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Antiretroviral therapy (ART) inhibits HIV-1 replication and disease progression but does not lead to a cure. During ART, the integrated HIV-1 genome persists mainly in memory CD4+ T lymphocytes, as well as in other immune cells, such as macrophages. Most of these cells do not produce viral particles, establishing a latent reservoir. Much progress has been made in identifying factors that contribute to the establishment and maintenance of latent reservoirs; however, they remain the main hurdle for HIV-1 eradication. In this review, we discuss the role of microRNAs in the development of the viral reservoir. These modulators of gene expression target effectors governing productive infection and have even direct impacts on viral transcripts. In this review, we consider current unresolved questions regarding host microRNAs in HIV-1 persistence, particularly those involved in viral latency. Additionally, given that current strategies have yet to effectively reduce viral reservoirs, the potential use of microRNAs to counter the persistence of latent reservoirs is also discussed. [ABSTRACT FROM AUTHOR]

Résumé: Le syndrome de susceptibilité mendélienne aux infections mycobactériennes (SSMIM) est un syndrome génétique rare prédisposant aux infections à des mycobactéries normalement non pathogènes pour l’homme (mycobactéries atypiques ou non tuberculeuses) et au bacille vaccinal de Calmette et Guérin (BCG), chez des enfants indemnes de déficits immunitaires classiques. Ce syndrome est lié à une altération de l’immunité antimycobactérienne médiée par l’axe IL12/INF-γ (interleukine 12/interféron gamma), constituant un nouveau type de déficit immunitaire. Nous rapportons l’observation d’une enfant ayant présenté une infection disséminée à Mycobacterium avium. Le défaut moléculaire en cause était la présence de 2 mutations au niveau du gène IL12Rβ1 (gène codant pour la chaîne β1 du récepteur de l’IL12) responsable d’un défaut d’expression, à la surface des lymphocytes T, du récepteur de l’IL12. Les mutations touchant le gène IL12Rβ1 sont les anomalies moléculaires les plus fréquentes du SSMIM. À l’heure actuelle, on connaît 6 gènes impliqués dans le SSMIM, responsables de 13 maladies génétiques distinctes, caractérisées par une grande variété de présentations cliniques. La description des bases moléculaires et immunologiques de ce syndrome a permis d’expliquer la physiopathologie de l’immunité antimycobactérienne et s’avère indispensable pour comprendre et prendre en charge ces infections. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoids exert their actions at nuclear levels through genomic mechanisms including both transcriptional activation (transactivation) and gene expression repression (transrepression). Transactivation mechanisms are mediated by transcription factors, the main one being the activated glucocorticoid receptor (GR). These mechanisms contribute to both powerful therapeutic effects of glucocorticoids on inflammatory and immune diseases, and adverse effects than can be harmful on vital functions. Non-genomic mechanisms, which act faster than genomic ones, have also been explored. They also involve the GR in different membranous and cytosolic sites. The phenomenon of glucocorticoid resistance is also complex and several different mechanisms may mediate this phenomenon. Among them are alterations in number, binding affinity or phosphorylation status of the GR, changes in capacity of cellular apoptosis, polymorphic changes or expression of proteins involved in the genomic actions of glucocorticoids. Finally, some proteins, which mediate glucocorticoid activity could be therapeutic targets for reducing glucocorticoid-induced adverse effects. [Copyright &y& Elsevier]

Résumé: Les spondyloarthrites sont encore présumées réactionnelles à des infections et non dues à la rémanence de bactéries dormantes, pour plusieurs raisons : la règle de n’évoquer une infection que si le germe peut être cultivé ; l’absence de démonstration de bactéries dormantes dans les tissus cibles des spondyloarthrites ; l’absence présente d’incidences thérapeutiques, puisque les antibiotiques sont inopérants sur les bactéries dormantes et les spondyloarthrites ; la fréquence des formes de passage entre spondyloarthrites et rhumatismes psoriasiques, voire polyarthrites rhumatoïdes, qui devrait induire que ces affections aussi sont favorisées par des infections dormantes. Les connaissances acquises récemment sur les bactéries dormantes ont pourtant relancé cette hypothèse. Le caractère non cultivable des bactéries dormantes tient au fait qu’elles n’expriment qu’un petit nombre de gènes, appelé régulon, dont des facteurs de transcription qui bloquent l’expression des gènes bactériens usuels. Certains stress cellulaires, comme le mauvais repliement de molécules, facilitent l’adoption par les bactéries d’un état dormant, lequel induit une sécrétion à bas bruit par la cellule hôte de cytokines, dont le TNF. Reste à vérifier si le mauvais repliement de HLA-B27 facilite la persistance de bactéries dormantes dans les tissus cibles des spondyloarthrites. Si tel était le cas, des traitements capables de réveiller les bactéries dormantes pourraient permettre de rendre celles-ci sensibles à certains antibiotiques, et pourraient être d’utiles compléments aux AINS et anti-TNF. Ces derniers ne réveillent que rarement les bactéries assoupies, réserve faite du bacille de Koch dont la dormance est, avec celle des cellules métastatiques, le modèle de latence le plus étudié. [Copyright &y& Elsevier]

Résumé: Objectif: Les biomarqueurs actuellement disponibles (facteurs rhumatoïdes [FRs], anti-CCP2, VS/CRP et érosions osseuses) ne suffisant pas à prédire les dommages structuraux de la polyarthrite rhumatoïde (PR), déterminer si l’expression dans le tissu synovial d’un ou plusieurs marqueurs pourrait constituer un (de) nouveau(x) facteur(s) pronostique(s). Méthode: L’étude a été menée sur 18 patients de la cohorte VErA, inclus prospectivement, naïfs de tout traitement par DMARD et glucocorticoïdes, et présentant une arthrite très récente (ancienneté médiane des symptômes : quatre mois). Les données recueillies à l’inclusion étaient les suivantes : paramètres cliniques et biologiques (VS, CRP, isotypes du FRs, anti-CCP2, ostéoprotégérine, taux de RANK-L et COMP) ; expression dans le tissu synovial (HLA-DR, CD163, CD3, CD20, VEGF, ostéoprotégérine, RANK-L, Bcl2 et indice global d’inflammation) à partir d’une biopsie de synoviale de l’articulation métacarpophalangienne. Les radiographies de la main et du pied à l’inclusion et à trois ans ont été évaluées au moyen du score de Sharp modifié par van der Heijde ; son évolution durant le suivi constituait le critère de jugement. Le coefficient de corrélation de Pearson a été utilisé pour tester l’association entre échantillons appariés. Résultats: À l’inclusion, une corrélation significative a été mise en évidence entre lésions érosives et marqueurs de l’activation des lymphocytes B, notamment l’expression de CD20 dans le tissu synovial (r =0,68 ; p =0,0001). Quantifiée par la variation du score d’érosion de Sharp modifié, la progression des dommages structuraux à trois ans était significativement corrélée avec : les taux sériques de FR-IgG (r =0,75 ; p =0,0003), -IgM (r =0,69 ; p =0,001), anti-CCP2 (r =0,53 ; p =0,02) et RANK-L (r =0,61 ; p =0,007), ainsi que l’expression de CD20 dans le tissu synovial (r =0,70 ; p =0,001). Conclusion: Cette analyse de la valeur pronostique d’un large panel de marqueurs synoviaux au sein d’un échantillon limité de patients suivis prospectivement, et bien documentés, suggère qu’à la fois le CD20 synovial et les taux sériques de RANK-L pourraient représenter de nouveaux facteurs prédictifs de la progression des dommages structuraux à un stade très précoce de la PR. [Copyright &y& Elsevier]

