Hepatitis C virus infection and MALT-type ocular adnexal lymphoma.
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Conjunctival Neoplasms↗
Biomedical subjects
P Arnaud
Publications and source records attributed to P Arnaud.
Limited evolutionary conservation of imprinting in the human placenta.
The epigenetic phenomenon of genomic imprinting provides an additional level of gene regulation that is confined to a limited number of genes, frequently, but not exclusively, important for embryonic development. The evolution and maintenance of imprinting has been linked to the balance between the allocation of maternal resources to the developing fetus and the mother's well being. Genes that are imprinted in both the embryo and extraembryonic tissues show extensive conservation between a mouse and a human. Here we examine the human orthologues of mouse genes imprinted only in the placenta, assaying allele-specific expression and epigenetic modifications. The genes from the KCNQ1 domain and the isolated human orthologues of the imprinted genes Gatm and Dcn all are expressed biallelically in the human, from first-trimester trophoblast through to term. This lack of imprinting is independent of promoter CpG methylation and correlates with the absence of the allelic histone modifications dimethylation of lysine-9 residue of H3 (H3K9me2) and trimethylation of lysine-27 residue of H3 (H3K27me3). These specific histone modifications are thought to contribute toward regulation of imprinting in the mouse. Genes from the IGF2R domain show polymorphic concordant expression in the placenta, with imprinting demonstrated in only a minority of samples. Together these findings have important implications for understanding the evolution of mammalian genomic imprinting. Because most human pregnancies are singletons, this absence of competition might explain the comparatively relaxed need in the human for placental-specific imprinting.
Alleles↗
Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human.
Genomic imprinting is limited to a subset of genes that play critical roles in fetal growth, development and behaviour. One of the most studied imprinted genes encodes insulin-like growth factor 2, and aberrant imprinting and DNA methylation of this gene is associated with the growth disorders Beckwith-Wiedemann and Silver-Russell syndromes and many human cancers. Specific isoforms of this gene have been shown to be essential for normal placental function, as mice carrying paternal null alleles for the Igf2-P0 transcript are growth restricted at birth. We report here the identification of three novel human transcripts from the IGF2 locus. One is equivalent to the mouse Igf2-P0 transcript, whereas the two others (INSIGF long and short) originate from the upstream INS gene that alternatively splices to downstream IGF2 exons. In order to elucidate the molecular mechanisms involved in the complex imprinting of these novel IGF2 transcripts, both the allele-specific expression and methylation for all the IGF2 promoters including P0 and the INSIGF transcripts were analysed in human tissues. Similar to the mouse, the human IGF2-P0 transcript is paternally expressed; however, its expression is not limited to placenta. This expression correlates with tissue-specific promoter methylation on the maternal allele. The two novel INSIGF transcripts reported here use the INS promoter and show highly restricted tissue expression profiles including the pancreas. As previously reported for INS in the yolk sac, we demonstrate complex, tissue-specific imprinting of these transcripts. The finding of additional transcripts within this locus will have important implications for IGF2 regulation in both cancer and metabolism.
Alternative Splicing↗
Optimization of entrapment of metronidazole in amphiphilic beta-cyclodextrin nanospheres.
Several aspects of the manufacture of nanospheres containing metronidazole were studied. Nanospheres made of amphiphilic beta-cyclodextrin containing metronidazole were prepared by adding an acetone solution of amphiphilic cyclodextrin to an aqueous solution of metronidazole with or without Pluronic PE/F68 as the surfactant. An optimized formulation with high encapsulation efficiencies and with an appropriate particle size for intravenous administration, was developed. The entrapment of metronidazole was strongly dependent of the method of preparation and drug concentrations. These nanospheres prepared by nanocrystallization are promising carriers for metronidazole in the treatment of hepatic abscess.
Antiprotozoal Agents↗
High survival rate with the LMT-89 regimen in lymphoblastic lymphoma (LL), but not in T-cell acute lymphoblastic leukemia (T-ALL).
