A statistical methodology to select covariates in high-dimensional data under dependence. Application to the classification of genetic profiles in oncology.

We propose a new methodology for selecting and ranking covariates associated with a variable of interest in a context of high-dimensional data under dependence but few observations. The methodology successively intertwines the clustering of covariates, decorrelation of covariates using Factor Latent Analysis, selection using aggregation of adapted methods and finally ranking. A simulation study shows the interest of the decorrelation inside the different clusters of covariates. We first apply our method to transcriptomic data of 37 patients with advanced non-small-cell lung cancer who have received chemotherapy, to select the transcriptomic covariates that explain the survival outcome of the treatment. Secondly, we apply our method to 79 breast tumor samples to define patient profiles for a new metastatic biomarker and associated gene network in order to personalize the treatments.

Towards a better understanding of biomarker response in field survey: a case study in eight populations of zebra mussels.

In order to provide reliable information about responsiveness of biomarkers during environmental monitoring, there is a need to improve the understanding of inter-population differences. The present study focused on eight populations of zebra mussels and aimed to describe how variable are biomarkers in different sampling locations. Biomarkers were investigated and summarised through the Integrated Biomarker Response (IBR index). Inter-site differences in IBR index were analysed through comparisons with morphological data, proteomic profiles and genetic background of the studied populations. We found that the IBR index was a good tool to inform about the status of sites. It revealed higher stress in more polluted sites than in cleaner ones. It was neither correlated to proteomic profiles nor to genetic background, suggesting a stronger influence of environment than genes. Meanwhile, morphological traits were related to both environment and genetic background influence. Together these results attest the benefit of using biological tools to better illustrate the status of a population and highlight the need of consider inter-population difference in their baselines.

Comparative phylogeography among hydrothermal vent species along the East Pacific Rise reveals vicariant processes and population expansion in the South.

The use of sequence polymorphism from individual mitochondrial genes to infer past demography has recently proved controversial because of the recurrence of selective sweeps acting over genes and the need for unlinked multilocus data sets. However, comparative analyses using several species for one gene and/or multiple genes for one species can serve as a test for potential selective effects and clarify our understanding of historical demographic effects. This study compares nucleotide polymorphisms in mitochondrial cytochrome oxidase I across seven deep-sea hydrothermal vent species that live along the volcanically active East Pacific Rise. Approximate Bayesian Computation (ABC) method, developed to trace shared vicariant events across species pairs, indicates the occurrence of two across species divergence times, and suggests that the present geographical patterns of genetic differentiation may be explained by two periods of significant population isolation. The oldest period dates back 11.6 Ma and is associated with the vent limpet Lepetodrilus elevatus, while the most recent period of isolation is 1.3 Ma, which apparently affected all species examined and coincides with a transition zone across the equator. Moreover, significant negative Tajima's D and star-like networks were observed for all southern lineages, suggesting that these lineages experienced a concomitant demographic and geographical expansion about 100 000-300 000 generations ago. This expansion may have initiated from a wave of range expansions during the secondary colonization of new sites along the Southern East Pacific Rise (founder effects below the equator) or recurrent bottleneck events because of the increase of eruptive phases associated with the higher spreading rates of the ridge in this region.

[Cutaneous drug-reactions to nevirapine: study of risk factors in 101 HIV-infected patients]. / Toxidermie à la névirapine.

BACKGROUND: Several studies have shown a high prevalence of rash induced by nevirapine. However, there is little knowledge about the risk factors associated with nevirapine-induced rash. The aim of this study was to identify risk factors associated with the occurrence of rash during the treatment with nevirapine of HIV-infected patients. METHODS: A retrospective study was conducted in the dermatology department of Besançon university teaching hospital between November 1998 and September 2001. The study included all HIV-infected patients receiving HAART regimens that included nevirapine. The following data were collected: age, sex, CDC classification of HIV, CD4 and CD8 lymphocyte counts, plasma HIV RNA load, hepatitis B, C and cytomegalovirus serostatus, history of drug allergy, concomitant medication (other antiretroviral drugs, corticosteroids, antihistamines). Univariate analysis was performed using a Chi2 test or Fischer's test and Student's t test. Fischer's test and the Cox proportional hazards model were used in the multivariate analysis. RESULTS: During the study period, 101 HIV-infected patients (74 men and 27 women; mean age: 41.6 +/- 10.3 years) were treated with HAART regimens including nevirapine. Fourteen developed cutaneous drug-reactions attributable to nevirapine (13.86%). We observed 13 cases of maculopapular exanthema and 1 case of DRESS. In the univariate analysis, female gender (p=0.002), plasma HIV RNA load > 10,000 copies/ml (p=0.05), heterosexual transmission (p=0.002) and abacavir treatment (p=0.05) constituted risk factors associated with rash. In the multivariate analysis, only female gender (p<0.0001) and plasma HIV RNA load > 10,000 copies/ml (p=0.0007) were associated with rash. DISCUSSION: The results of this study confirm the high frequency of toxidermy associated with nevirapine therapy. The risk factors associated with occurrence of rash due to nevirapine therapy were female gender and plasma RNA > 10,000 copies/ml. Several studies showed absence of any protective effect of antihistamines and corticosteroids in preventing the cutaneous adverse reactions associated with nevirapine. The identification of risk factors closely associated with nevirapine-induced rash could help physicians determine new strategies for safer use of nevirapine in the HAART regimen.