Microsatellite instability is the molecular fingerprint of a deficient mismatch repair system. This alteration occurs in 15% of colorectal cancers, with two-third being linked to a sporadic disease, and one-third to an inheritance syndrome, the Lynch syndrome. This status, which can be assessed by molecular biology and immunohistochemistry, now belongs to the usual tests performed by the pathologist involved in digestive pathology. MSI determination is a screening method to detect patients who are prone to be affected by Lynch syndrome. Indeed, MSI is present in nearly all patients having Lynch syndrome. In this setting, immunohistochemistry may be helpful in selecting the gene harboring the germline mutation for which the encoded protein is not expressed. The distinction between sporadic and inherited MSI cases can be based on BRAF and hMLH1 hypermethylation. These alterations have never been encountered in Lynch syndrome. In addition, MSI identification in stage II colorectal carcinoma does not favor 5-FU chemotherapy, because this treatment has been shown to negatively impact on overall survival. In order to be optimal, molecular and immunohistochemistry techniques have to be performed in an environment in connection with quality insurance programs. [ABSTRACT FROM AUTHOR]

Invasive breast carcinoma's prognosis is defined using clinico-pathological parameters among which proliferation is essential. Ki67 has strong prognostic and predictive values. Ki67 is expressed during all the cell cycle but G0. The determination of its expression with the MIB1 antibody, on tissue sections, requires well-controlled preanalytical steps for tissue preparation (fixation and paraffinembedding) and an accurate protocol for immunohistochemistry. These technical issues are limiting but largely balanced with immunohistochemistry's low cost and its wide utilization in pathology laboratories. Ki67 staining's interpretation follows international guidelines recently published without any recommended cut-off. However, the most commonly used is 20% of stained cells. Genome complexity assessed with DNA arrays provides another level of prognostic information. The higher the number of chromosome breakpoints, the poorer the prognosis. However, until now, this tool remains useful in the context of clinical trials in specialized centers. [ABSTRACT FROM AUTHOR]

Conventional histology and immunohistochemistry remain the basic tools for the diagnosis and classification of sarcomas. However, molecular biology can enrich the pathologists analysis: the identification of a specific molecular abnormality can confirm diagnosis, rule out a differential diagnosis, and sometimes provide prognostic information. About 15% of sarcomas bear a specific translocation, such as rearrangements of SS18 (SYT) [synovial sarcoma], DDIT3 (CHOP) [myxoid liposarcoma], FUS (TLS) [low-grade fibromyxoid sarcoma, myxoid liposarcoma], FOXO1 (FHKR) [alveolar rhabdomyosarcoma], PDGFB (dermatofibrosarcoma protuberans), and ALK (inflammatory myofibroblastic tumor). Rearrangements of the EWSR1 gene are less specific as found in many sarcomas (Ewing sarcoma, desmoplastic round cell tumor, clear cell sarcoma, myxoid liposarcoma, andmyoepithelioma). The search for an amplification of MDM2 gene is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/welldifferentiated liposarcomas and dedifferentiated liposarcomas (ALT/WDL). The same molecular abnormality can be observed in several tumor types, emphasizing the importance of integrating the results of any molecular study within clinical, morphological, and immunohistochemical context: ASPSCR1 (ASPL)-TFE3 translocation can be observed in alveolar soft tissue sarcoma but also in juvenile renal carcinomas, ETV6 (TEL)-NTRK3 (TRKC) translocation in infantile fibrosarcoma and secretory breast carcinoma, ALK rearrangements in inflammatory myofibroblastic tumors, anaplastic lymphomas, and lung adenocarcinomas. In some cases immunochemistry can highlight the consequence of a molecular abnormality: MDM2 overexpression in ALT/WDL, loss of INI1 expression in rhabdoid tumors and epithelioid sarcoma, and overexpression of ALK in inflammatory myofibroblastic tumors. [ABSTRACT FROM AUTHOR]

Abstract: As for hemopoietic stem cells, it is thought although not formally demonstrated that bone marrow mesenchymal stem cells (BMMSC) reside in a specific microenvironment or niche characterized by a low O2 tension. In support of this hypothesis is the observation that MSC can be amplified in vitro under 1–8% O2 while retaining multipotent capacities. Culture in hypoxic condition may therefore be useful in therapy as the low number of MSC is a major limitation to their use in regenerative medicine and to a lesser extent in the treatment of some autoimmune and overt inflammatory diseases. However hypoxia may modify MSC with significant effects on their metabolism and gene expression hence modifications in their differentiation abilities to mature in specialized cells. This review discusses the various effects of hypoxia on the fate and behavior of MSC and potential clinical applications of culture under hypoxic conditions in regenerative medicine and immune/inflammatory disorders. [Copyright &y& Elsevier]

Abstract: Four susceptibility patterns of wild types of enterobacteria against old beta-lactams including aminopenicillins, carboxypenicillins and first-generation cephalosporins were individualized during the 1980s : susceptible, penicillinase low level, cephalosporinase and a combination of penicillinase and cephalosporinase. Such indirect detection of a mechanism of resistance allowed an interpretative reading for this class of antibiotics. At the present time, seven susceptibility patterns were proposed for this family of gram negative bacilli. Nevertheless, an analysis of results in terms of MICs and diameters of inhibition zone sizes of the main bacterial species of enterobacteria, mainly obtained from the databank of European Committee on Antimicrobial Susceptibility Testing (EUCAST), compared to that observed when overproducing strains were isolated in vivo and in vitro and to the type of beta-lactamase identified and their amino acid sequences conducted to a proposal of five susceptibility patterns. The fifth wild type individualized in several enterobacteria since 2005 is related to the synthesis of various chromosomal extended-spectrum beta-lactamases (ESBL) which hydrolyze many beta-lactams including oxyimino-cephalosporins such as ceftriaxone or cefotaxime. Their expression in a wild strain is characteristic and conducted to our interest for their role as progenitors of the transferable CTM-M types. Otherwise, a medical biologist must consider the possibility of selection of a mutant with a chromosomal overproduced beta-lactamase. But within the same beta-lactam susceptibility pattern such as for Klebsiella pneumoniae and K. oxytoca or Citrobacter amalonaticus, the spectrum of inactivation will be highly variable according to the type of enzyme overproduced. Finally, a nice synergy observed between clavulanic acid and cefotaxime or ceftriaxone or even aztreonam does not mean anytime a transferable ESBL. In some cases according to the result of enterobacterial identification, the epidemiological impact will be very low, because without multidrug resistance (MDR). [Copyright &y& Elsevier]

