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We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress in the absence of protective antioxidants normally induced by Nuclear factor erythroid 2–related factor 2 activation. As such, TACIMA-218 represses RNA translation and triggers cell signaling cascade alterations in AKT, p38, and JNK pathways. In addition, TACIMA-218 manifests thiol-alkylating properties resulting in the disruption of redox homeostasis along with key metabolic pathways. When administered to immunocompetent animals as a monotherapy, TACIMA-218 has no apparent toxicity and induces complete regression of pre-established lymphoma and melanoma tumors. In sum, TACIMA-218 is a potent oxidative stress inducer capable of selective cancer cell targeting.

Supplementary data.

Supplementary Fig. S1: Percentage of drugs per drug class among drug libraries used in the HTS; Supplementary Fig. S2: Synergistic GFP reactivation in YB5 cells by HDACi TSA and positive hits identified in the HTS; Supplementary Fig. S3: Optimization of the treatment schedule of the decitabine and proscillaridin A combination; Supplementary Fig. S4: Transcriptome analysis using Metascape; Supplementary Table S1: List of GO-Terms identified by Metascape analysis in gene data sets exclusively up-regulated by proscillaridin A treatment and exclusively up-regulated by the combination treatment; Supplementary Table S2: List of GO-Terms identified by Metascape analysis among down-regulated genes shared by proscillaridin A and the combinatorial treatment with decitabine; Supplementary Table S3: Antagonistic hits identified in combination HTS with sequential decitabine treatment; Supplementary Table S4. Antagonistic hits identified in combination HTS with simultaneous decitabine treatment; Supplementary Table S5. Antagonistic hits identified in combination HTS with sequential TSA treatment.

Supplementary Table 3: Ingenuity Pathway Analysis (IPA) for genes which gain promoter DNA methylation in C1 relative to C2 epi-cluster. Supplementary Table 4: Gene Ontology analysis for differentially methylated regions (DMR) between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 5: List of motifs enriched in differentially methylated regions between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 6: DAVID functional annotations analysis for enriched pathways related to genes which gain DNA methylation in renal cell carcinoma samples. Supplementary Table 7: List of gene promoters located in CG islands and which are assessed for DNA methylation using DREAM. The genes which showed the highest frequency of DNA methylation in our dataset are in the top. Furthermore, the frequency of gene promoters which gain DNA methylation in either RCC samples derived from the proximal or distal cells of the nephron are also reported. Supplementary Table 8: Validation dataset showing the prevalence of promoter DNA methylation for 25 genes in clear-cell renal cell carcinoma dataset of The Cancer Genome Atlas (TCGA) project. Those genes were both methylated and repressed in the TCGA dataset.

Table S1. Drug screening results after treatment at 10 µM for 72h

Unsupervised clustering of DNA methylation using 56 genes epi-signature in an independent data set encompassing 37 renal cell carcinomas cases. C2 contains the majority of oncocytoma and chromophobe RCC cases (n=11/13) as compared to C1 which encompasses the remaining RCC subtypes including clear-cell RCC (ccRCC) , papillary RCC (pRCC) and translocation RCC (tRCC).

Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer. Cancer Res; 76(6); 1494–505. ©2015 AACR.

Purpose: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype–phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron.Experimental Designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets.Results: Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.Conclusions: Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236–46. ©2016 AACR.

Supplementary Materials and Methods and Supplementary Figure Legends

Raw data for β-values of probe sets related to our 56 genes signature in an independent dataset encompassing 4 normal kidneys and 37 renal cell carcinomas belonging to diverse histopathological subtypes.

Supplementary Table 10: List of samples misclassified among the clear-cell renal cell carcinomas dataset with the corresponding new classification. Among those, many of them have been demonstrated to belong to the C4 cluster of long non-coding RNA classification. The first table reports the 5 misclassified TCGA clear-cell RCC (KIRC) using gene expression and which turned out to be chromophobe RCC (chRCC). The second table reports on misclassified TCGA KIRC cases with DNA methylation available. Supplementary Table 11: List of importance scores for genes used in the statistical model for predicting outcome of patients with clear-cell RCC. Supplementary Table 12: Associations (both training and validation datasets) between mutational load, TCGA clear-cell renal cell carcinomas transcriptomic subtypes classification and recurrent somatic mutations (VHL, PBRM1, BAP1 and KDM6A) identified in clear-cell renal cell carcinoma TCGA dataset with our 56 genes epi-signature. P-values less than 0.05 is considered as statistically significant.