[Effects of imiquimod on latent human papillomavirus anal infection in HIV-infected patients]. / Effets de l'imiquimod sur l'infection périanale latente à papillomavirus humain chez des malades infectés par le virus de l'immunodéficience humaine.

INTRODUCTION: High risk human papillomaviruses (HPV) have emerged as risk factors for anal carcinoma particularly in HIV-infected patients who demonstrate a high rate of anal HPV infection. Considering the relationship between the presence of anal infection and the development of neoplastic lesions, we wished to assess the capacity of imiquimod to eradicate latent HPV infection in HIV-infected patients. PATIENTS AND METHODS: We conducted a prospective, randomized, double-blind and vehicle controlled study. Two consecutive anal swabs were taken at 2 month intervals and only patients with two consecutive tests positive for the detection of HPV-DNA (Hybrid Capture II) were included. Patients with persistent latent HPV infection were divided into 2 groups who applied imiquimod versus vehicle during 6 weeks. HPV-DNA presence was then investigated 2 and 4 months following the onset of treatment. RESULTS: Among the 80 HIV-infected patients, 26 (32.5 p. 100) had 2 positive consecutive assays, and 19 patients were included in the study. After randomization, 9 patients received imiquimod and 10 vehicle. There was no significant difference between treatment groups according to the following criteria: gender, route of HIV transmission, CDC stage, prior medical history of sexually transmitted diseases or anogenital warts. 33.3 p. 100 (3/9) of patients treated with imiquimod were negative at M2, whereas 100 p. 100 (10/10) vehicle treated-patients remained positive (p=0.08). Similar results were observed at the M4 visit. DISCUSSION: Our study confirmed the increased prevalence of latent HPV-DNA infection in HIV-infected patients. In spite of the low number of treated patients, we did not observe a statistically significant decrease in HPV-DNA in anal swabs from imiquimod-treated patients as compared to placebo-treated patients.

[Unilateral primary adrenal lymphoma: a case report]. / Lymphome primitif unilatéral de la surrénale: a propos d'un cas.

The authors report a case of unilateral primary adrenal lymphoma presenting with abdominal and dorsal pain. Primary lymphoma of the genitourinary tract, specifically adrenal localisation, is a rare disease. CT is the current best imaging modality for evaluating retroperitoneal masses and improving detection, characterization as well as assessing extension. Diagnosis is based on histology.

Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro.

Several matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were studied in highly invasive (MDA-MB-231) and slightly invasive (MCF-7, T47D, BT-20) breast cancer cell lines. Investigations were carried out at the protein level and/or at the mRNA level, either in cells cultured as monolayers on plastic, or in cells seeded on a thin layer of Matrigel basement membrane matrix. Analysis of MMP expression by RT-PCR showed expression of MMP-1. MMP-3, and MMP-13 in highly invasive MDA-MB-231 cells, but not in slightly invasive cell lines. The extracellular secretion of MMP-1 and MMP-3 by MDA-MB 231 cells could be also shown by ELISA. TIMP-1 and TIMP-2 mRNAs were found in all cell lines, however, the extracellular secretion of both TIMPs was much higher in MDA-MB-231 cells than in the other cell lines. When the cells were cultured on Matrigel matrix, MMP-9 expression was induced in MDA-MB-231 cells only, as assessed by RT-PCR and zymography experiments. The invasive potential of MDA-MB-231 cells evaluated in vitro through Matrigel was significantly inhibited by the MMP inhibitor BB-2516, by 25% and 50% at the concentrations of 2 x 10(-6) M and 10(-5) M, respectively. In conclusion, our data show that highly invasive MDA-MB-231 cells but not slightly invasive T47D, MCF-7 and BT-20 cells express MMP-1, MMP-3, MMP-9 and MMP-13. MMP-9 which is specifically up-regulated by cell contact to Matrigel, may play a key role in the invasiveness of MDA-MB-231 cells through basement membranes.

