96 results on '"Fromont G"'
Search Results
2. Analysis of malpractice claims: The Franco-Belgian “Cœlio Club” experience
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Auvray, S., Barthes, T., Bellouard, A., Bertrand, C., Bokobsa, B., Burnon, D., Charbit, L., Closset, J., Cossa, J.P., Dabrowski, A., Delaby, J., Deleuze, A., Denet, C., Desfachelles, J.P., Dugue, T., Framery, D., Fromont, G., Hauters, P., Herbiere, P., Johanet, H., Landenne, J., Ledaguenel, P., Lepere, M., Longeville, J.H., Maisonnette, F., Magne, E., Malvaux, P., Marchand, P., Merlier, O., Navez, B., Olagne, E., Piquard, A., Portet, R., Rubay, R., Saint-Marc, O., Schramm, R., Siriser, F., Valverde, A., Vernay, L., Zaranis, C., Delaunay, F., Delaunay, T., Van Vyve, E., and Cardin, J.-L.
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- 2019
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- View/download PDF
3. The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis
- Author
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Gueguinou, M, Crottès, D, Chantôme, A, Rapetti-Mauss, R, Potier-Cartereau, M, Clarysse, L, Girault, A, Fourbon, Y, Jézéquel, P, Guérin-Charbonnel, C, Fromont, G, Martin, P, Pellissier, B, Schiappa, R, Chamorey, E, Mignen, O, Uguen, A, Borgese, F, Vandier, C, and Soriani, O
- Published
- 2017
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4. 1472P Biomarkers of the response in metastatic papillary renal cell carcinoma
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De Vries-Brilland, M., primary, Rioux-Leclercq, N., additional, Blanc, E., additional, Fromont, G., additional, Gravis Mescam, G., additional, Geoffrois, L., additional, Chevreau, C.M., additional, Gross Goupil, M., additional, Escudier, B., additional, Negrier, S., additional, and Albiges, L., additional
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- 2022
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5. Assessing prognosis and optimizing treatment in patients with postchemotherapy viable nonseminomatous germ-cell tumors (NSGCT): results of the sCR2 international study
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Fizazi, K., Oldenburg, J., Dunant, A., Chen, I., Salvioni, R., Hartmann, J.T., De Santis, M., Daugaard, G., Flechon, A., de Giorgi, U., Tjulandin, S., Schmoll, H.J., Bouzy, J., Fossa, S.D., and Fromont, G.
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- 2008
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6. Functional outcomes in symptomatic versus asymptomatic patients undergoing incisional hernia repair: Replacing one problem with another? A prospective cohort study in 1312 patients
- Author
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Smet, G.H.J. de, Sneiders, D. (Dimitri), Yurtkap, Y. (Yağmur), Menon, A.G. (Anand), Jeekel, J. (Hans), Kleinrensink, G.J. (Gert Jan), Lange, J.F. (Johan), Gillion, J.-F. (Jean-François), Abet, E. (E.), Ain, J.-F. (J. F.), Arnalsteen, L. (L.), Baraket, O. (O.), Beck, M. (M.), Bellouard, A. (A.), Benizri, E. (E.), Berney, C. (C.), Bilem, D. (D.), Binot, D. (D.), Blanc, B. (B.), Blazquez, D. (D.), Bonan, A. (A.), Boukortt, T. (T.), Brehant, O. (O.), Cas, O. (O.), Champault-Fezais, A. (A.), Chau, A. (A.), Chollet, J.-M. (J. M.), Constantin, M. (M.), Cossa, J.-P. (J. P.), Dabrowski, A. (A.), David, A. (A.), Demaret, S. (S.), Dubuisson, V. (V.), Dugue, T. (T.), El Nakadi, I., Faure, J.-P. (J. P.), Frileux, P. (P.), Fromont, G. (G.), Gadiri, N. (N.), Gillion, J.F. (Jean-Francois), Glehen, O. (O.), Hennequin, S. (S.), Isambert, M. (M.), Jurczak, F. (F.), Khalil, H. (H.), Lamblin, A. (A.), Largenton, C. (C.), Lavy, M. (M.), Lepère, M. (M.), Le Toux, N. (N.), Magne, E. (E.), Manfredelli, S. (S.), Mariette, C. (Christophe), Marion, Y. (Y.), Mercoli, H.