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Accueil Nota Bene Cancer V2 Numéro 133 du 24 April 2012 Biologie

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Biologie

Aberrations chromosomiques

Menée initialement sur 997 échantillons tumoraux prélévés sur des patientes atteintes d'un cancer du sein, puis validée sur 995 échantillons complémentaires, cette étude met en évidence des anomalies de nombres de copies de gènes en association avec le pronostic de la maladie

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    Menée initialement sur 997 échantillons tumoraux prélévés sur des patientes atteintes d'un cancer du sein, puis validée sur 995 échantillons complémentaires, cette étude met en évidence des anomalies de nombres de copies de gènes en association avec le pronostic de la maladie

    “The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups”

    • Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graf, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel

    The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a ...


Mots clés : Sein; Biologie (Aberrations chromosomiques)

Menée sur 31 échantillons tumoraux prélevés sur 31 patients atteints d'un cancer du poumon non à petites cellules, cette étude de séquençage des exons identifie des mutations somatiques de différents gènes, notamment le gène CSMD3 dont la perte induit une prolifération accrue de cellules épithéliales des voies aériennes supérieures

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    Menée sur 31 échantillons tumoraux prélevés sur 31 patients atteints d'un cancer du poumon non à petites cellules, cette étude de séquençage des exons identifie des mutations somatiques de différents gènes, notamment le gène CSMD3 dont la perte induit une prolifération accrue de cellules épithéliales des voies aériennes supérieures

    “Identification of Somatic Mutations in Non-Small Cell Lung Carcinomas Using Whole-Exome Sequencing”

    • Liu, Pengyuan;Morrison, Carl;Wang, Liang;Xiong, Donghai;Vedell, Peter;Cui, Peng;Hua, Xing;Ding, Feng;Lu, Yan;James, Michael;Ebben, John;Xu, Haiming;Adjei, Alex A.;Head, Karen;Andrae, Jaime W.;Tschannen, Michael R.;Jacob, Howard;Pan, Jing;Zhang, Qi;Van den Bergh, Francoise;Xiao, Haijie;Lo, Ken C.;Patel, Jigar;Richmond, Todd;Watt, Mary-Anne;Albert, Thomas;Selzer, Rebecca;Anderson, Marshall;Wang, Jiang;Wang, Yian;Starnes, Sandra;Yang, Ping;You, Ming

    Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most of lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole exome sequencing in 31 NSCLC and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas (ADC) and squamous cell carcinomas (SCC), two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational ...


Mots clés : Poumon; Biologie (Aberrations chromosomiques)

Cet article passe en revue les travaux récents sur les causes de l'hétérogénéité observée à l'intérieur des tumeurs

  • Intra-tumour heterogeneity: a looking glass for cancer?
    Nature Reviews Cancer, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur les causes de l'hétérogénéité observée à l'intérieur des tumeurs

    “Intra-tumour heterogeneity: a looking glass for cancer?”

    • Marusyk, Andriy;Almendro, Vanessa;Polyak, Kornelia

    Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour ...


Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par l'expression du récepteur des produits de glycation avancée (RAGE) dans les premières étapes d'une cancérogenèse du pancréas

  • The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia
    Proceedings of the National Academy of Sciences, sous presse, 2012 (résumé)
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    Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par l'expression du récepteur des produits de glycation avancée (RAGE) dans les premières étapes d'une cancérogenèse du pancréas

    “The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia”

    • Kang, Rui;Loux, Tara;Tang, Daolin;Schapiro, Nicole E.;Vernon, Philip;Livesey, Kristen M.;Krasinskas, Alyssa;Lotze, Michael T.;Zeh, Herbert J.

    Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)–mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6–induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:KrasG12D/+ (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and ...


Mots clés : Pancréas; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par une enzyme, l'histone déméthylase KDM1A, dans la régulation des cellules souches leucémiques

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    Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par une enzyme, l'histone déméthylase KDM1A, dans la régulation des cellules souches leucémiques

    “The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells”

    • Harris, William J;Huang, Xu;Lynch, James T;Spencer, Gary J;Hitchin, James R;Li, Yaoyong;Ciceri, Filippo;Blaser, Julian G;Greystoke, Brigit F;Jordan, Allan M;Miller, Crispin J;Ogilvie, Donald J;Somervaille, Tim C P.

    Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect. º KDM1A is a key effector of the differentiation block in MLL leukemia º KDM1A sustains expression of the MLL-AF9 oncogenic program º Nanomolar KDM1A inhibitor concentrations induce ...


