The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype.

BACKGROUND: Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet. OBJECTIVES: To determine the expression and the functions of NOR1 in human alternative macrophages. METHODS AND RESULTS: In vitro IL-4 polarization of primary monocytes into alternative M2 macrophages enhances NOR1 expression in human but not in mouse macrophages. Moreover, NOR1 expression is most abundant in CD68+MR+ alternative macrophage-enriched areas of human atherosclerotic plaques in vivo. Silencing NOR1 in human alternative macrophages decreases the expression of several M2 markers such as the Mannose Receptor (MR), Interleukin-1 Receptor antagonist (IL-1Ra), CD200 Receptor (CD200R), coagulation factor XIII A1 polypeptide (F13A1), Interleukin 10 (IL-10) and the Peroxisome Proliferator-Activated Receptor (PPAR)γ. Bioinformatical analysis identified F13A1, IL-1Ra, IL-10 and the Matrix Metalloproteinase-9 (MMP9) as potential target genes of NOR1 in human alternative macrophages. Moreover, expression and enzymatic activity of MMP9 are induced by silencing and repressed by NOR1 overexpression in M2 macrophages. CONCLUSIONS: These data identify NOR1 as a transcription factor induced during alternative differentiation of human macrophages and demonstrate that NOR1 modifies the alternative macrophage phenotype.

Genome-wide gene expression profiling to predict resistance to anthracyclines in breast cancer patients.

Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset.

[Vertical reduction mammaplasty for gigantomastia with massive fibroadenomatosis: a case report]. / Réduction mammaire selon la technique verticale pour gigantomastie avec fibroadénomatose massive: à propos d'un cas clinique.

Vertical reduction mammaplasty is one of the most debated << short-scar >> breast reduction technique. Advantages and drawbacks of the technique are discussed; most of the authors do not accept it as the technique of choice for high glandular resection weights. In our case report we achieve it for a resection weight up to two kilograms with an areolar transposition distance of more than ten centimetres. We show that it is reasonable to realize it dealing with gigantomastia. The massive fibroadenomatosis is observed following immunosuppressive treatment for kidney transplantation. Cyclosporine intake, even sporadic, is at the origin of the growth of these multiple, bilateral and large fibroadenomas. Drug-induced cytokines stimulate their development.

Trisomy 16 as the sole anomaly in hematological malignancies. Three new cases and a short review.

We report on three cases, two with myelodysplastic syndrome (MDS) and one with acute lymphoblastic leukemia (ALL), displaying trisomy 16 as the sole cytogenetic anomaly. In none of these cases was a concomitant inv(16)(p13q22) detected by fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR). Summarizing the literature, only six other cases cytogenetically characterized by an isolated trisomy 16 have been reported in hematological malignancies. These patients had either MDS, acute myeloblastic leukemia (AML), myelofibrosis, or ALL. All but one of these cases were aged less than 50.

MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23.

We here report the clinical, cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data on 14 patients with a myeloid malignancy and structural aberration of chromosome band 11q23 associated with overrepresentation or amplification of the MLL gene. The number of copies of MLL varied from three (two cases) to a cluster consisting of multiple hybridization spots. Together with previous reports, available data indicate that amplification of 11q23/MLL is a recurrent genetic change in myeloid malignancy. It affects mainly elderly patients and is often associated with dysplastic bone marrow changes or with complex karyotypic aberrations, suggestive of genotoxic exposure. It is associated with a poor prognosis. In addition, FISH analysis of nine cases with additional 11q probes showed that the overrepresented chromosomal region is generally not restricted to MLL, and Southern blot analysis indicated that amplification does not involve a rearranged copy of this gene. The significance of MLL amplification and the mechanisms by which it could play a role in leukemogenesis and/or disease progression remain to be elucidated.

Clinical benefit from erythropoietin.