Supplementary Figure S1. Drug screening based on the measurement of GFP fluorescence by flow cytometry. Supplementary Figure S2. Dose response curves of GFP reactivation after cardiac glycosides treatment. Supplementary Figure S3. Tumor suppressor genes reactivation after treatment with validated hits. Supplementary Figure S4. Analysis DNA methylation and histone modifications following treatments with validated hits. Supplementary Figure S5. Characterization of Ca2+ fluxes in YB5 and HEK293 cells. Supplementary Figure S6: Tumor suppressor gene reactivation is dependent on CamK activity. Supplementary Figure S7. Promoter occupancy of MeCP2 is decreased after cardiac glycoside treatment. Supplementary Figure S8: Specificity of MeCP2 antibody. Supplementary Figure S9: Assessing the specificity of MeCP2 redistribution after proscillaridin treatment. Supplementary Figure S10. Percentage of YB5 cells expressing GFP after drug treatment is significantly reduced after leptomycin treatment. Supplementary Figure S11. Cell viability assays show that drug induced toxicity is dependent on CamK activity in SW48 colon cancer cell line. Supplementary Figure S12. Cell viability assays show that drug induced toxicity is dependent on CamK activity in K562 leukemia cell line. Supplementary Figure S13. Cell viability assays show that drug induced toxicity is dependent on CamK activity in HL-60 leukemia cell line. Supplementary Figure S14. Scheme describing proposed mechanism of action of newly identified candidate epigenetic drugs.

List of 95 CpG located in promoter CG islands which are differentially methylated and expressed between C1 and C2 epi-clusters.

List of DNA methylation levels for each CpG sites detected by DREAM in the 2 normal kidneys and the 22 renal cell carcinomas samples. Each column represents one sample and each raw one CpG site with the relative annotations (coordinates, CpG islands or not, distance from transcription start site (TSS). The coordinates of each CpG sites are provided according to Hg18 version of the Human Genome.

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DNA methylation is commonly thought of as a “molecular lock” that leads to permanent gene silencing. To investigate this notion, we tested 24 different histone deacetylase inhibitors (HDACi) on colon cancer cells that harbor a GFP locus stably integrated and silenced by a hypermethylated cytomegalovirus (CMV) promoter. We found that HDACi efficiently reactivated expression of GFP and many other endogenous genes silenced by DNA hypermethylation. After treatment, all promoters were marked with active chromatin, yet DNA hypermethylation did not change. Thus, DNA methylation could not prevent gene reactivation by drug-induced resetting of the chromatin state. In evaluating the relative contribution of DNA methylation and histone modifications to stable gene silencing, we followed expression levels of GFP and other genes silenced by DNA hypermethylation over time after treatment with HDACi or DNA-demethylating drugs. Reactivation of methylated loci by HDACi was detectable for only 2 weeks, whereas DNA-demethylating drugs induced permanent epigenetic reprogramming. Therefore, DNA methylation cannot be considered as a lock for gene expression but rather as a memory signal for long-term maintenance of gene silencing. These findings define chromatin as an important druggable target for cancer epigenetic therapy and suggest that removal of DNA methylation signals is required to achieve long-term gene reactivation. Cancer Res; 72(5); 1170–81. ©2012 AACR.