Résumé: Objectif: Cette étude a été menée pour détecter l’expression de la protéine BNIP3 (Bcl-2/adenovirus E1B19-kDa-interacting protein 3) au cours de l’apoptose des cellules du noyau pulpeux induite par carence nutritionnelle, de manière à mieux comprendre le mécanisme de l’apoptose dans ces cellules. Méthodes: Les cellules isolées de disque caudal de rat ont été cultivées pendant un maximum de trois jours sous deux conditions de culture différant, soit par le pourcentage en oxygène, soit par les concentrations en glucose et en sérum. Les effets des deux conditions de culture ont été comparés lors d’un test de viabilité cellulaire, la mesure du potentiel membranaire mitochondrial (Δψm) et la détection de l’apoptose. L’expression et la localisation de la protéine BNIP3 ont été évaluées par PCR en temps réel et par marquage immunofluorescent. Résultat: La viabilité cellulaire et le potentiel membranaire mitochondrial (Δψm) ont été réduits significativement en absence d’oxygène, de glucose et de sérum, tandis que le pourcentage de cellules en apoptose était significativement augmenté, en comparaison avec les cellules cultivées en conditions normales d’oxygène, de glucose et de sérum. L’expression de BNIP3 a été augmentée significativement en absence d’oxygène, de glucose et de sérum, notamment à 72heures. De plus, la protéine a été retrouvée adressée vers les mitochondries. Conclusion: La surexpression de BNIP3 et son adressage vers la mitochondrie pourraient être impliqués dans l’apoptose des cellules du noyau pulpeux induite par carence nutritionnelle. [ABSTRACT FROM AUTHOR]

Abstract: Breast cancer treatment guidelines are based on usual prognostic factors such as size, histological grade, axillar lymph node involvement, expression of hormonal receptors. The intrinsic molecular classification is giving additional information over clinical and pathological features. Predictive models for systemic relapse have been established and are currently under clinical investigation to determine precisely when chemotherapy is needed. This review will look after the implications of this classification in terms of radiobiology: on one hand, we will look if this classification helps for loco-regional relapse prediction and on the other hand, if it is able to change the radiotherapy schedule within the molecular classification. [Copyright &y& Elsevier]

Knowledge acquired over the last decade has shown that castration-resistant prostate cancer (CRPC) remains sensitive to treatments that target androgen receptors (AR) and their ligands. Intracrine synthesis of androgens and the increase in AR expression are the main mechanisms involved in CRPC tumour growth. Abiraterone acetate (AA) is a selective inhibitor of the P450 c17 (CYP17) cytochrome, a principal enzyme involved in androgen synthesis. A phase III trial has demonstrated an increased survival rate in patients who have had failed preliminary chemotherapy with docetaxel. Promising results were obtained from a phase II trial with MDV3100, a second-generation anti-androgen, with an increased AR affinity compared with bicalutamide, and that limits its nuclear translocation, its DNA binding and the recruitment of transcription coactivators. Subsequent studies will need to determine the optimum use sequences for these molecules, their potential use in association, and their optimum integration with new emerging treatments. [ABSTRACT FROM AUTHOR]

Abstract: Autoinflammatory diseases (MAI) are syndromes of systemic expression whose origin is a defective regulation of innate immunity. The most common and best known are hereditary recurrent fevers (HRF). The recent discovery of several genes responsible for inherited forms has been an invaluable value for the diagnosis of these rare diseases. A decision tree and prerequisites established by the French network for genetic diagnosis of MAI (GenMAI) effectively target the testing order, which is almost exclusively indicated for postsymptomatic diagnosis. The results should be interpreted with caution because most of the mutations are point substitutions, and it is sometimes difficult in case of detection of a new sequence variant to assess its real involvement in the clinical picture of the patient. [Copyright &y& Elsevier]

Résumé: La maladie de Dupuytren (MDD) est une fibrose progressive de l’aponévrose palmaire caractérisée par la formation d’un nodule palmaire évoluant vers une corde. La MDD est la plus fréquente maladie héréditaire du tissu conjonctif affectant préférentiellement les caucasoïdes originaires d’Europe du Nord. Certains facteurs environnementaux sont associés à la MDD, notamment la consommation d’alcool, de tabac et possiblement les activités manuelles. Le diabète et l’épilepsie constituent les associations pathologiques les plus fréquemment rapportées. Le mode de transmission génétique de la MDD demeure mal connu et semble hétérogène : le plus souvent autosomique dominant avec une pénétrance variable et rarement, autosomique récessif ou maternel (matrilinéaire) évoquant une hérédité mitochondriale. Tout d’abord, une suggestion de liaison avec le locus DUPC1 en 16q a été mise en évidence. Ensuite, parmi les variations génomiques dans la MDD, ont été rapportées une altération du nombre de copies des gènes dans les régions chromosomiques 10q22, 16p12.1 et 17p12, une association avec l’allèle HLA-DRB1*15 et une mutation dans le gène de l’ARNr 16S, observée dans les formes avec hérédité matrilinéaire. Enfin, une étude pangénomique a montré une association génétique de la MDD avec les chromosomes 6, 11 et 16. La physiopathologie de la MDD implique principalement les myofibroblastes et la matrice extracellulaire de collagène. Les études d’expression génique et protéique ont confirmé le rôle central des voies de la β-caténine et du TGFβ dans la pathogénie de la MDD. [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to test the effects of melatonin on oxidative stress in the yellowtail clownfish, Amphiprion clarkii, as produced by light emitting diodes (LEDs): red, green, and blue. We investigated the effects of the different LEDs on oxidative stress by measuring the mRNA expression of arylalkylamine N-acetyltransferase (AANAT2), the expression and activities of antioxidant enzymes (superoxide dismutase, SOD (EC 1.15.1.1); and catalase, CAT (EC 1.11.1.6)), and plasma H2O2 and plasma melatonin levels. In red light, the expression of AANAT2, SOD, and CAT mRNA was significantly higher than those under the other light spectra. SOD and CAT activities and plasma H2O2 and melatonin levels were also significantly higher for the red spectra than those for the other light spectra. These results indicate that red light induces oxidative stress. To investigate the effects of melatonin on oxidative stress, we injected melatonin into live fish (in vivo) or treated cultured pineal organ (in vitro) with melatonin. We found that AANAT2, SOD, and CAT mRNA expression levels, SOD and CAT activities, and plasma H2O2, lipid peroxidation (LPO) and melatonin levels were significantly lower than those for the controls. Therefore, our results indicate that red light induces oxidative stress and melatonin plays the role of a strong antioxidant in yellowtail clownfish. [Copyright &y& Elsevier]

