marital status, alcoholic recurrence. The same variables were compared between alcohol relapsers and non-relapsers. RESULTS: Recovery of employment was the only significantly different variable between alcoholic (30%) and non-alcoholic patients (60%). Two factors influenced survival in the absence of alcohol recidivism: age and abstinence before transplantation. For all other variables, there were no differences between alcoholic and non-alcoholic patients, and, within the alcoholic group, between relapsers and non-relapsers. The recidivism rate was 32%. CONCLUSION: The data indicate that liver transplantation is justified for alcoholic cirrhosis, even in cases of recidivism, which did no affect survival and compliance with the immunosuppressive regimen. These good results should help in educating the general population about alcoholic disease.

Adult↗
PubMed1998

A dielectric omnidirectional reflector

A design criterion that permits truly omnidirectional reflectivity for all polarizations of incident light over a wide selectable range of frequencies was used in fabricating an all-dielectric omnidirectional reflector consisting of multilayer films. The reflector was simply constructed as a stack of nine alternating micrometer-thick layers of polystyrene and tellurium and demonstrates omnidirectional reflection over the wavelength range from 10 to 15 micrometers. Because the omnidirectionality criterion is general, it can be used to design omnidirectional reflectors in many frequency ranges of interest. Potential uses depend on the geometry of the system. For example, coating of an enclosure will result in an optical cavity. A hollow tube will produce a low-loss, broadband waveguide, whereas a planar film could be used as an efficient radiative heat barrier or collector in thermoelectric devices.

Journal Article↗
PubMed1998

Xenoantibodies to pig endothelium are expressed in germline configuration and share a conserved immunoglobulin VH gene structure with antibodies to common infectious agents.

BACKGROUND: The rejection of pig xenografts in humans is initiated by preformed antibodies that may be related to the natural antibodies that formulate a first line of defense against infectious agents. Immunoglobulin gene variable domains encoding the antibodies that react with similar epitopes expressed on xenoantigens and bacteria may share structurally similar antigen-binding site configurations. METHODS: We sequenced the VH immunoglobulin genes and germline progenitors of two rat monoclonal antibodies that recognize pig xenoantigens. Nucleic and amino acid sequences of these xenoantibodies were compared with immunoglobulin genes encoding antibodies that react with bacteria or viruses. RESULTS AND CONCLUSIONS: VH genes encoding rat anti-pig xenoantibodies are expressed in germline configuration and share structural similarities, including identical amino acids in key antigenic contact sites that define antibody canonical structural groups, with antibodies to infectious agents.

Amino Acid Sequence↗
PubMed1998

CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling.

CD137 (ILA/4-1BB), a member of the TNF receptor family, was shown previously to inhibit proliferation and to induce apoptosis in T lymphocytes. In this study, we identify CD137 as a novel and potent monocyte activation factor. CD137 protein induces expression of IL-6, IL-8, and TNF-alpha, and inhibits expression of IL-10. Furthermore, CD137 differentially regulates expression of cell surface receptors. It induces expression of ICAM and reduces expression of FcgammaRIII, while levels of HLA-DR remain unchanged. CD137 also promotes adherence of monocytes. These effects of CD137 require immobilization of CD137 protein, indicating that they are mediated by cross-linking of a corresponding ligand/coreceptor expressed on monocytes.

Antigens, CD↗
PubMed1998

A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis.

CD137 (ILA/4-1BB) is a member of the tumor necrosis factor receptor family and regulates activation, proliferation and programmed cell death in T lymphocytes. Here we show the existence of a soluble form of CD137 (sCD137) of 16 kDa. sCD137 is released by activated lymphocytes, and in contrast to membrane-bound CD137, expression of sCD137 seems to be restricted to lymphocytes. sCD137 is generated by alternative splicing and two splice variants were identified. sCD137 is present at low levels in sera of some healthy donors (5/12; mean = 0.18 ng/ml) and is significantly enhanced in sera of patients with rheumatoid arthritis (12/12; mean = 3.58 ng/ml).

Antigens, CD↗
PubMed1998

Aortic valve replacement in children: are we on the right track?