Advances continue in erythropoietin biology, and additional data reviewed here have recently become available on complex feedback mechanisms describing the interrelations of hypoxia and its effects on anemia and tumor behavior (eg, apoptosis, angiogenesis). In addition to biology, other clinically relevant data in oncology are included and an attempt is made to identify patients who are most likely to benefit from treatment. The latter aspects will better define the profile of the target patient, probably prevent overtreatment, and improve cost-benefit ratios. Interesting data on radiotherapy results improved by increasing tissue hemoglobin have been published but will need further confirmation.

Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross an in vitro model of the blood-brain barrier.

A cell culture model of the blood-brain barrier (BBB) consisting of a coculture of bovine brain capillary endothelial cells and rat astrocytes has been used to examine the ability of 60-nm nanoparticles with different physicochemical characteristics to cross the BBB. Neutral, anionic, and cationic nanoparticles were made from crosslinked malto-dextrins derivatized or not (neutral) with phosphates (anionic), quaternary ammoniums (cationic) ligands. Then, these particles were coated or not with a lipid bilayer made of dipalmitoyl phosphatidyl choline and cholesterol. Lipid coating of ionically charged nanoparticles was able to increase BBB crossing 3- or 4-fold compared with uncoated particles, whereas coating of neutral particles did not significantly alter their permeation characteristics across the endothelial cell monolayer. Lipid-coated nanoparticles were nontoxic toward BBB integrity, and crossed the BBB by transcytosis without any degradation. Furthermore, a 27-fold increase in albumin transport was observed when albumin had previously been loaded in the cationic lipid-coated nanoparticles. The influence of red blood cells was studied; a marked inhibition of the transport was observed, probably due to strong interaction between nanoparticles and red blood cells.

Complications and hospitalisation--duration after chemoembolisation for liver metastases.

In a retrospective study, all patients of the hemato-oncology department of the Centre Hospitalier who were treated from 1988 to 1997 by chemoembolisation for liver metastases were analysed for treatment-related hospitalisation duration, side effects and complications, in order to assess the treatment burden. Major side-effects were: pain in 17 of 29 patients, nausea in 8, vomiting in 7, persistent hickup in 3, fever in 12, a temporary confusional state in 4 patients. 1 patient experienced syncope, 2 patients developed homolateral pleral effusions, 1 patient suffered transient supraventricular arrhythmias. Major complications included 1 hemoperitoneum (under anticoagulant therapy), 1 hemorrhagic gastritis, 1 acute cholecystitis due to inflammatory tumoral choledochal obstruction and one iatrogenous acute pancreatic ischemic necrosis. Two patients died of post-embolic acute hepatic insufficiency, one 10 days, one 41 days after the last treatment session). In summary, chemo-embolisation of liver metastases is a complication-burdened treatment in a strictly palliative setting with inestimable efficacy. The treatment modalities have to be discussed with the patient beforehand and preferably in controlled study setting. Large randomised trials may indicate patients' subgroups for benefit.

In vitro model for evaluating drug transport across the blood-brain barrier.

The passage of substances across the blood-brain barrier (BBB) is regulated in the cerebral capillaries, which possess certain distinct different morphological and enzymatic properties compared with the capillaries of other organs. Investigations of the functional characteristics of brain capillaries have been facilitated by the use of cultured brain endothelial cells, but in most studies some characteristics of the in vivo BBB are lost. To provide an in vitro system for studying brain capillary functions, we have developed a process of coculture that closely mimics the in vivo situation by culturing brain capillary endothelial cells on one side of a filter and astrocytes on the other. In order to assess the drug transport across the blood-brain barrier, we compared the extraction ratios in vivo to the permeability of the in vitro model. The in vivo and the in vitro values showed a strong correlation. The relative ease with which such cocultures can be produced in large quantities facilitates the screening of new centrally active drugs. This model provides an easier, reproducible and mass-production method to study the blood-brain barrier in vitro.

[Spontaneous regression of pulmonary metastases in renal cancer]. / Régression spontanée de métastases pulmonaires d'un cancer rénal.