[Left ovarian vein syndrome]. / Syndrome de la veine ovarienne gauche.

Ovarian vein syndrome is classically described on the right side. Patients present with lumbar pain or renal colics due to a compression of the ureter between the external iliac artery and a dilated ovarian vein. We report an unusual case of left ovarian vein syndrome between a dilated ovarian vein and the psoas muscle, with a similar clinical presentation.

[Bladder adenomyomatosis. Apropos of a case of segmental involvement. Correlation ultrasonography-MRI]. / L'adénomyomatose vésiculaire. A propos d'un cas d'atteinte segmentaire. Corrélation échographie-IRM.

Adenomyomatosis of the gall bladder is a classical but seldom recognized cause of gallbladder wall thickening. The authors review the imaging features of this disease and emphasize the value of ultrasound and MRI. Although considered a benign disease, some recently described cases of neoplastic transformation may warrant surgery.

Relationship between a mild alpha 1 proteinase inhibitor deficiency and respiratory symptoms in a family.

A 34-year-old man with pulmonary emphysema was found to have a mild alpha 1 proteinase inhibitor (alpha 1 PI) deficiency. alpha 1 PI status was investigated in this patient and in 35 members of his family. The alpha 1 PI investigations included alpha 1 PI concentration and phenotype and serum inhibitory capacity for trypsin and pancreatic elastase. Fifteen members of the family had alpha 1 PI concentration and inhibitory capacities below the lower normal limit. Five of these members were characterized by the heterozygous MP phenotype and the 10 others by an apparently homozygous M phenotype, in which the M allele may be associated with another unidentified deficiency allele. Two members of the family had alpha 1 PI concentration and elastase inhibitory capacity below the lower normal limits and trypsin inhibitory capacity within the normal range. They were both characterized by the MP phenotype. Six of these 17 members (three of PI type M and three of PI type MP) showed chronic pulmonary symptoms, whereas among the 19 alpha 1 PI non deficient members, no member had a history of significant pulmonary symptoms.

Measurement of elastase and cysteine proteinases in synovial fluid of patients with rheumatoid arthritis, sero-negative spondylarthropathies, and osteoarthritis.

Synovial fluid samples were collected from 45 patients with rheumatoid arthritis, spondylarthropathy, or osteoarthritis, to study their content of elastase (EC 3.4.21.37) and of cysteine proteinases (EC 3.4.22.1, 3.4.22.15). We measured both elastase complexed with alpha 1-proteinase inhibitor and elastase activity toward the substrate L-pyroglutamyl-L-prolyl-L-valine-p-nitroanilide. Cysteine proteinase activities were measured with the substrates N-benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin (Z-Phe-Arg-AMC) and Z-Arg-Arg-AMC and the inhibitor E-64 [L-trans-epoxysuccinyl-leucyl-amido-(4-guanidino)-butane]. In all these enzyme assays, higher median values were obtained in inflammatory arthropathies than in osteoarthritis. The concentration of the elastase-alpha 1-proteinase inhibitor complex and of elastase and cysteine proteinase activities were statistically higher in patients with rheumatoid arthritis than in patients with osteoarthritis. The difference in results between patients with spondylarthropathy and patients with osteoarthritis was statistically significant only for the elastase-alpha 1-proteinase inhibitor complex. The median values of the complex and of both enzyme activities were higher in patients with rheumatoid arthritis than in patients with spondylarthropathy; however, the difference was statistically significant only for the cysteine proteinase activity measured with Z-Arg-Arg-AMC substrate. These results suggest that both elastase and cysteine proteinases, which are increased in patients with inflammatory arthritis, are involved in cartilage degradation in these arthropathies.

Effect of massive proximal small bowel resection on intestinal brush border membrane proteins in the dog.

Dog enterocyte brush border proteins have been studied after a 75% proximal resection of the small bowel. This study was carried on microvillar membrane preparations purified from ileal mucosa sampled before and after regeneration on neighbouring intestinal segments, each animal acting as its own control. After six weeks of regeneration a statistically significant decrease of the following enzyme specific activities was observed: lactase, cellobiase, maltase, sucrase, palatinase, dextranase, trehalase, alkaline phosphatase, aminopeptidase and gamma-glutamyl transferase. Analysis of brush border proteins by polyacrylamide gel electrophoresis in presence of sodium dodecyl sulphate have shown after regeneration a decreased rate for the proteins with a molecular weight higher than 100,000 daltons. Modifications of electrophoretic patterns seem to be related to the specific activity decreases observed for brush border enzymes after regeneration, since the molecular weight of these enzymes were found between 116,000 and 285,000 daltons, after gel filtration.