OBJECTIVE: The choice of the ideal prosthesis for aortic valve replacement (AVR) in children is still controversial. Early degeneration of bioprostheses and the potential risks related to anticoagulation in the child have renewed the interest of many surgeons towards the Ross operation. This study concerns our 22-year experience with AVR in children. METHODS: Forty-six children, aged 4 months to 16 years (mean 11.6 years), had AVR between April 1974 and December 1996. Preoperative diagnosis revealed aortic regurgitation (AR) in 25 cases, aortic stenosis (AS) in ten, combined AS and AR in nine and LVOTO in two patients. Of the 46 patients, 26 had 37 previous procedures. Isolated AVR was performed in 19 cases, 27 children underwent 36 concomitant intracardiac procedures. Mechanical prostheses were implanted in 30 children, bioprostheses in eight, aortic homografts in three. Five patients underwent a Ross procedure. RESULTS: There was one hospital death in the latter group (2.1%). Six of seven late deaths occurred in patients who underwent complex intracardiac procedures (15.2%). Reoperation rate was 19.5% (n = 10), differentiating 16.6% for mechanical (5/30 patients) and 50% (4/8 patients) for bioprostheses. The mean follow-up period was 8.01 years, ranging from 0.45 to 21.66 years (304.04 patient-years). There was one hemorrhagic event (2.1%) due to anticoagulation, thrombosis of the mechanical valve occurred in two patients (4.2%). CONCLUSIONS: AVR can be performed with acceptable mortality rate and good long-term results in children. We perform the Ross operation only in selected cases. According to our experience, mechanical prostheses show excellent performances in children with a low incidence of complications related to anticoagulation.

Adolescent↗
PubMed1998

Diaphragmatic and subcutaneous seeding of hepatocellular carcinoma following fine-needle aspiration biopsy.

AIMS/BACKGROUND: We report the discovery of associated metastatic subcutaneous and metastatic diaphragmatic nodules on the needle track after fine-needle biopsy aspiration under echography, which has not yet been reported in the literature. METHODS: A 35-year-old man with non-replicating hepatitis B virus presented with a tumor that suggested hepatocarcinoma with cirrhosis. A diagnostic needle biopsy was carried out before surgery. Twelve months later, he presented with a series of four continuous metastatic diaphragmatic nodules on the inner wall lining the needle track. Surgery was performed, followed by external radiation (40 Gy). CONCLUSIONS: The risk of seeding following fine-needle biopsy aspiration of hepatocellular carcinoma can no longer be considered negligable. The real risk is probably underestimated. Even for biopsy of lesions localized to the inferior part of the liver, diaphragmatic seeding is possible. This seeding necessitates surgical resection, increasing the therapeutic morbidity of hepatocellular carcinomas. We believe that in cases where investigation of a small hepatic tumor suggests a hepatocellular carcinoma that could be resected, or for candidate patients for liver transplantation. one should not puncture the tumor. If this diagnostic biopsy is essential, then the needle track could be resected upon surgery, after cutaneous external tattooing.

Adult↗
PubMed1998

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Administration, Oral↗
PubMed1997

The glucocorticoid receptor is associated with the RNA-binding nuclear matrix protein hnRNP U.

The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that is able to modulate gene activity by binding to its response element, interacting with other transcription factors, and contacting several accessory proteins such as coactivators. Here we show that GRIP120, one of the factors we have identified to interact with the glucocorticoid receptor, is identical to the heterogeneous nuclear ribonucleoprotein U (hnRNP U), a nuclear matrix protein binding to RNA as well as to scaffold attachment regions. GR.hnRNP U complexes were identified by blotting and coimmunoprecipitation. The subnuclear distribution of GR and hnRNP U was characterized by indirect immunofluorescent labeling and confocal laser microscopy demonstrating a colocalization of both proteins. Using a nuclear transport-deficient deletion of hnRNP U, nuclear translocation was seen to be dependent on GR and dexamethasone. Transient transfections were used to identify possible interaction domains. Overexpressed hnRNP U interfered with glucocorticoid induction, and the COOH-terminal domains of both proteins were sufficient in mediating the transcriptional interference. A possible functional role for this GR binding-protein in addition to its binding to the nuclear matrix, to RNA, and to scaffold attachment regions is discussed.

Cell Nucleus↗