The most appropriate treatment for lymphoblastic lymphomas (LL) remains uncertain. We treated 27 patients with newly diagnosed LL according to an LMT-89 protocol, which is a modified version of the LMT-81 protocol previously reported in pediatric patients. The median age was 31 years. Mediastinal enlargement was present in 25/27 patients, with pleural effusion in 12. Four patients had central nervous system involvement and 12 had bone marrow involvement and 24/27 (89%) had advanced Ann Arbor stage III-IV disease. Complete remission (CR) was achieved in 20/27 patients, unconfirmed complete remission in three patients (residual mediastinal lesion on computed tomography scan) and four failed induction therapy (ORR: 85%). Twelve patients (44%) remained in continuous CR with a median follow-up of 95 months. Survival at 3 years (when all the events occurred in our series) was 63%. Bone marrow involvement was associated with a poor outcome. Overall survival was 85+/-20% in patients without bone marrow involvement compared to 37+/-30% in patients with bone marrow involvement. The Ann Arbor stage, age and serum lactate dehydrogenase level did not influence outcomes. This LMT-89 protocol is a safe regimen and is highly effective in advanced LL without bone marrow involvement.
Adolescent↗
Prognostic value of the age-adjusted International Prognostic Index in chemosensitive recurrent or refractory non-Hodgkin's lymphomas treated with high-dose BEAM therapy and autologous stem cell transplantation.
High-dose therapy (HDT) is now recommended for patients under 60 years of age with chemosensitive relapsed aggressive non-Hodgkin's lymphoma. However, approximately half of these patients will be cured by HDT. Prognostic factors are needed to predict which patients with chemosensitive lymphoma to second-line therapy could benefit from HDT. We retrospectively investigated the prognostic value of the widely used age-adjusted International Prognostic Index (AA-IPI) calculated at the time of relapse (35 patients) or just before second-line salvage therapy for primary refractory disease (5 patients). The median age was 51 years (range 18-64 years). Thirty-six patients had diffuse large B-cell lymphoma. Salvage cytoreductive therapy before HDT was DHAP/ESHAP (cytarabine, cysplatin, etoposide, steroids) in 17 patients, VIM3-Ara-c/MAMI (high-dose cytarabine, ifosfamide, methyl-gag, amsacrine) in 17 patients, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or reinforced CHOP in 4 patients, high-dose cyclophosphamide and etoposide in 2 patients. The HDT regimen consisted of BEAM (carmusine, cytarabine, etoposide, melphalan) in all cases. Eleven patients were in partial remission and 29 in complete remission at the time of HDT. Ten patients had an IPI >1, 16 had relapsed early (<6 months after first-line therapy) or disease was refractory to first-line therapy (5 of the 16 patients). The median follow-up was 6.07 years (range 1.24-9.74 years). Overall survival was not statistically different in patients with refractory disease or in those who relapsed early compared with late failures (>6 months after first-line chemotherapy) (P=1), but the AA-IPI >1 was associated with a poor outcome (P=0.03). In conclusion, the AA-IPI could have a prognostic value in patients with chemosensitive recurrent lymphoma treated with BEAM HDT.
Adolescent↗
Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults.
PURPOSE: To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. PATIENTS AND METHODS: We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. RESULTS: Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m(2)), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P <.01), older age (P <.01), higher cumulative dose of doxorubicin or association with another anthracycline (P =.04), radiotherapy (P =.04), and being overweight (P =.04). CONCLUSION: Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.
Adult↗
Comparison of the cleavage profiles of oligonucleotide duplexes with or without phosphorothioate linkages by using a chemical nuclease probe.
A manganese porphyrin complex, Mn-TMPyP, associated with KHSO(5) is a chemical nuclease able to selectively recognize the minor groove of three consecutive AT base pairs of DNA and to mediate very precise cleavage chemistry at that particular site. This specific recognition and cleavage were used to probe the accessibility of the minor groove of DNA duplexes composed of one phosphodiester strand and one phosphorothioate strand. The cleavage of 5'-GCAAAAGC/5'-GCTTTTGC duplexes by Mn-TMPyP/KHSO(5) was monitored by HPLC coupled to electrospray mass analysis. Each single strand was synthesized with all-phosphate, all- Rp-phosphorothioate and all- Sp-phosphorothioate internucleotide bonds. We found that the manganese porphyrin was able to recognize its favorite (AT)(3)-box binding site within the heteroduplexes, as in the case of natural DNA. Molecular modeling studies on the interactions of the reactive porphyrin manganese-oxo species with both types of duplexes confirmed the experimental data.