-A. (H. A.), Mesli Smain, N. (N.), Moszkowicz, D. (D.), Najim, M. (M.), Oberlin, O. (O.), Odet, E. (E.), Ortega Deballon, P. (P.), Pavis d'Escurac, X. (X.), Pichot Delahaye, V. (V.), Putinier, J.B. (J. B.), Regimbeau, J.M. (J. M.), Renard, Y. (Y.), Romain, B. (B.), Rouquie, D. (D.), Soler, M. (M.), Soufron, J. (J.), Roos, S. (S.), Thillois, J.-M. (J. M.), Tiry, P. (P.), Vauchaussade De Chaumont, A. (A.), Vinatier, E. (E.), Vu, P. (P.), Verhaeghe, R. (R.), Zaranis, C. (C.), Zeineb, M. (M.), Smet, G.H.J. de, Sneiders, D. (Dimitri), Yurtkap, Y. (Yağmur), Menon, A.G. (Anand), Jeekel, J. (Hans), Kleinrensink, G.J. (Gert Jan), Lange, J.F. (Johan), Gillion, J.-F. (Jean-François), Abet, E. (E.), Ain, J.-F. (J. F.), Arnalsteen, L. (L.), Baraket, O. (O.), Beck, M. (M.), Bellouard, A. (A.), Benizri, E. (E.), Berney, C. (C.), Bilem, D. (D.), Binot, D. (D.), Blanc, B. (B.), Blazquez, D. (D.), Bonan, A. (A.), Boukortt, T. (T.), Brehant, O. (O.), Cas, O. (O.), Champault-Fezais, A. (A.), Chau, A. (A.), Chollet, J.-M. (J. M.), Constantin, M. (M.), Cossa, J.-P. (J. P.), Dabrowski, A. (A.), David, A. (A.), Demaret, S. (S.), Dubuisson, V. (V.), Dugue, T. (T.), El Nakadi, I., Faure, J.-P. (J. P.), Frileux, P. (P.), Fromont, G. (G.), Gadiri, N. (N.), Gillion, J.F. (Jean-Francois), Glehen, O. (O.), Hennequin, S. (S.), Isambert, M. (M.), Jurczak, F. (F.), Khalil, H. (H.), Lamblin, A. (A.), Largenton, C. (C.), Lavy, M. (M.), Lepère, M. (M.), Le Toux, N. (N.), Magne, E. (E.), Manfredelli, S. (S.), Mariette, C. (Christophe), Marion, Y. (Y.), Mercoli, H.-A. (H. A.), Mesli Smain, N. (N.), Moszkowicz, D. (D.), Najim, M. (M.), Oberlin, O. (O.), Odet, E. (E.), Ortega Deballon, P. (P.), Pavis d'Escurac, X. (X.), Pichot Delahaye, V. (V.), Putinier, J.B. (J. B.), Regimbeau, J.M. (J. M.), Renard, Y. (Y.), Romain, B. (B.), Rouquie, D. (D.), Soler, M. (M.), Soufron, J. (J.), Roos, S. (S.), Thillois, J.-M. (J. M.), Tiry, P. (P.), Vauchaussade De Chaumont, A. (A.), Vinatier, E. (E.), Vu, P. (P.), Verhaeghe, R. (R.), Zaranis, C. (C.), and Zeineb, M. (M.)
- Abstract
Background: Incisional hernias can be associated with pain or discomfort. Surgical repair especially mesh reinforcement, may likewise induce pain. The primary objective was to assess the incidence of pain after hernia repair in patients with and without pre-operative pain or discomfort. The secondary objectives were to determine the preferred mesh type, mesh location and surgical technique in minimizing postoperative pain or discomfort. Materials and methods: A registry-based prospective cohort study was performed, including patients undergoing incisional hernia repair between September 2011 and May 2019. Patients with a minimum follow-up of 3–6 months were included. The incidence of hernia related pain and discomfort was recorded perioperatively. Results: A total of 1312 patients were included. Pre-operatively, 1091 (83%) patients reported pain or discomfort. After hernia repair, 961 (73%) patients did not report pain or discomfort (mean follow-up = 11.1 months). Of the pre-operative asymptomatic patients (n = 221), 44 (20%, moderate or severe pain: n = 14, 32%) reported pain or discomfort after mean follow-up of 10.5 months. Of those patients initially reporting pain or discomfort (n = 1091), 307 (28%, moderate or severe pain: n = 80, 26%) still reported pain or discomfort after a mean follow-up of 11.3 months postoperatively. Conclusion: In symptomatic incisional hernia patients, hernia related complaints may be resolved in the majority of cases undergoing surgical repair. In asymptomatic incisional hernia patients, pain or discomfort may be induced in a considerable number of patients due to surgical repair and one should be aware if this postoperative complication.