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Background Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. Methods We analysed PCD/T in patients treated with D + T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. Results We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0 ng/mL; interquartile range (IQR) [4–945]) and of PCT (median: 8.6 ng/mL; IQR [5–39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P = 0.06). However, no difference was observed between mean PCD/T of progressing patients (n = 21; 125 ± 183 ng/mL and 9.3 ± 3.6 ng/mL, respectively) and responders (complete, partial or stable response) (n = 13; 159 ± 225 ng/mL, P = 0.58 and 10.6 ± 24.4 ng/mL, P = 0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n = 16) was significantly higher for female subjects (n = 18; 11.5 ± 4.8 ng/mL) than for male subjects (8.8 ng/mL ± 2.9, P = 0.01), but no difference was observed between sex and CPD (P = 0.32). Conclusion Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Embryonal rhabdomyosarcoma (eRMS) is the most common type of rhabdomyosarcoma in children. eRMS is characterized by malignant skeletal muscle cells driven by hyperactivation of several oncogenic pathways including the MYC pathway. Targeting MYC in cancer has been extremely challenging. Recently, we have demonstrated that the heart failure drug, proscillaridin A, produced anticancer effects with specificity toward MYC expressing leukemia cells. We also reported that decitabine, a hypomethylating drug, synergizes with proscillaridin A in colon cancer cells. Here, we investigated whether proscillaridin A exhibits epigenetic and anticancer activity against eRMS RD cells, overexpressing MYC oncogene, and its combination with decitabine. We investigated the anticancer effects of proscillaridin A in eRMS RD cells in vitro. In response to drug treatment, we measured growth inhibition, cell cycle arrest, loss of clonogenicity and self-renewal capacity. We further evaluated the impact of proscillaridin A on MYC expression and its downstream transcriptomic effects by RNA sequencing. Then, we measured protein expression of epigenetic regulators and their associated chromatin post-translational modifications in response to drug treatment. Chromatin immunoprecipitation sequencing data sets were coupled with transcriptomic results to pinpoint the impact of proscillaridin A on gene pathways associated with specific chromatin modifications. Lastly, we evaluated the effect of the combination of proscillaridin A and the DNA demethylating drug decitabine on eRMS RD cell growth and clonogenic potential. Clinically relevant concentration of proscillaridin A (5 nM) produced growth inhibition, cell cycle arrest and loss of clonogenicity in eRMS RD cells. Proscillaridin A produced a significant downregulation of MYC protein expression and inhibition of oncogenic transcriptional programs controlled by MYC, involved in cell replication. Interestingly, significant reduction in total histone 3 acetylation and on specific lysine residues (lysine 9, 14, 18, and 27 on histone 3) was associated with significant protein downregulation of a series of lysine acetyltransferases (KAT3A, KAT3B, KAT2A, KAT2B, and KAT5). In addition, proscillaridin A produced synergistic growth inhibition and loss of clonogenicity when combined with the approved DNA demethylating drug decitabine. Proscillaridin A produces anticancer and epigenetic effects in the low nanomolar range and its combination with decitabine warrants further investigation for the treatment of eRMS.

Aberrant transcription in cancer cells involves the silencing of tumor suppressor genes (TSGs) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA-hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSGs. To discover novel drugs that trigger TSG reactivation in cancer cells, we used a GFP-reporter system whose expression is silenced by promoter DNA hypermethylation and histone deacetylation. After screening a natural product drug library, we identified that toyocamycin, an adenosine-analog, induces potent GFP reactivation and loss of clonogenicity in human colon cancer cells. Connectivity-mapping analysis revealed that toyocamycin produces a pharmacological signature mimicking cyclin-dependent kinase (CDK) inhibitors. RNA-sequencing revealed that the toyocamycin transcriptomic signature resembles that of a specific CDK9 inhibitor (HH1). Specific inhibition of RNA Pol II phosphorylation level and kinase assays confirmed that toyocamycin specifically inhibits CDK9 (IC50 = 79 nM) with a greater efficacy than other CDKs (IC50 values between 0.67 and 15 µM). Molecular docking showed that toyocamycin efficiently binds the CDK9 catalytic site in a conformation that differs from other CDKs, explained by the binding contribution of specific amino acids within the catalytic pocket and protein backbone. Altogether, we demonstrated that toyocamycin exhibits specific CDK9 inhibition in cancer cells, highlighting its potential for cancer chemotherapy.

We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress in the absence of protective antioxidants normally induced by Nuclear factor erythroid 2–related factor 2 activation. As such, TACIMA-218 represses RNA translation and triggers cell signaling cascade alterations in AKT, p38, and JNK pathways. In addition, TACIMA-218 manifests thiol-alkylating properties resulting in the disruption of redox homeostasis along with key metabolic pathways. When administered to immunocompetent animals as a monotherapy, TACIMA-218 has no apparent toxicity and induces complete regression of pre-established lymphoma and melanoma tumors. In sum, TACIMA-218 is a potent oxidative stress inducer capable of selective cancer cell targeting.