Spontaneous regression of lung-metastases in kidney cancer (a case report) A case is reported of a 56-year old woman with renal cell carcinoma operated and treated adjuvantly for a year with Interferon alpha. Ten months thereafter the patient had histologically proven a large pulmonary metastatic disease that regressed spontaneously. Duration of the spontaneous remission was 8 months.

Inhibition of P-glycoprotein: rapid assessment of its implication in blood-brain barrier integrity and drug transport to the brain by an in vitro model of the blood-brain barrier.

PURPOSE: The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent. METHODS: An in vitro model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes was used. RESULTS: We demonstrate that P-glycoprotein expression is upregulated by the presence of astrocytes. Uptake in the cells and transport across endothelial cell monolayers of vincristine, cyclosporin A and doxorubicin were studied. Using S9788 or verapamil as reversing agents, we found an increase in vincristine transport across the endothelial cell monolayers. On the other hand, the association of S9788 or verapamil with cyclosporin A failed to increase the transport of this drug. An increase in the transport of doxorubicin from luminal to abluminal compartment was also observed, due to endothelial cell monolayer breakdown. CONCLUSIONS: Using this model, it is possible to predict the passage of a P-glycoprotein dependent drug to the brain or its sequestration in brain capillary endothelial cells when this drug is associated with a reversing agent, or its toxicity on the blood-brain barrier integrity.

Phase I/II clinical trial of epirubicin and paclitaxel followed by granulocyte colony-stimulating factor in a 2-week schedule in patients with advanced or metastatic breast cancer.

Anthracyclines and taxanes are the most potent cytotoxic agents available for treating breast cancer. With combined therapy (either epirubicin or doxorubicin with paclitaxel [Taxol; Bristol-Myers Squibb Company, Princeton, NJ]), response rates of 70% to 90% have been reported. To achieve a maximal dose intensity per week, we decided to combine epirubicin 100 mg/m2 with escalating doses of paclitaxel, at successive dose levels of 135, 150, 165, and 180 mg/m2 in a 2-week schedule, with administration of subcutaneous granulocyte colony-stimulating factor 5 microg/kg from days 2 through 10. To date, 16 patients have been included, with six patients treated at level 1 (100/135 mg/m2 epirubicin/paclitaxel), four at level 2 (100/150 mg/m2), four at level 3 (100/165 mg/m2), and two at level 4 (100/180 mg/m2). The median age of all subjects is 55 years (range, 41 to 65 years). Five patients had received chemotherapy in the adjuvant setting. Of 79 treatment courses, 78 are evaluable for toxicity. The mean number of courses per patient is six (range, two to six courses). At dose level 1, one episode of febrile neutropenia with grade 4 thrombocytopenia occurred. No grade 4 extrahematologic adverse event has been noted so far. At dose level 2, we achieved a dose intensity per week of epirubicin 50 mg/m2 and paclitaxel 75 mg/m2, as expected. At dose level 3, the dose intensity per week was 47.5 mg/m2 and 78.8 mg/m2, respectively (expected 50 and 82.5 mg/m2). The current response rate, evaluated in 14 of 16 patients, is four complete remissions and eight partial remissions, for an overall response rate of 85%. Two patients had stable disease. Granulocyte colony-stimulating factor following epirubicin/paclitaxel on a 2-week schedule permits a very high dose intensity per week for both drugs and produces a high response rate in patients with advanced or metastatic breast cancer.

Multidrug resistance: molecular and clinical aspects.

Clinical drug resistance, a common and compromising side-effect during anticancer chemotherapy, is an acquired cellular resistance simultaneously to several cytotoxic drugs. Expression of the multidrug resistance gene (mdr) is one of the most-studied potential underlying mechanisms. The human mdr gene family encompasses two homologous members, the first of which, called the mdr1 gene, is the best-characterized so far. The human mdr1 gene has been shown to encode a membrane P-170 glycoprotein that, on the basis of its structure, is considered to act as a drug-efflux pump excreting various drugs from cells. The human mdr1 gene is thus a major regulated gene playing an important role in the molecular mechanism of multidrug resistance. Its bipartite structure of two similarly organized halves is explained by a gene fusion event during evolution. However, the clinical significance of this particular feature, if it seemed obvious in the 1980s as a factor producing chemoresistance, is currently revised-being a marker of tumor aggressiveness rather than the cause of drug resistance.