Summary: Background: In Tunisia, Cryptosporidium is frequently identified in diarrheic stools of children and immunocompromised patients. The infection is usually self-limited in immunocompetent populations, but can be severe and life-threatening in immunocompromised individuals. Cryptosporidiosis is well-documented in patients with the human immunodeficiency virus; however, few data are available concerning children with primary immunodeficiencies (PIDs). Patients and methods: A retrospective study was conducted on 5 cryptosporidiosis cases diagnosed in 11 children with PIDs. Cryptosporidium was systematically investigated when patients presented chronic diarrhea. Stool samples were examined for the parasite oocysts by modified Ziehl-Neelsen staining, and DNA was systematically extracted for a nested polymerase chain reaction (PCR). The species were identified by the analysis of restriction patterns. Epidemiological and clinicobiological data were presented for each patient. Results: All cryptosporidiosis cases presented a CMH class II deficiency syndrome. Chronic diarrhea was associated with failure to thrive in all cases. PCR provided the diagnosis in all patients, while Ziehl-Neelsen staining revealed Cryptosporidium oocysts in only 3 cases. Species identification yielded Cryptosporidium hominis in 2 cases, Cryptosporidium meleagridis in 1 case, and Cryptosporidium parvum in 1 case; a C. hominis/C. meleagridis co-infection was observed in the last case. C. hominis was isolated in children from rural areas, suggesting that the infection could have been contracted in the hospital and thus a probability of nosocomial transmission. One of the C. hominis carriers developed sclerosing cholangitis with a high parasite load. Conclusion: Cryptosporidiosis with serious clinical symptoms is observed in PID patients, particularly those with CMH class II deficiency syndrome. Early, regular, and repeated screening, improved by PCR, is recommended in this group of patients. The predominance of C. hominis, the anthropophilic species, in children from rural areas should emphasize hygiene measures in care centers where PID cases are treated. [Copyright &y& Elsevier]

Abstract: Transcription factor Histone Nuclear Factor P (HiNF-P; gene symbol Hinfp) mediates cell cycle control of histone H4 gene expression to support the packaging of newly replicated DNA as chromatin. The HiNF-P/p220NPAT complex controls multiple H4 genes in established human cell lines and is critical for cell proliferation. The mouse Hinfp LacZ null allele causes early embryonic lethality due to a blastocyst defect. However, neither Hinfp function nor its temporal expression relative to histone H4 genes during fetal development has been explored. Here, we establish that expression of Hinfp is biologically coupled with expression of twelve functional mouse H4 genes during pre- and post-natal tissue-development. Both Hinfp and H4 genes are robustly expressed at multiple embryonic (E) days (from E5.5 to E15.5), coincident with ubiquitous LacZ staining driven by the Hinfp promoter. Five highly expressed mouse H4 genes (Hist1h4d, Histh4f, Hist1h4m and Hist2h4) account for >90% of total histone H4 mRNA throughout development. Post-natal expression of H4 genes in mice is most evident in lung, spleen, thymus and intestine, and with few exceptions (e.g., adult liver) correlates with Hinfp gene expression. Histone H4 gene expression decreases but Hinfp levels remain constitutive upon cell growth inhibition in culture. The in vivo co-expression of Hinfp and histone H4 genes is consistent with the biological function of Hinfp as a principal transcriptional regulator of histone H4 gene expression during mouse development. [Copyright &y& Elsevier]

Abstract: The physiopathology of systemic sclerosis remains unclear within a complex interaction between vasculopathy, perivascular inflammatory infiltrate, extensive tissue fibrosis and auto-immune manifestations. Chronology between vascular disease and adjacent inflammatory cell infiltration is still not yet clarified. There is growing evidence that T cell activation and its cytokine expression play a key role in vascular impairment occurrence and collagen dysregulation. Nevertheless, cytokine descriptions are mainly limited to blood and tissue measurement and the T cells differentiation analysis restricted to the Th1/Th2 balance. The purpose of this review is to establish an exhaustive cartography of cytokines involved in T cell differentiation, regarding the recent advance in T lymphocyte differentiation, including Th9, Th17, Th22 and regulatory T cells (Treg) pathways. This review will focus on Th17, Th22 and Treg differentiation, corresponding to the equilibrium between inflammation and tolerance. Finally, regarding published results in systemic sclerosis, T cells participation appears to be more a Th1/Th2 co-expression than an exclusive Th1 or Th2 polarization. Also, a possible Th22/Treg imbalance is suggested, leading to a Th22 overexpression and likely to tissue inflammation genesis. [Copyright &y& Elsevier]

Abstract: In the early 1980s, ulcerative colitis (UC) was considered to be a consequence of butyrate oxidation deficiency in the colonic mucosa, and so, a metabolic disease. The short-chain fatty acid butyrate, which is mainly produced in the lumen of the large intestine by the fermentation of dietary fibers, is the preferred energy source for the colonocyte and plays a major role in the physiology of the colonic mucosa. Recent data indicate that the butyrate oxidation deficiency is a consequence of its reduced intracellular availability, due to the inflammation-related down-regulation of the monocarboxylate transporter MCT1. MCT1 expression levels, so butyrate oxidation, are inversely correlated to the intensity of inflammation. The loss of MCT1 expression could explain the lack of efficacy of butyrate enemas in severe UC. This could also lead to the inhibition of butyrate regulatory effects on cell proliferation / apoptosis balance and favour inflammatory bowel diseases-associated colorectal carcinogenesis. [Copyright &y& Elsevier]

Résumé: Les microARN (miARN) sont de petits ARN non codants qui contrôlent négativement l’expression des gènes au niveau post-transcriptionnel. Actuellement, il existe 939 séquences de miARN matures humains listées dans le registre Sanger. On estime à environ 1500 le nombre de gènes de miARN dans le génome humain susceptibles de réguler l’expression d’un tiers des gènes codant pour des protéines. En contrôlant l’accumulation des protéines ciblées dans les cellules productrices, ces petits ARN régulateurs participent à de nombreuses fonctions physiologiques clés, et leur dérégulation est impliquée dans un nombre croissant de pathologies humaines telles que le cancer et les infections. L’implication des miARN dans les pathologies auto-immunes comme la polyarthrite rhumatoïde (PR) a été récemment montrée, suggérant un potentiel thérapeutique prometteur pour des stratégies basées sur la modulation de l’expression des miARN dans ces maladies, mais également comme biomarqueurs diagnostiques et/ou pronostiques. Cette revue présente un état des lieux des miARN dans la PR, en abordant les caractéristiques systémiques et articulaires de la pathologie. [ABSTRACT FROM AUTHOR]

Summary: Netherton syndrome is a rare autosomal recessive disorder characterized by the triad of ichthyosiform erythrodermia, typical hair dysplasia, and severe atopic features. The broad range of variable expression of this disease is well described and 20% of complications occur during the neonatal period such as hypernatremic dehydration, electrolyte imbalances, recurrent or severe infections, and failure to thrive. Mutation of the SPINK5 gene has been identified as disease-causing in Netherton syndrome, but the pathophysiology still remains unclear. Almost all SPINK5 mutations result in the absence of the serine-protease inhibitor LEKTI protein in both keratinocytes and lymphocytes. In this study, we report on a severe form of Netherton syndrome observed in three patients within a large inbred Rom family. All of them died in the first months of life despite early treatment. They were found to be homozygous for the c.1431-12G>A SPINK5 gene mutation, which has not been associated with a lethal form of the disease thus far. This family illustrates the extreme phenotype of Netherton disease of neonatal onset. Molecular diagnosis allowed further genetic counseling and prenatal testing during other pregnancies. [Copyright &y& Elsevier]