Background Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide. Current therapies for NSCLC include chemotherapy, immunotherapy, and targeted molecular agents such as tyrosine kinase inhibitors and epigenetic drugs such as DNA methyltransferase inhibitors. However, survival rates remain low for patients with NSCLC, especially those with metastatic disease. A major cause for therapeutic failure is drug resistance, highlighting the need for novel therapies and combination strategies. Given that epigenetic modulators such as protein arginine methyltransferases (PRMTs) are frequently overexpressed in cancers, PRMT inhibitors are a promising class of cancer therapeutics. We screened a library of epigenetic and anticancer drugs to identify compounds that would synergize with MS023, a type I PRMT inhibitor, in decreasing the viability of methylthioadenosine phosphorylase (MTAP)-negative NSCLC cells. Results Among 181 compounds, we identified PARP inhibitors (PARPi) as having a strong synergistic interaction with type I PRMT inhibition. The combination of MS023 and the PARP inhibitor BMN-673 (Talazoparib) demonstrated strong synergistic interaction at low nanomolar concentrations in MTAP-negative NSCLC cell lines A549, SK-LU-1 and HCC4006. The re-introduction of MTAP decreased the sensitivity of the combination therapy in A549. The combination therapy resulted in elevated γ-H2AX foci indicating increased DNA damage causing decreased cell viability. Lastly, the combination therapy was effective in PARPi resistant ovarian cancer cells, suggesting that type I PRMT inhibitors could mitigate PARPi resistance, thus potentially having an important clinical impact for cancer treatment. Conclusions These findings identify a novel cancer drug combination therapy, which is more potent than the separate single-agent therapies. Thus, combining PARP inhibitors and type I PRMT inhibitors represents a new therapeutic opportunity for MTAP-negative NSCLC and certain cancer cells resistant to PARP inhibitors.

Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results.We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32).Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Introduction Le DRESS est une toxidermie severe rare et potentiellement fatale. La variabilite des presentations cliniques peut etre source d’errance diagnostique et de retard a la prise en charge. Le but de notre etude etait de decrire les caracteristiques du DRESS en population pediatrique. Materiel et methodes Etude retrospective multicentrique des cas de DRESS (Regiscar ≥ 3) chez des enfants ≤ 18 ans hospitalises entre 2000 et 2020. Resultats Nous avons inclus 53 cas, issus de 15 hopitaux francais. L’âge moyen etait de 8,6 ans avec une predominante feminine (54,7 %). Le DRESS survenait au cours d’une hospitalisation chez 11 enfants (20,8 %). Parmi les 90 molecules imputables, 57,8 % etaient des antibiotiques (AB), 21 % des antiepileptiques (AE). Le delai median d’apparition apres l’introduction etait de 13 jours (AB : 12, AE : 17). On notait un retard diagnostique median de 5 jours (jusqu’a 28). Un exantheme morbiliforme etait decrit dans 58,4 % des cas, une erythrodermie dans 26,4 %. La duree mediane de l’eruption etait de 20 jours (jusqu’a 90). Une fievre etait observee chez tous les enfants, un œdeme du visage chez 64,2 % et des adenopathies chez 67,9 %. Les organes touches etaient le foie (79,2 %), le rein (22,6 %), le poumon (20,8 %), la rate (13,2 %) et le systeme digestif (11,3 %). 83 % des enfants presentaient une hypereosinophilie > 500/mm3 (60,4 % > 1500/mm3). 17 (44,1 %) sur les 38 testes avaient une reactivation virale (PCR positive) : 7 HHV-6, 2 HHV-7, 4 Parvovirus B19, 2 EBV et 2 co-reactivations EBV-CMV. Pour le traitement du DRESS, 52,8 % des enfants ont eu une corticotherapie locale (duree mediane 8), 54,7 % une corticotherapie systemique (duree mediane 36,5 [min–max : 1 jour–11 mois]), 11,3 % des immunoglobulines intraveineuses et 3,8 % de la ciclosporine. La duree d’hospitalisation mediane etait de 11 jours. Des sequelles a long terme etaient observees chez 3 patients (5,7 %) : 1 HTA cortico-induite, 1 insuffisance corticotrope et 1 hyperpigmentation. Un enfant est decede d’un arret cardiorespiratoire sur myocardite. Vingt-cinq enfants (47,1 %) ont eu un bilan allergologique : 20 patch tests, 10 IDR, 3 pricks, 1 test de transformation lymphocytaire et 1 test de reintroduction. Quinze (60 %) avaient des tests positifs, 2 avaient une allergie a 2 molecules. Discussion Notre etude est la plus grande serie de DRESS pediatrique rapportee. Nos resultats sont concordants avec les cas publies (revues systematiques et cohortes retrospectives) et permettent de mieux preciser les caracteristiques clinicobiologiques du DRESS chez l’enfant. Les medicaments imputables sont frequemment des AB avec delai de survenue assez court ( Conclusion Le DRESS est mal connu des pediatres. Ce diagnostic doit etre systematiquement evoque chez l’enfant devant un exantheme cutane febrile des lors qu’un nouveau traitement a ete introduit dans les 12 dernieres semaines.