  • Breaking the LSD1/KDM1A Addiction: Therapeutic Targeting of the Epigenetic Modifier in AML
    Cancer Cell, Vol. 21 (4), pp. 451-453, 2012 (commentaire)
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    Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par une enzyme, l'histone déméthylase KDM1A, dans la régulation des cellules souches leucémiques

    “Breaking the LSD1/KDM1A Addiction: Therapeutic Targeting of the Epigenetic Modifier in AML”

    • Lokken, Alyson A ; Zeleznik-Le, Nancy J

    KDM1A/LSD1, a histone H3K4/K9 demethylase and epigenetic regulator with roles in both gene activation and repression, has increased expression in multiple cancer types. Harris et al., in this issue of Cancer Cell, and Schenk et al. show that KDM1A may be a viable therapeutic target in treating AML.


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à partir d'échantillons de sang et de moelle osseuse prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence un mécanisme d'interaction entre les facteurs de transcription TLX1 ou TLX3 et la protéine proto-oncogénique ETS1

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    Menée à partir d'échantillons de sang et de moelle osseuse prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence un mécanisme d'interaction entre les facteurs de transcription TLX1 ou TLX3 et la protéine proto-oncogénique ETS1

    “TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCR alpha Gene Expression”

    • Dadi, Saïda;Le Noir, Sandrine;Payet-Bornet, Dominique;Lhermitte, Ludovic;Zacarias-Cabeza, Joaquin;Bergeron, Julie;Villarèse, Patrick;Vachez, Elodie;Dik, Willem A;Millien, Corinne;Radford, Isabelle;Verhoeyen, Els;Cosset, François-Loïc;Petit, Arnaud;Ifrah, Norbert;Dombret, Hervé;Hermine, Olivier;Spicuglia, Salvatore;Langerak, Anton W;Macintyre, Elizabeth A;Nadel, Bertrand;Ferrier, Pierre;Asnafi, Vahid

    Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) ± enhanceosome activity and blocked TCR-J± rearrangement. TLX1/TLX3 abrogation or enforced TCR±² expression leads to TCR± rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCR±-driven TLX1 expression supports TLX addiction in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3. º TLX1 and TLX3 proteins interact with the ETS1 proto-oncogene in T-ALL º TLX-ETS1 protein interaction blocks TCR± ...


  • Hijacking T Cell Differentiation: New Insights in TLX Function in T-ALL
    Cancer cell, Vol. 21 (4), pp. 453-455, 2012 (commentaire)
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    Menée à partir d'échantillons de sang et de moelle osseuse prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence un mécanisme d'interaction entre les facteurs de transcription TLX1 ou TLX3 et la protéine proto-oncogénique ETS1

    “Hijacking T Cell Differentiation: New Insights in TLX Function in T-ALL”

    • King, Bryan ; Ntziachristos, Panagiotis ; Aifantis, Iannis

    TLX1 and TLX3 are two closely-related homeobox transcriptional repressors frequently misexpressed and translocated in T cell acute lymphoblastic leukemia (T-ALL). In this issue of Cancer Cell, Dadi et al. provide new insights into how these factors are recruited by ETS-1 to the TCR± enhancer and actively repress differentiation.


Mots clés : Leucémie; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel un stress chronique, en agissant sur l'expression de p53, favorise une tumorigenèse

  • Chronic restraint stress attenuates p53 function and promotes tumorigenesis
    Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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    Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel un stress chronique, en agissant sur l'expression de p53, favorise une tumorigenèse

    “Chronic restraint stress attenuates p53 function and promotes tumorigenesis”

    • Feng, Zhaohui;Liu, Lianxin;Zhang, Cen;Zheng, Tongsen;Wang, Jiabei;Lin, Meihua;Zhao, Yuhan;Wang, Xiaowen;Levine, Arnold J.;Hu, Wenwei

    Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53+/− mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum- and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 ...


Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

Cet article passe en revue les travaux récents menés dans un cadre évolutionniste pour analyser le rôle des infections dans l'oncogenèse

  • Infection, mutation, and cancer evolution
    Journal of Molecular Medicine, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents menés dans un cadre évolutionniste pour analyser le rôle des infections dans l'oncogenèse

    “Infection, mutation, and cancer evolution”

    • Ewald, Paul;Swain Ewald, Holly

    An understanding of oncogenesis can be fostered by an integration of mechanistic studies with evolutionary considerations, which help explain why these mechanisms occur. This integration emphasizes infections and mutations as joint essential causes for many cancers. It suggests that infections may play a broader causal role in oncogenesis than has been generally appreciated. An evolutionary perspective also suggests that oncogenic viruses will tend to be transmitted by routes that provide infrequent opportunities for transmission, such as transmission by sexual and salivary contact. Such routes increase the intensity of natural selection for persistence within hosts, and molecular mechanisms for persistence often compromise critical barriers to oncogenesis, particularly cell cycle arrest, apoptosis, and a cap on the total number of divisions that a cell can undergo.


Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant le récepteur alpha des œstrogènes dans le stroma, l'estradiol favorise la croissance d'un cancer du sein ER-

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    Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant le récepteur alpha des œstrogènes dans le stroma, l'estradiol favorise la croissance d'un cancer du sein ER-

    “Stromal ER-alpha promotes tumor growth by normalizing an increased angiogenesis”

    • Pequeux, Christel;Raymond-Letron, Isabelle;Blacher, Silvia;Boudou, Frédéric;Adlanmerini, Marine;Fouque, Marie-José;Rochaix, Philippe;Noel, Agnes;Foidart, Jean-Michel;Krust, Andrée;Chambon, Pierre;Brouchet, Laurent;Arnal, Jean-François;LENFANT, Françoise B.

    Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERα-deficient mice, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in ...


Mots clés : Sein; Biologie (Progression et métastases)

Menée sur des lignées cellulaires, à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur des patients atteints de mélanome, cette étude met en évidence le rôle joué par la protéine PHIP dans le processus métastatique

  • Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis
    Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)
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    Menée sur des lignées cellulaires, à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur des patients atteints de mélanome, cette étude met en évidence le rôle joué par la protéine PHIP dans le processus métastatique

    “Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis”

    • De Semir, David;Nosrati, Mehdi;Bezrookove, Vladimir;Dar, Altaf A.;Federman, Scot;Bienvenu, Geraldine;Venna, Suraj;Rangel, Javier;Climent, Joan;Meyer Tamgüney, Tanja M.;Thummala, Suresh;Tong, Schuyler;Leong, Stanley P. L.;Haqq, Chris;Billings, Paul;Miller, James R.;Sagebiel, Richard W.;Debs, Robert;Kashani-Sabet, Mohammed

    Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP ...


Mots clés : Mélanome; Biologie (Progression et métastases)

Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique, cette étude met en évidence un mécanisme de régulation des cellules souches leucémiques dans le micro-environnement

  • Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia
    Cancer cell, Vol. 21 (4), pp. 577-592, 2012 (article en libre accès)
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    Menée à l'aide d'un modèle murin et sur des échantillons tumoraux prélevés sur des patients atteints d'une leucémie myéloïde chronique, cette étude met en évidence un mécanisme de régulation des cellules souches leucémiques dans le micro-environnement

    “Altered Microenvironmental Regulation of Leukemic and Normal Stem Cells in Chronic Myelogenous Leukemia”

    • Zhang, Bin;Ho, Yin Wei;Huang, Qin;Maeda, Takahiro;Lin, Allen;Lee, Sung-uk;Hair, Alan;Holyoake, Tessa L;Huettner, Claudia;Bhatia, Ravi

    We characterized leukemia stem cells (LSC) in chronic phase chronic myelogenous leukemia (CML) using a transgenic mouse model. LSC were restricted to cells with long-term hematopoietic stem cell (LTHSC) phenotype. CML LTHSC demonstrated reduced homing and retention in the bone marrow (BM), related to decreased CXCL12 expression in CML BM, resulting from increased G-CSF production by leukemia cells. Altered cytokine expression in CML BM was associated with selective impairment of normal LTHSC growth and a growth advantage to CML LTHSC. Imatinib (IM) treatment partially corrected abnormalities in cytokine levels and LTHSC growth. These results were validated using human CML samples and provide improved understanding of microenvironmental regulation of normal and leukemic LTHSC and their response to IM in CML. º CML LSC demonstrate altered proliferation, differentiation and localization º Abnormal localization is related to leukemia-induced decrease in BM CXCL12 expression º Altered ...


Mots clés : Leucémie; Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

Cet article compare deux modèles de consentement proposés aux patients pour le don d'échantillons biologiques à des fins de recherche

  • Consent for Research With Biological Samples: One-Time General Consent Versus a Gift Model
    Annals of Internal Medicine, Vol. 156 (8), pp. 596-598, 2012 (résumé)
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    Cet article compare deux modèles de consentement proposés aux patients pour le don d'échantillons biologiques à des fins de recherche

    “Consent for Research With Biological Samples: One-Time General Consent Versus a Gift Model”

    • Wendler, David

    Technological advances have dramatically increased the scientific value of the hundreds of millions of human tissue and blood samples that are currently stored in laboratories and the tens of millions of new samples that are obtained each year (1, 2). These advances have led to continuing debate over what consent process should be used to obtain and store human biological samples for future research (3). Some commentators argue that, as with other types of research with humans, donors should consent to the specific studies for which their samples will be used when the studies are proposed (4). This approach allows people to know the details of the studies for which their samples will be used. However, it also requires investigators to keep track of donors (sometimes for decades) and to obtain consent repeatedly for studies that often vary in minor details only (5). Given these shortcomings, an Advance Notice of Proposed Rulemaking, issued on 26 July 2011, considered the endorsement of ...


Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))

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