Abstract: Individual response to ionizing radiation is an important information required to apply an efficient radiotherapy treatment against tumour and to avoid any adverse effects in normal tissues. In 1981, Fertil and Malaise have demonstrated that the post-irradiation local tumor control determined in vivo is correlated with clonogenic cell survival assessed in vitro. Furthermore, these authors have reminded the relevance of the concept of intrinsic radiosensitivity that is specific to each individual organ (Fertil and Malaise, 1981) . To date, since clonogenicity assays are too time-consuming and do not provide any other molecular information, a plethora of research groups have attempted to determine the molecular bases of intrinsic radiosensitivity in order to propose reliable and faster predictive assays. To this aim, several approaches have been developed. Notably, the recent revolution in genomic and proteomic technologies is providing a considerable number of data but their link with radiosensitivity still remains to be elucidated. On another hand, the systematic screening of some candidate genes potentially involved in the radiation response is highlighting the complexity of the molecular and cellular mechanisms of DNA damage sensoring and signalling and shows that an abnormal radiation response is not necessarily due to the impairment of one single protein. Finally, more modest approaches consisting in focusing some specific functions of DNA repair seem to provide more reliable clues to predict over-acute reactions caused by radiotherapy. In this review, we endeavoured to analyse the contributions of these major approaches to predict human radiosensitivity. [Copyright &y& Elsevier]

Résumé: Le lupus érythémateux systémique (LES) se caractérise par une atteinte multiviscérale et, sur le plan biologique, par une réponse auto-immune dirigée contre des antigènes d’origine nucléaire. Les mécanismes physiopathologiques responsables du LES restent imparfaitement connus, mais de nombreux travaux récents ont souligné le rôle majeur joué par l’immunité innée. En effet, les Toll-like récepteurs (TLR), récepteurs situés au cœur de la résistance innée à la plupart des infections, sont aussi impliqués dans des phénomènes inflammatoires aigus ou chroniques induits par des ligands endogènes. De nombreuses équipes ont ainsi démontré, in vitro, le rôle des TLR7 et TLR9 dans la reconnaissance de complexes immuns. La stimulation de ces récepteurs est alors responsable de l’activation de cellules de l’immunité et notamment des lymphocytes B et des cellules dendritiques et d’une production inappropriée de nombreuses cytokines connues pour avoir un rôle direct dans la pathogénie lupique. Ces résultats ont motivé, dans différents modèles lupiques murins, des études d’inactivation ou de surexpression des gènes codant pour les TLR ou pour des molécules impliquées dans les voies de signalisation de ces TLR. Ces travaux ont permis de confirmer l’importance du TLR7 et d’évoquer le rôle du TLR4 dans l’induction d’une réponse auto-immune agressive. En revanche, les données obtenues in vivo sur l’implication du TLR9 contredisent celles obtenues in vitro et suggèrent un rôle protecteur. Enfin, chez l’homme, des études génétiques ont permis la mise en évidence de polymorphismes associés à un risque accru de développer un LES. [Copyright &y& Elsevier]

Résumé: Objectif: Examiner les facteurs potentiels prédictifs de la réponse aux traitements de fond (DMARD) classiques dans la polyarthrite rhumatoïde (PR). Méthodes: (1) design de l’étude : étude prospective sur six mois de suivi. Participants : patients avec une PR active ; (2) intervention et suivi : introduction d’un DMARD. Réponse au traitement évaluée à six mois (critères ACR20) ; (3) analyse : facteurs potentiels prédictifs de la réponse : critères démographiques, activité de la maladie, pourcentages de sous-populations de cellules mononucléées du sang périphérique (CMSP) exprimant la glycoprotéine P, taux d’interleukine 1 bêta (IL-1β) sérique, IL-6, IL-8, IL-10, IL-12 et de facteur de nécrose tumorale alpha (TNF-α), évalués au moyen d’une analyse univariée et d’une analyse en régression logistique multivariée. Des courbes ROC ont été construites afin d’obtenir des seuils permettant la prédiction d’une réponse. Résultats: Quarante-deux patients (âge moyen=57±13ans, ancienneté de la maladie=5,4±7,2 ans en moyenne) ont été inclus. Du méthotrexate (MTX) a été donné à 30 d’entre eux. La réponse à la thérapie était prédite par le taux sérique de TNF-α à l’inclusion (moyenne=30,2pg/ml±18 chez les non-répondeurs versus 11,9pg/ml±11,2 chez les répondeurs). Le seuil prédictif de la réponse au traitement, avec la meilleure précision possible, était de 20,1pg/ml (sensibilité, spécificité, valeurs prédictives positive et négative respectivement de 75 ; 78,9 ; 83,3 et 69,2 % ; aire sous la courbe (AUC)=80,3 %, IC 95 %=62,8–97,7 %). Des résultats similaires ont été obtenus dans les sous-groupes de patients traités par MTX et de patients avec une PR précoce de moins de trois ans d’ancienneté. Conclusion: Dans cette étude, la concentration sérique en TNF-α était corrélée avec la réponse ultérieure aux DMARD. D’autres travaux sont nécessaires pour confirmer ce résultat et évaluer si un tel biomarqueur pourrait être utilisé pour prédire la réponse aux DMARD au niveau individuel. [Copyright &y& Elsevier]

Abstract: Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). This imprint is tissue-specific, mainly localized in the kidney and the thyroid. Only the maternal allele is expressed at this level. An alteration in the coding sequence of the gene leads to an haplo-insufficiency and a dysmorphic phenotype (Albright''s syndrome). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as a PHP1a. If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudo-pseudo-hypoparathyroidism (PPHP). Methylation anomalies of GNAS locus, in particular of exon 1A, are responsible for a lack of expression of Gαs at kidney and thyroid levels only. If these anomalies concern the maternal allele (the only one expressed) with a paternal pattern, there is no haplo-insufficiency and no dysmorphic syndrome. The hormonal resistance is yet again limited to PTH and TSH. The phenotype is known as PHP1b. In the familial forms, these methylation anomalies are associated with a deletion of the syntaxine 16 gene in the maternal allele. This gene contains probably the imprinting center of the locus. [Copyright &y& Elsevier]

Abstract: Study goal: A repeat blood donor genotyping project was launched by Héma-Québec in October 2007. The objective was to screen 21,000 samples for 22 polymorphisms for red blood cell and platelet blood groups to build a database to easily find compatible donors. Materials and methods: Donors who have donated at least three times during the last year were selected. A drop of blood was spotted on FTA paper and sent to the Pharmacogenomic Centre at the Montreal Heart Institute for analysis. All genotype results were compared to the known phenotype. In parallel, the RHD gene of D negative blood donors was examined. Results: Less than two years were necessary to complete the database. The genotype/phenotype concordance was 99.6% with only 165 discrepancies observed and further analysed. More than 55% of these discrepancies confirmed the initial genotype. The RHD study done on D negative samples found 13 donors positive for a variant RHD gene. Four were RHD*Ψ positive, while the other nine presented variant polymorphisms precluding a reduced expression of the D antigen. Conclusion: Thanks to this project, Héma-Québec is able to answer increasing demands for compatible blood more rapidly. The organisation has also demonstrated the security of its D negative inventory. [ABSTRACT FROM AUTHOR]