Introduction Le MISOPROSTOL,medicament de reference lors des interruptions medicales et volontaires de grossesse (IVG et IMG),peut etre inducteur d’hypersensibilite (HS)immediate. Methodes Mme E, 33 ans, adressee pour suspicion d’allergie au MISOONE, IBUPROFENE et VOGALENE lors d’une IVG. Elle a eu 3 fausses couches spontanees (FCS), 1 IVG medicamenteuse en 2019. Dans l’heure suivant l’IVG, presence d’un angioedeme des muqueuses buccales avec œdeme lingual, oropharynge, dysphagie, pas de reaction cutanee, ni gene respiratoire. Pas de tryptase dosee. Trois medicaments imputes de principe jusqu’a realisation de l’enquete allergologique. Resultats Pricks tests (PT) + aux specialites de MISOPROSTOL (MISOONE,GEEMISO). Erytheme a 10 mm sans papule (T+ erythemateux). PT VOGALENE et PRIMPERAN, IDR PRIMPERAN. Enquete allergologique en cours (TPO VOGALENE prevu et realisation test d’activation basophiles au MISOPROSTOL).Reprise IBUPROFENE avec excellente tolerance (non imputable). Discussion Le MISOPROSTOL est un analogue synthetique de la Prostaglandine E1. Indique dans les IMG et IVG pour son effet de contraction des fibres musculaires lisses du myometre, il provoque le relâchement du col uterin et l’expulsion. Selon l’Institut National d’Etudes Demographiques, nombre d’IVG en 2017 : 216 685 pour 767 000 naissances, taux d’IVG a 14,8 pour 1000 femmes. Selon le rapport de l’agence de la biomedecine de 2016 : 5926 IMG en 2015. Le MISOPROSTOL est un medicament d’usage courant en gynecologie. Il peut provoquer des reactions d’HS immediates rarement decrites dans la litterature. Pour ceux decrits, les reactions arrivent dans les 5 min a 1 h avec des grades II a III Ring et Messmer. Reactions d’HS retardees egalement decrites. Selon les donnees de notre centre de pharmacovigilance, au niveau de la base mondiale, 930 cas d’HS ont deja ete decrits avec 62 cas francais dont 80 % lies au CYTOTEC. Conclusion Le MISOPROSTOL, medicament indispensable lors d’IVG et IMG, gestes de pratique journaliere en gyneco-obstetrique, ne presente pas, pour la majorite des cas, d’effets indesirables majeurs. Cependant, de rares cas d’HS ont ete decrits. Au vu de ses observations, une declaration des effets indesirables plus systematique semble souhaitable.

Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficient in monotherapy against hematologic malignancies, the potential of DNA methyltransferase inhibitors to synergize with small molecules targeting chromatin or immunotherapy will provide additional opportunities for their future clinical application against leukemia and solid tumors.

