Desmoplastic small round cell tumor: impact of 18F-FDG PET induced treatment strategy in a patient with long-term outcome

The desmoplastic small round cell tumor (DSRCT) is an uncommon and highly aggressive cancer. The role of 18F-FDG PET in management of DSRCT is little reported. We report a case of metastasized abdominal DSRCT detected in a 43-year old patient whose diagnostic and therapeutic approaches were influenced by 18F-FDG PET-CT. The patient is still alive ten years after diagnosis. 18F-FDG PET-CT seems to be a useful method for assessing therapeutic efficiency and detecting early recurrences even in rare malignancies such as DSRCT

Dynamique de l’innovation en médecine nucléaire : une décennie propice pour la diffusion de la TEP

International audienceAvec plus d’un demi-million d’examens annuels, les examens TEP FDG occupent depuis quelques années la première place du nombre d’examens réalisés dans les services de médecine nucléaire, devant les scintigraphies myocardiques et osseuses. En une décennie, le nombre de caméras TEP a été multiplié par 2 et le nombre d’examens TEP par 3 en France. Le nombre d’examens TEP reste cependant 10 fois inférieur au nombre d’actes scanographiques réalisés, cette proportionnalité étant retrouvée dans le rapport entre le nombre de médecins nucléaires et le nombre de radiologues. L’analyse comparative de l’évolution décennale des actes d’imagerie médicale semble cependant indiquer une dynamique positive propre de la TEP. Selon une analyse rétrospective des données disponibles (enquêtes nationales annuelles de la SFMN [2013–2019], enquête ANAIMEN [2018], rapport d’audit de radioprotection de l’IRSN [2019], rapport de la cour des comptes sur l’imagerie médicale [2016]), la tendance décennale favorable à l’échelle nationale concernant l’activité TEP masque des disparités territoriales ; la mise en perspective de cette dynamique intrinsèque avec celle du domaine de l’imagerie médicale ou avec les données épidémiologiques en cancérologie doit permettre de contextualiser cette tendance. Alors que les données médico-économiques concernant le bénéfice à intégrer la TEP dans les algorithmes décisionnels en oncologie s’accumulent, cette réalité scientifique contraste avec le constat fait sur le terrain d’une adoption inégale de cette solution technologique innovante par la communauté médicale. Vingt ans après l’émergence des premières caméras hybrides TEP-TDM, à l’heure de la TEP numérique, les facteurs ayant facilité ou ralenti les changements organisationnels inhérents à l’introduction de ces innovations demeurent à l’état d’hypothèses, mais n’ont pas fait l’objet de travaux scientifiques approfondis. La cartographie de la dynamique de la TEP en France au cours de la dernière décennie s’inscrit en préambule d’un travail doctoral portant sur la diffusion de l’innovation médicale en oncologie nucléaire. Avec l’émergence des nouveaux radiopharmaceutiques et de la théranostique, il devient indispensable de comprendre les déterminants socio-organisationnels facilitant la diffusion et l’adoption de solutions innovantes proposées par la communauté de médecine nucléaire

MORC2 restriction factor silences HIV proviral expression

Abstract The HUSH complex (composed of TASOR, MPP8 and periphilin) represses HIV-1 expression from its promoter by inducing both propagation of repressive epigenetic marks and degradation of the nascent transcript. Vpx from HIV-2, and Vpr proteins from some simian lentiviruses (SIVs), antagonize HUSH, thereby increasing proviral expression. The chromatin-remodelling MORC2 protein plays a critical role in the epigenetic silencing of host genes by HUSH. Here, we deciphered the role of MORC2 in retroviral silencing. We show that MORC2, in contrast to HUSH components, presents strong signatures of positive selection during primate evolution. Like HUSH, MORC2 represses proviral expression in two models of HIV-1 latency. However, while HUSH is degraded upon HIV-2 infection in a Vpx-dependent manner, MORC2 levels are increased, raising the question of a feedback control mechanism without HUSH. Upon infection with an HIV-1-derived virus, MORC2 and TASOR antiviral effects are interdependent. However, once the lentiviral DNA is integrated into the host genome, MORC2 may maintain the repression independently of HUSH. At the post-transcriptional level, both MORC2 and HUSH act in association with CNOT1 of the CCR4-NOT deadenylase complex and the TRAMP-like PAXT complex. Finally, MORC2, but not HUSH components, is expressed in primary quiescent CD4+ T cells. Altogether, our data highlight MORC2 as an HIV restriction factor and a chromatin remodelling protein operating both at the transcriptional and post-transcriptional levels. We speculate that MORC2 could serve as an immune gatekeeper following HUSH inactivation by Vpx and contribute to the maintenance of retroviral silencing in reservoir CD4+ T cells. Significance statement One hurdle to HIV eradication is viral latency, which refers to the persistence of the virus in reservoir cells despite antiretroviral treatment. The HUSH complex represses HIV expression, once the viral genome is integrated into the host genome. HUSH activity on host genes depends on MORC2, a protein incriminated in the Charcot-Marie-Tooth neuronal disease. Here, we first show that MORC2 presents signs of evolutionary arms-races in primates. Furthermore, MORC2 contributes to HIV silencing in cooperation with HUSH, but also, likely without HUSH. Despite identified as a chromatin remodeler, MORC2 also works at a post-transcriptional level. Altogether, MORC2 appears as a host defense factor, which plays a role in HIV latency