Summary: Introduction: The aim of this study was to determine the effects of 8 weeks of intense endurance training on cardiac expression of β1- et β2-adrenoceptors in diabetic and control rats. Facts: β1-adrenoceptor expression of sedentary diabetic rats is significantly decreased (p <0.05) while β2-adrenoceptor expression is not modified. Endurance training during diabetes has no effect on β1-adrenoceptor expression but displays a significant decrease in β2-adrenoceptor expression (p <0.01). Conclusion: Eight weeks of intense endurance training during diabetes induce a β2-adrenoceptor expression decrease, which may constitute a protection mechanism of diabetic heart against a catecholaminergic overstimulation. [ABSTRACT FROM AUTHOR]

Depuis plus de dix ans, le développement continu de nouvelles technologies d’analyse à haut débit offre aux scientifiques la possibilité d’étudier la biologie du vivant en général et des cancers en particulier par des voies aussi différentes que complémentaires. Ainsi, les altérations de la structure de l’ADN (amplification, délétion, gain), les pertes d’hétérozygotie (LOH), les altérations du niveau d’expression des gènes, les altérations du contrôle posttranscriptionnelle des microARN, l’activation des complexes protéiques peuvent être analysées simultanément à l’échelle du génome humain. Nous présentons ici un résumé des découvertes obtenues par l’analyse à haut débit du profil d’expression des cancers du sein, en insistant particulièrement sur l’impact majeur de ces travaux sur la connaissance et la prise en charge clinique de ces patientes. Les terabytes de données biologiques accumulées par les scientifiques depuis plus de dix ans ne répondent pas simplement à une lubie technologique mais sont au contraire des outils déterminants de la dissection moderne de ces tumeurs. L’amélioration du pronostic des patientes atteintes de cancer du sein passe nécessairement par l’utilisation de ces technologies. [ABSTRACT FROM AUTHOR]

Les progrès des analyses biologiques ont permis de sous classer les cancers du sein en différentes entités moléculaires, et d’identifier un panel de cibles thérapeutiques candidates. L’identification de ces cibles impose, dorénavant, d’évaluer chaque médicament dans des populations définies par les analyses moléculaires. Ce changement dans le développement des médicaments pose un certain nombre de problèmes. Tout d’abord, il impose, dorénavant, de tester les médicaments dans des maladies moléculaires rares. Ensuite, il nécessite la mise au point de tests moléculaires, dont le nombre élevé pourrait à terme être un frein. Enfin, il pose le problème de l’organisation des soins autour des analyses moléculaires. Dans cette revue, nous décrirons dans un premier temps les différentes cibles thérapeutiques candidates observées dans le cancer du sein, puis nous discuterons les implications du développement de la médecine personnalisée par les analyses moléculaires. [ABSTRACT FROM AUTHOR]

Les critères usuels cliniques et pathologiques ne permettent pas de définir précisément le pronostic individuel des patientes traitées pour cancer du sein et entraînent un « surtraitement » adjuvant d’un grand nombre d’entre elles. Trois outils fondés sur l’expression génique, à moyen ou haut débit, ont été développés pour tenter de pallier cette imprécision. Leurs validations sur des séries indépendantes ont abouti à leur développement commercial. Les études sont en cours pour savoir dans quelle mesure ces signatures génomiques apportent un bénéfice cliniquement perceptible en termes de pronostic et de meilleure indication thérapeutique. Ces signatures moléculaires de première génération reposent essentiellement dans leur composition sur les voies des récepteurs aux estrogènes, du gène HER2 et de la prolifération. Il reste à démontrer qu’une utilisation de marqueurs immunohistochimiques de routine, correctement calibrés et combinés n’apporte pas une information équivalente. [ABSTRACT FROM AUTHOR]

Abstract: Bipolar disorder is an often devastating illness characterized by the implication of genetic, environmental and developmental factors. Although family, twin and adoption studies consistently indicate a strong genetic component, studies aiming at identifying genetic vulnerability factors produced conflicting results. This chapter gives an overview of linkage, case/control and Whole Genome Association studies in bipolar disorder. Chromosomal regions with the best evidence for the presence of vulnerability factors are presented and synthesized. These include areas on chromosome 1q, 4q, 5p, 7q, 8q, 10p, 11p, 12q, 13q, 16p, 17q, 18p, 18q, 21q, 22q and Xq, with consistent independent linkage and association results with candidate genes. [Copyright &y& Elsevier]

Abstract: The authors propose a pragmatic and dialogical model to bring to light, in a “decisive” manner, discontinuities which appear in verbal interaction. The relationship between such discontinuities and possible syndromic specificities of schizophrenic pathology and then the question of inconsistency are discussed. This strategy leads to a more precise description of the positive, negative and disorganization syndromes in schizophrenia. The authors specify and differentiate syndromes in verbal interaction in the form of specific discontinuities. Then this approach allows speculation about some distinctive properties of the specific cognitive processes which underlie them. This model has an obvious diagnostic interest. This research contributed to describe communication disorders more precisely by elaborating and developing the concept of “pragmatic pathology”, i.e. pathologies of the use of language. The result is that the pragmatic approach is able to provide new knowledge about the definition and apprehension of “inconsistency”. This work thus ensures a better understanding of “pathological interactions” on the level of their similarities as well as on the level of their divergences with other interlocutions situations which are connected with ordinary conversations. From a diagnostic point of view, the development of a model of apprehension of the discontinuity of the decisive type and of the ensuing formalization suggests the possibility of clarifying, and even of making the concept of “formal thought disorders” operational. [Copyright &y& Elsevier]

Abstract: The polyunsaturated fatty acids made of 18 atoms of carbon from the omega-6 and omega-3 series are necessarily supplied by food. These essential precursors are converted into long-chain derivatives which are major functional components of membrane cells, the arachidonic and docosahexaenoic acids (DHA), respectively. The conversion pathway involves successive reactions of desaturations and elongations, taking place mainly in the liver, which genes are regulated through the action of cognate transcription factors. We review litterature data on the influence of sexual dimorphism on the regulation pathway of omega-3 metabolism. It is shown that a-linolenic acid, the essential precursor of omega-3 series, is mainly oxidised to acetyl-coA in mitochondries while only a minor fraction is converted to DHA through endoplasmic reticulum and peroxisomal processing. The metabolic parts intended for oxidation and conversion are, respectively, lower and higher in women than in men. In standard nutritional conditions, the DHA content in blood lipids is generally higher in women, especially in those having estrogenic treatments. As a whole, the published data support the hypothesis that the steroid hormonal status impacts on the signaling pathway that regulates the gene expression of lipid metabolism. [Copyright &y& Elsevier]