Binding Sites↗
Identification and properties of imprinted genes and their control elements.
Imprinted genes have the unusual characteristic that the copy from one parent is destined to remain inactive. Though few in number they nonetheless constitute a functionally important part of the mammalian genome. With their memory of parental origin, imprinted genes represent an important model for the epigenetic regulation of gene function and will provide invaluable paradigms to test whether we can predict epigenetic state from DNA sequence. Since their first discovery, systematic screens and some good fortune have led to identification of over seventy imprinted genes in the mouse and human: recent microarray analysis may reveal many more. With a significant number of imprinted genes now identified and completion of key mammalian genome sequences, we are able systematically to examine the organization of imprinted loci, properties of their control elements and begin to recognize common themes in imprinted gene regulation.
Alleles↗
Autoimmune thrombocytopenic purpura after autologous stem cell transplantation.
The pathogenesis of thrombocytopenia occurring after autologous stem cell transplantation (ASCT) remains unclear. Six cases of classical peripheral thrombocytopenia that developed after ASCT for non-Hodgkin's lymphoma (NHL) are presented. Resolution of this complication was obtained by usual treatment such as steroids, splenectomy or progressively resolved without specific treatment. Five out of six patients have been followed for more than 5 years after hematopoietic transplantation and are still alive in complete remission despite poor prognostic factors at diagnosis. Several arguments suggest that this phenomenon represents autoimmune thrombocytopenia and may be the consequence of an altered immune balance. Consequently, development of autoimmune reactions after bone marrow transplantation might be associated with an antitumoral effect (graft-versus-lymphoma effect).
Adult↗
[The interferons: pharmacology, mechanism of action, tolerance and side effects].
BACKGROUND: Interferons are a recombinant form of endogenous interferon. By inducing the release of intracellular enzymes such as 2'5' oligoadenylate synthetase and double stranded RNA dependent protein kinase, the drug causes degradation of viral messenger RNA and inhibits protein synthesis. MAIN POINTS: Interferons are cytokines efficient in the treatment of infections diseases. Three main types are described as alpha, beta and gamma depending on their antigenic specificity. They have antiviral activity, antiproliferative and immunomodulation properties in response to a viral infection or other enzyme inducers. Furthermore, they increase expression of major histo-compatible complex antigens, increase natural killer and cytotoxic T cell activity, cytokine induction and production of endogenous interferon. Adverse effects frequently occur but are generally wild and reversible at current dosages. The pharmacokinetics of interferons have been fairly well described. The decline in serum concentrations is rapid after intravenous administration. The volume of distribution approximates 20-60% of bodyweight. Terminal elimination half lives range from 4-16 hrs, 1-2 hrs and 25-35 min for alpha, beta, gamma respectively. Intra-muscular and subcutaneous administration of interferons alpha and bêta results in protracted but fairly good absorption > 80% for interferon alpha to 70% for interferon gamma. Pegylated interferon safety and pharmacodynamic profiles were comparable. Pegylated interferon demonstrated delayed clearance compared with non-pegylated interferon, consistent with once-weekly administration. The severity of adverse effects is dose dependent. Most patients treated have an influenza like syndrome within 2-8 hrs of drug administration. Other effects such as fatigue, lethargy, anorexia are usually dose limiting. Neuropsychiatric reactions may also become dose limiting. Interferon induced the formation of serum neutralizing antibodies in approximately 10-20% of treated patients. PERSPECTIVES: The development of pegylated forms, a greater understanding of action mechanisms, and the combination with other therapies should reinforce the place of interferons in the therapeutic arsenal.
Absorption↗
Epileptic seizures after autologous peripheral blood progenitor infusion in a patient treated with high-dose chemotherapy for myeloma.