Background Cardiac glycosides are approved for the treatment of heart failure as Na+/K+ pump inhibitors. Their repurposing in oncology is currently investigated in preclinical and clinical studies. However, the identification of a specific cancer type defined by a molecular signature to design targeted clinical trials with cardiac glycosides remains to be characterized. Here, we demonstrate that cardiac glycoside proscillaridin A specifically targets MYC overexpressing leukemia cells and leukemia stem cells by causing MYC degradation, epigenetic reprogramming and leukemia differentiation through loss of lysine acetylation. Methods Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. Drug-induced epigenetic changes were studied by chromatin post-translational modification analysis, expression of chromatin regulators, chromatin immunoprecipitation, and mass-spectrometry. Results At a clinically relevant dose, proscillaridin A rapidly altered MYC protein half-life causing MYC degradation and growth inhibition. Transcriptomic profile of leukemic cells after treatment showed a downregulation of genes involved in MYC pathways, cell replication and an upregulation of hematopoietic differentiation genes. Functional studies confirmed cell cycle inhibition and the onset of leukemia differentiation even after drug removal. Proscillaridin A induced a significant loss of lysine acetylation in histone H3 (at lysine 9, 14, 18 and 27) and in non-histone proteins such as MYC itself, MYC target proteins, and a series of histone acetylation regulators. Global loss of acetylation correlated with the rapid downregulation of histone acetyltransferases. Importantly, proscillaridin A demonstrated anticancer activity against lymphoid and myeloid stem cell populations characterized by MYC overexpression. Conclusion Overall, these results strongly support the repurposing of proscillaridin A in MYC overexpressing leukemia. Electronic supplementary material The online version of this article (10.1186/s13046-019-1242-8) contains supplementary material, which is available to authorized users.

Introduction Le syndrome IFAP (ichtyose folliculaire, alopecie et photophobie) est une ichtyose syndromique liee a une mutation dans MBTPS2 localise sur le chromosome X. Il code une proteine impliquee dans le metabolisme du cholesterol. Nous en rapportons six observations. Materiel et methodes Analyse phenotypique retrospective des patients porteurs d’une mutation dans MBTPS2 identifiee dans notre centre. Observations Entre 2000 et 2019, 6 garcons (âge moyen = 10,5 ans ; ecart-type 7,1 ans ; forme sporadique n = 4) ont ete inclus. Le diagnostic etait clinique (n = 6). Tous ont presente un RCIU severe ; deux etaient nes prematures (33 SA, 35 SA). A la naissance, l’atrichie et l’ichtyose folliculaire, constantes, s’accompagnaient de hernie inguinale (n = 3) et/ou ombilicale (n = 1), d’une keratodermie plantaire isolee et diffuse, ni transgrediente ni progrediente (n = 5) et une atteinte psoriasiforme gluteale (n = 3). L’atteinte ungueale, apparue chez les 2 patients les plus âges, etait psoriasiforme aux doigts (paronychie et hyperkeratose distale) et pseudomycosique aux orteils (analyse mycologique negative). La photophobie constante et severe, compliquee de keratite ponctuee superficielle (n = 5) et d’insuffisance limbique avec neo-vaisseaux corneens (n = 2) justifiait l’utilisation de ciclosporine collyre (n = 1, 27 mois). L’atteinte neurologique etait constante : retard des acquisitions (n = 4) et/ou psychomoteur (n = 4), crises convulsives (n = 2, âge Discussion – l’association atrichie et hernie inguinale et/ou ombilicale est evocatrice du diagnostic des la naissance ; – l’examen maternel considere jusqu’ici comme normal peut montrer une ichtyose non folliculaire, une keratodermie plantaire et des anomalies ungueales ; – la surveillance endocrinologique est essentielle a la recherche d’un retard pubertaire et/ou de croissance. L’hypothyroidie, deja rapportee une fois, doit etre recherchee. La proteine MBTPS2 est exprimee dans la thyroide normale ; – initialement reduit aux seules manifestations de l’acronyme IFAP, le caractere polymalformatif et evolutif de ce syndrome a ete rassemble dans un nouvel acronyme BRESHECK pour anomalies cerebrales (« Brain »), retard des acquisitions, dysplasie ectodermique, deformations du squelette, maladie de Hirschsprung, anomalies oculaires et auditives (« Ear/Eye »), cryptorchidie et fente palatine (« Cleft ») et anomalies renales (« Kidney »). Ainsi, la prise en charge est pluridisciplinaire. Le syndrome IFAP est un syndrome complexe, de prise en charge multidisciplinaire, dont le diagnostic clinique est souvent possible des la naissance.