Résumé: Objectifs: Déterminer les variations d’expression des ARNm de la leptine dans les cellules mononuclées du sang (PBMC) de patients atteints de spondylarthrite ankylosante (SA) ainsi que la production de cytokines pro-inflammatoires. Méthodes: Vingt patients présentant une SA active ont été inclus, et l’index d’activité BASDAI et les taux de protéines de la phase aiguë ont été mesurés. L’expression des ARNm et de protéine de la leptine, de l’interleukine (IL)-6, du facteur nécrosant des tumeurs (TNF)-α étaient déterminée dans les PBMC de patients atteints de SA par RT-PCR semi-quantitative et par Elisa. Les résultats de dosage ainsi que les paramètres biologiques d’activité de la maladie ont été comparés à ceux de 20 sujets sains. Les modifications d’expression des cytokines pro-inflammatoires des PBMC en réponse à la leptine ont aussi été déterminées. Résultats: L’expression des ARNm de la leptine, de l’IL-6 et du TNF-α des patients atteints de SA était significativement plus élevée que chez les témoins. Il existait aussi des différences significatives dans les taux de cytokines et de leptine des surnageants de culture. De plus, les taux de leptine étaient corrélés à ceux de l’IL-6 (r =0,871, p <0,001) et des scores BASDAI (r =0,691, p <0,001) chez les patients atteints de SA. La stimulation des PBMC par de la leptine exogène induisait une augmentation significative et dose-dépendante de la production d’IL-6 et de TNF-α par les PBMC de patients atteints de SA. Ces augmentations étaient plus prononcées que chez les témoins. Conclusion: Nos résultats montrent que, chez les patients atteints de SA, la production de leptine augmente et que cette molécule induit une production significativement accrue de cytokines pro-inflammatoires par les PBMC. L’ensemble de ces données suggère un rôle pro-inflammatoire de la leptine dans la SA. [Copyright &y& Elsevier]

Abstract: In breast cancer, optimal locoregional treatment allows high local control rates and impact long-term survival. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis data showed that radiation therapy (RT) can decrease the risk of breast cancer death at 15 years. In the adjuvant setting, whole breast RT remains the standard of care. Adjuvant systemic therapies, RT indications, techniques and volumes are determined according to the known standard prognosis factors such as age, tumor size and location, nodal involvement, grade, hormone receptors status, proliferative index and lymphovascular invasion. One of the future challenges in breast cancer management is to determine new prognosis and predictive factors that could help to define the subgroups of patients, who will either really benefit from new treatment strategies or particular RT techniques, or for those for whom aggressive local therapeutic option is not needed, as their prognosis is mainly related to an early risk of metastatic diffusion. In the new era of fine biological diagnosis, a better understanding of tumor biology allows a significant development of targeted therapies. Adjuvant strategies including locoregional RT have to be based on the tailored treatment concept. These strategies have to take into account not only the patients profiles regarding the well-established parameters, but also the tumor biology, the new breast cancer subtype classification and gene profiles. [Copyright &y& Elsevier]

Abstract: The DNA methylation is a post-replicative event that provides secondary information to that formed by DNA. Addition of this information involves DAM methyltransferase, which methylates DNA on specific sites (5′-GATC-3′). This modification of DNA may play a role in regulating various processes in eukaryote or prokaryote cells. It was well understood that deoxyadenosine methyltransferase (DAM) methylates the adenine of the GATC sequence. Following DNA replication, however, DNA is transiently hemimethylated, and the new strand is then methylated by DAM. In Escherichia coli, removing the dam gene produces several phenotypes indicating multiple functions of methylation: (i) modulation of gene expression, (ii) DNA repair, (iii) initiation of replication, and (iv) stabilising the chromosome. To cite this article: A. Chatti, A. Landoulsi, C. R. Biologies 331 (2008). [Copyright &y& Elsevier]

Abstract: Folates are group B vitamins involved in the one-carbon metabolism. They are required for purine and pyrimidine, and thus DNA synthesis, as well as for the remethylation of homocysteine into methionine which is further metabolized into S-adenosylmethionine, the universal methyl donor for transmethylation of DNA. By this way, folates play a key role in epigenetic regulation of gene expression. Folate deficiency, either by insufficient nutritional uptake or linked to some single nucleotide polymorphism, will lead to an impaired DNA synthesis and repair, a hypomethylation of DNA and other molecules, and homocysteine accumulation. This situation has been associated with several pathologies, such as cardiovascular and neurodegenerative diseases, and pregnancy complications. However, much less is known until now about the impact of one-carbon metabolism on initial events of human reproduction, from gametogenesis to early embryonic development. The present review will deal with these aspects of folate metabolism with respect to male and female fertility. [Copyright &y& Elsevier]

Para comparar la eficiencia de diferentes procedimientos para la evaluación genética mediante el uso del Blup Modelo, se analizó en el genotipo Siboney de Cuba un total de 36 086 pesajes individuales, correspondientes a 3 827 lactancias de la Empresa Pecuaria «Camilo Cienfuegos», en Pinar del Río, Cuba. Los datos corresponden al período 1998-2000, distribuidos en 24 vaquerías, que representan la progenie de 99 sementales, agrupados en 1, 2, 3, 4, 5 y ≥ 6 lactancias. Se empleó el Modelo Animal para las evaluaciones genéticas, con expresiones clásicas para la producción de leche a los 305 d. Se introdujeron modelos en el día de control, considerándose los criterios de Ptak y Schaeffer (1993). Estos últimos mostraron que la varianza residual (Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) representó la mayor parte (en términos relativos 78 % y 82 %) de la varianza fenotípica total (Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.). Esto sugiere que los factores no genéticos son los principales responsables de la variabilidad de este carácter. Se estudió la eficiencia y exactitud de estas expresiones en la estimación del valor genético. Se demostró que con la aplicación del Blup Modelo en modelos de covarianza, a partir de pesajes en el día de control y medidas repetidas, se eleva la precisión y exactitud de los valores genéticos. Estos modelos pueden superar a los que consideran la información resumen. Se comprobó que este es un procedimiento más dinámico para evaluaciones de vacas y sementales, y que además considera el efecto de la curva de lactancia. [ABSTRACT FROM AUTHOR]

Abstract: We carried out a prospective study including 554 vaginal swabs simultaneously tested for antenatal screening of Group B Streptococcus (GBS or Streptococcus agalactiae) using culture on the chromogenic medium Strepto B ID (Biomérieux, Marcy l''Etoile, France) and real time gene amplification on LightCycler (Roche Applied Science). We centrifuge the swabs with “SETS” device and separate centrifugates in 2 parts: one for the culture and the other one for molecular biology. First half of the centrifugate is inoculated onto Todd-Hewitt broth enriched with antibiotics. This broth is incubated to 35 °C during 24 hours and then subcultured on a Strepto B ID medium. This last one is incubated during 24 hours to 35 °C in capnophilic conditions before interpretation. DNA extraction for molecular biology is simply obtained by heating the microtubes to 95 °C in a water bath. The cfb gene is amplified, allowing a specific gene amplification of GBS even within a polymorphic flora. The concordance between both methods is 94.8%. The sensitivity and negative predictive values obtained are respectively 88.0 and 97.4% for real time PCR and 83.0 and 96.4% for culture on Strepto B ID. Both methods are thus concordant, with equal sensitivity and valid for detection of GBS colonization in pregnant women. However real time gene amplification allows reducing turn around time since molecular biology process (extraction+amplification) does not exceed 1 hour. [Copyright &y& Elsevier]