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Antineoplastic Combined Chemotherapy Protocols↗
Amifostine reduces mucosal damage after high-dose melphalan conditioning and autologous peripheral blood progenitor cell transplantation for patients with multiple myeloma.
High-dose melphalan (HDM) has been adopted as standard therapy in the treatment of multiple myeloma. This treatment is associated with non-selective cytotoxicity, causing oral mucositis as the major non-hematological side-effect. Amifostine is a cytoprotector which prevents toxicity induced by anticancer therapy. We prospectively compared two groups of patients who either received (group A, n = 21) or did not receive (group B, n = 20) amifostine (740 mg/m(2)) before HDM (200 mg/m(2)) followed by autologous peripheral blood progenitor cell transplantation. The occurrence of severe oral mucositis was significantly decreased in group A in comparison to group B (33% vs 65%, P < 0.05). Six patients in group A required opioid analgesic therapy during a mean period of 4.8 days as compared to eight patients for 6.5 days in group B (P = NS). Delayed vomiting was less frequent in group A (43% vs 70%, P = 0.07) and significantly less severe in group A (grade 2-4) vomiting: two patients vs nine patients, P < 0.02). No difference was observed between the two groups in either hematological toxicity after HDM or in response rate. Grade I emesis was the only immediate side-effect observed after amifostine administration. We conclude that amifostine can reduce mucositis induced by HDM.
Adult↗
In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions.
The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at < >-eutectic composition as our preliminary data show that the plasma concentration (C(5h)) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.
Administration, Oral↗
Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome.
PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.
Adolescent↗
Skin lesions in malignancy. Case 3. Yellow nail syndrome in non-Hodgkin's lymphoma.
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Humans↗
HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer.
The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans. The similarity of both the diffusion coefficients and permeability values obtained for a range of hydrophilic and lipophilic compounds in the two models indicates that the mucus layer secreted by the human adenocarcinoma HT29-MTX goblet cells does not constitute a diffusion barrier to such compounds. The lack of P-glycoprotein (P-gp) in the HT29-MTX cell line may explain the higher permeability values obtained for cimetidine and sumatriptan in this model compared with those derived from the Caco-2/TC7 monolayers. The results suggest that the HT29-MTX model can be used to rank order the passive permeability of compounds, irrespective of their potential interaction with P-gp, which may facilitate optimization of the physicochemical features of compounds within a chemical series.
Administration, Oral↗
A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction.
BACKGROUND: Despite high patency rates, primary angioplasty for myocardial infarction does not necessarily result in optimal myocardial reperfusion and limitation of infarct size. Experimentally, trimetazidine limits infarct size, decreases platelet aggregation, and reduces leukocyte influx into the infarct zone. To assess trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction a prospective, double-blind, placebo-controlled pilot trial was performed. METHODS: 94 patients with acute myocardial infarction were randomized to receive trimetazidine (40 mg bolus followed by 60 mg/day intravenously for 48 h) (n=44) or placebo (n=50), starting before recanalization of the infarct vessel by primary angioplasty. Patients underwent continuous ST-segment monitoring to assess return of ST-segment deviation to baseline and presence of ST-segment exacerbation at the time of vessel recanalization. Infarct size was measured enzymatically from serial myoglobin measurements. Left ventricular angiography was performed before treatment and repeated at day 14. RESULTS: Blinded ST segment analysis showed that despite higher initial ST deviation from baseline in the trimetazidine group (355 (32) vs. 278 (29) microV, P=0.07), there was an earlier and more marked return towards baseline within the first 6 h than in the placebo group (P=0.014) (change: 245 (30) vs. 156 (31) microV respectively, P=0.044). There was a trend towards less frequent exacerbation of ST deviation at the time of recanalization in the trimetazidine group (23.3 vs. 42.2%, P=0.11). There was no difference in left ventricular wall motion at day 14, or in enzymatic infarct size. There was no side effect from treatment. Clinical outcomes were similar between groups. CONCLUSION: Trimetazidine was safe and led to earlier resolution of ST-segment elevation in patients treated by primary angioplasty for acute myocardial infarction.
Adolescent↗