Introduction Les mucormycoses, infections fongiques invasives rares dues a des moisissures opportunistes sont de traitement non consensuel et difficile. Nous rapportons les differentes etapes du traitement d’une forme severe chez un enfant atteint de syndrome KID (Keratite-Ichtyose-Surdite). Observations Un garcon de 2 ans, atteint d’un syndrome KID confirme sur le plan moleculaire (mutation G45 V de GJB2, codant pour la connexine 26), presentait une infection du cuir chevelu a Lichtheimia romosa (mucorale). Examen clinique : fievre (39 °C), large erosion du cuir chevelu, fibrineuse et necrotique. Paraclinique : CRP : 80 mg/l, PCR Lichtheimia positive dans le sang sans atteinte systemique ; prelevements microbiologiques cutanes : P. aeruginosa ; L. romosa sur 2 zones necrotiques superficielles ; recherche d’un deficit immunitaire negative. Le traitement associait amphotericine B liposomale jusqu’a 10 mg/kg/j, antibiotherapie et detersion chirurgicale toutes les 48 h. Apres 3 mois, devant l’echec de la strategie initiale avec extension necrotique et positivite des prelevements (cultures et PCR mucorales), intensification therapeutique avec ajout d’isavuconazole, pansements locaux d’Ambisome®, exerese chirurgicale des regions macroscopiquement pathologiques avec resection jusqu’au fascia/galea et traitement hyperbare. La caspofongine etait introduite pour surinfection cutanee a Aspergillus flavus. A 4 mois, la persistance des lesions necrotiques en surface et la positivite des PCR mucorales conduisaient a une exerese large de tout l’hemiscalp residuel, en preservant le plan fascial/galeal, suivie par greffe de peau mince en filet. A 6 mois : cicatrisation du cuir chevelu et negativite des prelevements. Discussion La prise en charge medico-chirurgicale des infections a mucorales est difficile avec une morbi-mortalite elevee. Des formes invasives ont ete decrites chez des patients immunodeprimes (hemopathie, transplantation, diabete) ou avec alteration de la barriere cutanee (brulures, traumatismes, prematures). Des infections fongiques, candidose cutaneo-muqueuse chronique, onychomycoses ou infections cutanees etendues, sont classiques chez les patients atteints de KID, mais aucun cas de mucormycose rapporte. Une alteration de la fonction barriere (connexine 26 = proteine des jonctions GAP), un defaut de signalisation des TLR ou une diminution des cellules de Langerhans, indispensables pour la reponse TH17, pourraient expliquer la susceptibilite aux infections fongique. La mutation de notre patient porte sur le meme acide amine que les mutations letales (G45E), questionnant sur la fonction de cette partie de la proteine. Seule l’exerese du cuir chevelu jusqu’au fascia, puis l’autogreffe de peau ont permis la remission et la cicatrisation, confortant l’importance de la prise en charge medico-chirurgicale dans ce type d’infection.

Marine protected areas (MPAs) are a primary marine conservation strategy in the US territory of American Samoa, which has a goal to protect 20 percent of its coral reef area under “no-take” MPAs. T...

Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.

This is the first multiplatform evaluation involving data from the new Sentinel-3A altimeter. An experiment was undertaken in the Algerian Basin, employing an ocean glider and a ship mission, along the same track and synchronous with an overpass of the Sentinel-3A mission. This provided three independent views of the ocean velocity field, along a section that encompassed three different oceanographic regimes. The results demonstrate the capacity of Sentinel-3A to retrieve fine-scale oceanographic features (~20 km). The intercomparison with in situ platforms showed a significant improvement, order 30% in resolution and 42% in velocity accuracy using a synthetic aperture radar mode with respect to lower-resolution mode of conventional altimetry. In addition, the three-platform view provided valuable insight into the variability of evolving oceanographic features, in an area of the Mediterranean that remains chronically under sampled.

D’octobre 2011 à septembre 2012, un praticien assure la prise en charge médico-chirurgicale des pathologies urgentes et programmées relevant de l’ORL et de la chirurgie de la face et du cou, au profit des militaires français et de la coalition, ainsi qu’au profit des populations civiles. L’analyse de cette année d’activité au sein de la structure internationale de l’Hôpital médico-chirurgical de Kaboul International Airport, permet de légitimer la présence de cette spécialité chirurgicale. En effet, la présence d’un ORL sur un Role 3 apporte une expertise dans la prise en charge des lésions traumatiques de guerre de l’extrémité céphalique et, à travers une activité réglée adaptée au théâtre, permet également d’assurer une prise en charge programmée, conséquente, au profit des populations locales.