Representation of genes deregulated by the Tax-1, -2, -3 proteins in MOLT4 cells.

<p>Venn diagram representation performed on 239 cellular genes up-regulated by Tax expression in the MOLT4 cells (Cut-off: 3-fold above the control). Gene ontology (GO) analysis using DAVID Bioinformatics web-tool was performed on genes commonly deregulated following Tax1, -2 and -3 expression or specifically deregulated by Tax1 and Tax-3 expression in the MOLT4 cells. The first five clusters implicated in biological processes and possessing the highest enrichment scores were selected.</p

Heat Map analysis of cellular genes deregulated by the Tax-1, -2, -3 proteins in MOLT4 cells.

<p>Representation of the 48 cellular genes deregulated in MOLT4 cells following Tax proteins expression using Heat Map analysis (log transformation and mean centered data performed in Cluster and TreeView softwares). The mean fold change expression is indicated on the right of each graphic. *Genes were already reported in HTLV literature. CHST15 is an alias of GALNAC4S-6ST.</p

Functional analysis of genes deregulated following Tax-1, -2, -3 expression in MOLT4 cells.

<p>(A) Schematic representation of the 48 cellular genes implicated in molecular interactions, using the STRING software. Width of the lines reflects the score of molecular interaction and the circles are colored according to the GO Biological Process association. The color legend is indicated in the table below the network. Each color represents the main GO terms associated with genes composing the network, identified by BINGO analysis (Hypergeometric test and Benjamini & Hochberg False Discovery Rate (FDR) correction; significance level <0.05). (B) Sub-networks correspond to 2 densely connected regions of the main molecular interaction network identified by MCODE plugin. Each sub-network was re-analyzed for GO enrichment and results are indicated in the tables next to each sub-network.</p

Detection of Tax and cellular genes expression by RT-PCR.

<p>(A) Total RNA was extracted from water (lane 1), or 293 T cells transduced with Lenti-IRES-GFP (lane 2), Lenti-Flag-Tax-1 (lane 3), Lenti-Flag-Tax-2 (lane 4) and Lenti-Flag-Tax-3 (lane 5). The primer sequences used for amplifying (a) <i>tax-1</i>, (b) <i>tax-2</i>, (c) <i>tax-3</i>, (d) <i>GAPDH</i>, (e) <i>IL-15</i>, (f) <i>GADD45B</i>, (g) <i>BIRC-3</i> and (h) <i>ICAM1</i> transcripts are summarized in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041003#pone.0041003.s004" target="_blank">Table S1</a>. (B) Western blot analyses were performed on 70 µg of cellular extracts from 293 T cells transduced by Lenti-IRES-GFP, Lenti-Flag-Tax-1, Lenti-Flag-Tax-2 or Lenti-Flag-Tax-3 lentiviruses, as indicated. Membranes were probed with anti-Flag-M2, anti-β-actin or anti-BIRC-3 antibody.</p

Heat Map analysis of 70 cellular genes specifically deregulated in Tax-1 and Tax-3 transduced cells.

<p>Representation of the 70 cellular genes specifically deregulated in MOLT4 cells following Tax1 and Tax-3 proteins expression using Heat Map analysis (log transformation and mean centered data performed in Cluster and TreeView softwares). The mean fold change expression is indicated on the right of each graphic. Tax-2 values were added as control. *Genes were already reported in HTLV literature. CSRNP1, BHLHE40 and CDGAP are aliases of AXUD1, BHLHB2 and ARHGAP31, respectively.</p