[New diagnostic approaches to deep venous thrombosis]. / Nouvelles approches diagnostiques des thromboses veineuses profondes.

This review summarizes a number of recent articles reconsidering the use of phlebography as the golden standard for deep venous thrombosis. Compression ultrasound and color-coded duplex doppler seem to be reasonably sensitive to provide safety in detecting lower limb thrombosis while less invasive. A clinical risk factor panel may further enhance diagnostic security.

Epirubicin cardiotoxicity: a study comparing low- with high-dose-intensity weekly schedules.

Epirubicin is one of the less cardiotoxic alternatives to doxorubicin. We were interested in studying the cardiotoxic effect of the total cumulative dose, and weekly schedules of low compared to high dose intensity. Fifty-seven patients were treated with different epirubicin-containing regimens. We confirm the classical notion that total cumulative doses of less than 600 mg/m2 do not induce significant cardiotoxicity, whereas doses above 600 mg/m2 are associated with a trend towards cardiotoxicity. Patients receiving a high weekly dose intensity (> 40 mg/m2), however, did have a significantly lower incidence of cardiotoxicity than those receiving a low dose intensity per week (< 40 mg/m2) (22.8% versus 50%; P < 0.05). We identified the association of a dose intensity of more than 40 mg m-2/ week-1 and a cumulative dose of 400-899 mg/m2 or a dose intensity of less that 40 mg m-2/week-1 and a cumulative dose of less than 400 mg/m2 to have the lowest incidence rate of cardiotoxicity. We conclude from this study that epirubicin in weekly schedules of high dose intensity is not more cardiotoxic than in weekly schedules of low dose intensity.

Rapid quantification of alpha-tocopherol in plasma and low- and high-density lipoproteins.

We have developed two methods for measuring the alpha-tocopherol content in plasma and lipoproteins (LDL and HDL). In procedure 1, plasma or lipoproteins are deproteinized with ethanol containing delta-tocopherol as internal standard and then extracted with hexane or ethyl acetate. The organic layer is removed and evaporated, and the residue is redissolved in methanol and injected into a reversed-phase HPLC. In procedure 2, plasma or lipoproteins are diluted in a methanol and ethanol mixture containing the same internal standard. The solution is vortex-mixed, centrifuged, and directly injected into the column. The tocopherols are eluted with an isocratic methanol mobile phase at a flow rate of 1 mL/min and detected by fluorescence (lambda(exc)= 295 nm, lambda(em)= 330nm). Recoveries are approximately 100% in both cases. Between-run CVs were 8.39% for procedure 1 and 6.55% for procedure 2. Small sample requirement, simplicity of sample preparation, short assay time, and good reproducibility make procedure 2 ideal for clinical or research use. This method was applied to determination of alpha-tocopherol in plasma of patients whose diet was supplemented with alpha-tocopherol and in LDL and HDL.

What Does Multidrug Resistance (MDR) Expression Mean in the Clinic?

For 15 years, an overflowing literature has been published about MDR-1 gene expression in tumor cell lines and in cancerous tissues at various stages of disease and treatment (chemotherapy-naive, during treatment and at relapse). However, the clinical significance of this particular feature, if it seemed obvious in the 1980s as a factor responsible for the development of chemoresistance, is currently reconsidered. MDR-1 gene expression seems to be, at least in some instances, a hallmark of tumor cell aggressiveness and of chemoresistance rather than its cause, the mechanisms of which are probably far more complex. The failure of MDR reversal trials might result from the misunderstood or overvalued role of MDR expression in cancer cells rather than from a lack of control of pharmacological parameters. This review summarizes recent data and hypothesis about the expression of P-170 and its clinical significance in some important human tumor types, suggesting that it should rather be considered in the future as an adverse prognostic factor.