Abstract: Introduction: Large-scale genomic studies based on DNA microarrays improve our understanding of the pathophysiology of cancers. The use of these research findings to improve diagnosis, prognosis and treatment is the current challenge of research in genomics. Exegesis: The article briefly describes the DNA microarrays technology and use in oncology and underlines the steps required to translate research findings of correlations between gene expression and type of cancer, outcome or response to chemotherapy into robust clinical tools. Conclusion: Genomic technologies available today are sufficient to develop useful molecular markers for individual patient management. [Copyright &y& Elsevier]

Abstract: Breast cancer is the first cause of death between 35 and 55 years. Genetic alterations and modifications in gene expression are found during different steps of tumor progression. These changes are translated at the protein level where quantitative and qualitative modifications are found in tumor compared to normal samples. Similarly to studies aimed at deciphering transcriptional changes important in cancer, proteomic approaches allow the global and comparative study of proteins in normal and pathological samples. The objective of this article is to present common proteomic methods and to review the first published results concerning proteomics studies applied to breast cancer with an emphasis on reports obtained using the SELDI-TOF MS (Surface Enhanced Laser Desorption Ionization Time-Of-Flight Mass Spectrometry). In breast cancer, it is possible to explore the tumoral proteome and/or the blood derived proteome. The first studies are aimed at globally understanding the disease while the latter are aimed at discovering serum proteins or biomarkers useful for the early detection, diagnosis, prognosis and management of cancer. Promising results are obtained using these emerging methods and these novel biomarkers should be validated in the future and will have an important impact for the management of breast cancer patients. [Copyright &y& Elsevier]

DNA chips are among the major technological advances in recent years that have led to a more comprehensive and in-depth understanding of tumor biology. This technique, through the hybridization of complementary DNA synthesized from a tumor sample on a surface containing various gene sequences, makes it possible in one step to establish a quantitative assessment of the expression of several thousand genes found in the tumor. Due to their biological and clinical heterogeneity, malignant lymphoma represents an ideal model for the use of this new tool. Complex bioinformatics analyses of several series of samples recently made it possible to described the signaling pathways activated in these lymphoid tumors, which led to recognition of either proximity or individualization of certain histological subtypes, to identification of diagnostic or prognostic biological predictors and, finally, to characterization of new targets for these specific pharmacological agents. By looking at current published studies, we will discuss the impact of this technique on the understanding of the biology and the clinical approach to both Hodgkin’s and non-Hodgkin’s malignant lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: Purpose. – The observation of inherited drug response variability gave rise to the field of pharmacogenetics. Pharmacogenetic research on drug targets, particularly platelet enzymes and receptors, is more recent and is becoming an emerging field. Current knowledge and key points. – In the Framingham study, the heritability of platelet aggregation response ranges from 44 to 62%, depending on the agonists used. The gene coding for GPIIIa, a sub-unit of the fibrinogen receptor GPIIbIIIa, is one of the most extensively studied gene in relation with aggregation tests and antiplatelet drugs. The GPIIIa PLA1/PLA2 polymorphism has been associated with clopidogrel and orbofiban platelet response. However, data are more controversial concerning the association with aspirin response. Recently, Cox-1 and GPIa (part of the GPIaIIa collagen receptor) genetic variations have also been pointed out as possible candidates to explain part of the variability of the response to antiplatelet agents. Finally, the H1/H2 polymorphism of the platelet ADP receptor P2Y12 gene has been associated with ADP-induced platelet aggregation response and peripheral arterial disease. This polymorphism may modulate the effect of P2Y12 antagonists like clopidogrel and its clinical implication is currently under study. Future prospects and projects. – Gene-expression profiling and proteomics may allow the identification of new candidate genes whose variations may be associated with the heritability of platelet aggregation response. In the next future, phenotypic or genotypic studies could be available to tailor the prescription of antiplatelet drugs. [Copyright &y& Elsevier]

Abstract: Genomic imprinting is a process that appeared in mammals. This phenomenon blocks the normal development of parthenogenic and androgenic conceptuses, that is to say benign ovarian teratomas and hydatidiform moles respectively. Pathological modifications of these conceptuses depend on whether the chromosomes come from the mother or father. These pathologies are associated with an accidental anomaly during gametogenesis and/or fertilizing. These reproductive anomalies are sporadic and some familial cases may exist suggesting a genetic control of such diseases. The human andro- and parthenogenetic conceptuses, but more frequently the moles, may be invasive (choriocarcinoma). An imbalance of the imprinting genes may initiate the deregulation of other genes, including oncogenes and anti-oncogenes, which can explain the cancerous modification. Immunological and environmental factors must be also considered (presence of the only paternal chromosomes in the choriocarcinoma). Numerous works on this subject are published and some recent important discoveries underline the roles of genes HOX, Tim P3, E-cad and p-16, and the recurrent chromosome anomalies 7q21+and 8p21- in the mole to choriocarcinoma processing. Although these phenomena are complex and heterogeneous, the andro- and parthenogenote conceptuses are particularly interesting models with which to understand developmental disorders and cancerous progression. [Copyright &y& Elsevier]

Abstract: Aging is associated with alterations of the circadian rhythms (shortened amplitude and phase-advance). We studied by quantitative RT-PCR the influence of aging on the expression of circadian clock genes (Clock, Bmal1, Cry1,2, Per1-3) in peripheral tissues (liver and heart) of middle-aged (13 months) and old (27 months) rats of the Wag/Rij strain exposed to a 12 hours light/12 hours dark cycle. Rats were killed at the light–dark transition (8 am and 8 pm). In the liver, Per, Cry et Bmal1 genes showed a morning/evening difference of expression; in addition, old rats exhibited a significant decrease of Per gene expression in the evening vs middle-aged rats. The heart showed similar profiles with only a tendency toward a decrease of Per expression and an increased Bmal1 expression in the evening in old rats. These results show that aging is associated with circadian gene expression changes. [Copyright &y& Elsevier]

Multidrug resistance (MDR) proteins belong to the ATP-binding cassette proteins superfamily (ABC proteins). These proteins are constitutively expressed in various organs where they work as transporters or contribute to physiological barrier constituents. Only a few ABC proteins are involved in drug transport and, therefore, are implicated in bio-distribution. In such cases, ABC proteins are expected to play a role in drug response. Numerous gene polymorphisms have been described, which may affect ABC proteins expression and/or activity. Such variants could affect the distribution and activity of anticancer drugs, especially in the case of oral administration. [ABSTRACT FROM AUTHOR]

Predicting drug response is a challenging problem in oncology. Between 1975-1985, important efforts were devoted to the generation of cellular assays able to predict, on an individual basis, the in vitro response of tumour cells to chemotherapeutic agents, but such methods could not be adopted in routine. New molecular biology techniques have been developed in order to identify the genes involved in drug sensitivity and resistance. The availability of techniques of gene expression profiling has allowed to establish correlations between gene expression and drug sensitivity of tumour cells or human cancers. This type of approach has been initiated on in vitro systems by the National Cancer Institute (NCI) in the USA and is pursued by a growing number of public and private laboratories around the world. In the clinical setting, gene expression profiles are currently developed for the diagnosis and overall prognosis of human cancers, but should rapidly allow the prediction of drug response, so that clinicians would be able to prescribe individual treatments on a rational basis. [ABSTRACT FROM AUTHOR]