Background MRI can detect both inflammatory and structural lesions in the sacroiliac joints (SIJ) of patients with axial SpA. However, standard MRI sequences do not directly depict bone and the appearance of erosion may vary according to the presence/absence of inflammation. Consequently, further validation using an accepted gold standard, namely, computed tomography (CT), is essential. Objectives We aimed to assess the detection of structural lesions in the SIJ by MRI using CT as the gold standard. Methods CT scans from 44 patients (26 females, mean age 49.4 years, mean symptom duration 9.1 years) were reconstructed in the semicoronal plane parallel to the superior border of the sacrum, as for conventional MRI evaluation of the SIJ, and scoring of lesions by CT was confined to this plane. Structural lesions were scored in consecutive slices in SIJ quadrants (erosion, sclerosis) or SIJ halves (ankylosis) on a dichotomous basis (present/absent) using the same anatomical principles for defining SIJ quadrants as developed for the SPARCC MRI SIJ inflammation and structural scores. T1W MRI scans of the SIJ from the same cases conducted at the same time as CT were assessed independently for structural lesions (erosion, fat, backfill, ankylosis, sclerosis) blinded to CT assessments using the SPARCC method. Agreement between CT and MRI was assessed by kappa statistics. Sensitivity/specificity of MRI for CT lesions was calculated. The primary analysis was based on lesions detected concordantly by both readers at the level of the individual iliac/sacral joint surface (erosion, sclerosis) or the individual joint (ankylosis, backfill). Results With CT as gold standard and a lesion defined as being present when recorded in the same location on at least 1 coronal slice by both readers, MRI-defined ankylosis had 56.3% sensitivity and 100% specificity for CT ankylosis (Table). For erosion, sensitivity and specificity of MRI was 81.3% and 96.2%, and for sclerosis, sensitivity and specificity of MRI was 50% and 97%, respectively. Agreement between CT and MRI for erosion increased when the cut-off for presence of a lesion was set at 2 slices but only marginally for sclerosis, even when the cut-off for presence of a lesion was set at 3 slices. Lesions observed on CT corresponding to backfill on MRI were ankylosis, erosion, and sclerosis, in 66.7%, 66.7%, and 80% of backfill lesions, respectively. Conclusions Ankylosis and erosion on MRI correspond closely with the same type of lesion observed on CT. Both new bone formation and erosion are frequently evident on CT at locations where backfill is observed on MRI supporting the hypothesis that backfill is an intermediary tissue between erosion and ankylosis. Disclosure of Interest None declared

Background Computed tomography (CT) is considered the imaging benchmark for the assessment of certain structural lesions in the sacroiliac joints (SIJ) of patients with axial spondyloarthritis (axSpA). Availability of low dose radiation techniques may lead to more widespread use, potentially as a structural endpoint in clinical trials research. Objectives We aimed to validate a new CT-based scoring method, the CT Sacroiliac Structural Score (CT-SSS), for assessing structural lesions in the SIJ. Methods CT scans of the SIJ from 44 patients (26 females, mean age 49.4 years, mean symptom duration 9.1 years) were reconstructed in the semicoronal plane parallel to the superior border of the sacrum and scoring of lesions was confined to this plane. Structural lesions were scored in consecutive slices in SIJ quadrants (erosion, sclerosis) or SIJ halves (ankylosis) on a dichotomous basis (present/absent) using the same anatomical principles as developed for the SPARCC MRI SIJ inflammation and structural scores. The most anterior slice is defined as visible joint ≥1cm vertical height and when Results Scoring was feasible (5–10 minutes per scan) and both ankylosis (ICC=0.95) and erosion (ICC=0.81) were reliably scored (Table). Sclerosis was less reliably scored (ICC=0.39). Presence/absence of ankylosis was reliably detected irrespective of whether this was based on a single slice (κ=0.77) or 3 consecutive slices (κ=0.81). Reliable detection was lower for erosion (κ=0.50 for 1 or 3 slices) and sclerosis (κ=0.44 and 0.48 for 1 and 3 slices, respectively). Bland-Altman graphs illustrate reliability across the range of scores for ankylosis and erosion. Conclusions The CT-SSS method is feasible and reliable for scoring ankylosis and erosion with minimal calibration. Sclerosis requires further standardization and calibration. Disclosure of Interest None declared