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- 2020
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7. Functional outcomes in symptomatic versus asymptomatic patients undergoing incisional hernia repair: Replacing one problem with another? A prospective cohort study in 1312 patients
- Author
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de Smet, Gijs H.J., primary, Sneiders, Dimitri, additional, Yurtkap, Yagmur, additional, Menon, Anand G., additional, Jeekel, Johannes, additional, Kleinrensink, Gert-Jan, additional, Lange, Johan F., additional, Gillion, Jean-François, additional, Abet, E., additional, Ain, J.-F., additional, Arnalsteen, L., additional, Baraket, O., additional, Beck, M., additional, Bellouard, A., additional, Benizri, E., additional, Berney, C., additional, Bilem, D., additional, Binot, D., additional, Blanc, B., additional, Blazquez, D., additional, Bonan, A., additional, Boukortt, T., additional, Brehant, O., additional, Cas, O., additional, Champault-Fezais, A., additional, Chau, A., additional, Chollet, J.-M., additional, Constantin, M., additional, Cossa, J.-P., additional, Dabrowski, A., additional, David, A., additional, Demaret, S., additional, Dubuisson, V., additional, Dugue, T., additional, El Nakadi, I., additional, Faure, J.-P., additional, Frileux, P., additional, Fromont, G., additional, Gadiri, N., additional, Gillion, J.-F., additional, Glehen, O., additional, Hennequin, S., additional, Isambert, M., additional, Jurczak, F., additional, Khalil, H., additional, Lamblin, A., additional, Largenton, C., additional, Lavy, M., additional, Lepère, M., additional, Le Toux, N., additional, Magne, E., additional, Manfredelli, S., additional, Mariette, C., additional, Marion, Y., additional, Mercoli, H.-A., additional, Mesli Smain, N., additional, Moszkowicz, D., additional, Najim, M., additional, Oberlin, O., additional, Odet, E., additional, Ortega Deballon, P., additional, Pavis d’Escurac, X., additional, Pichot Delahaye, V., additional, Putinier, J.B., additional, Regimbeau, J.M., additional, Renard, Y., additional, Romain, B., additional, Rouquie, D., additional, Soler, M., additional, Soufron, J., additional, Roos, S., additional, Thillois, J.-M., additional, Tiry, P., additional, Vauchaussade De Chaumont, A., additional, Vinatier, E., additional, Vu, P., additional, Verhaeghe, R., additional, Zaranis, C., additional, and Zeineb, M., additional
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- 2020
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8. Ex-vivo experimental 7 Tesla high resolution magnetic resonance imaging of localized prostate cancer
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Durand, M., primary, Bessede, T., additional, Treacy, P-J., additional, Bentellis, I., additional, Corcuera-Solano, I., additional, Taouli, B., additional, Rastinehad, A., additional, Tang, C.Y., additional, Wang, V., additional, Reddy, B., additional, Raffaelli, C., additional, Fromont, G., additional, Puech, P., additional, Kaines, K., additional, Tewari, A., additional, and Villers, A., additional
- Published
- 2020
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9. Microsatellite instability as indicator of MSH2 gene mutation in patients with upper urinary tract transitional cell carcinoma
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Roupret, M, Catto, J, Coulet, F, Azzouzi, A-R, Amira, N, Karmouni, T, Fromont, G, Sibony, M, Vallancien, G, Gattegno, B, Meuth, M, Hamdy, F C, and Cussenot, O
- Published
- 2004
10. Analysis of malpractice claims: The Franco-Belgian “Cœlio Club” experience
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Delaunay, F., primary, Delaunay, T., additional, Van Vyve, E., additional, Cardin, J.-L., additional, Auvray, S., additional, Barthes, T., additional, Bellouard, A., additional, Bertrand, C., additional, Bokobsa, B., additional, Burnon, D., additional, Charbit, L., additional, Closset, J., additional, Cossa, J.P., additional, Dabrowski, A., additional, Delaby, J., additional, Deleuze, A., additional, Denet, C., additional, Desfachelles, J.P., additional, Dugue, T., additional, Framery, D., additional, Fromont, G., additional, Hauters, P., additional, Herbiere, P., additional, Johanet, H., additional, Landenne, J., additional, Ledaguenel, P., additional, Lepere, M., additional, Longeville, J.H., additional, Maisonnette, F., additional, Magne, E., additional, Malvaux, P., additional, Marchand, P., additional, Merlier, O., additional, Navez, B., additional, Olagne, E., additional, Piquard, A., additional, Portet, R., additional, Rubay, R., additional, Saint-Marc, O., additional, Schramm, R., additional, Siriser, F., additional, Valverde, A., additional, Vernay, L., additional, and Zaranis, C., additional
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- 2019
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11. Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of non-aggressive disease
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Kamoun, A., primary, Cancel-Tassin, G., additional, Fromont, G., additional, Elarouci, N., additional, Armenoult, L., additional, Ayadi, M., additional, Irani, J., additional, Leroy, X., additional, Villers, A., additional, Fournier, G., additional, Doucet, L., additional, Boyault, S., additional, Brureau, L., additional, Multigner, L., additional, Diedhiou, A., additional, Roupret, M., additional, Compérat, E., additional, Blanchet, P., additional, de Reyniès, A., additional, and Cussenot, O., additional
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- 2018
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12. PO-520 Comprehensive molecular classification of localised prostate adenocarcinoma reveals a tumour subtype predictive of a non-aggressive disease
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Kamoun, A., primary, Cancel-Tassin, G., additional, Fromont, G., additional, De Reyniès, A., additional, and Cussenot, O., additional
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- 2018
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13. S100A6 (Calcyclin) is a prostate basal cell marker absent\ud in prostate cancer and its precursors
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Rehman, I., Cross, S.S., Azzouzi, A.R., Catto, J.W.F., Deloulme, J.C., Larre, S., Champigneuille, J., Fromont, G., Cussenot, O., and Hamdy, F.C.
- Subjects
urologic and male genital diseases - Abstract
S100A6 (Calcyclin) is a calcium-binding protein that has been implicated in a variety of biological functions as well as tumorigenesis.\ud The aim of our study was to investigate the involvement of S100A6 during prostate cancer development and progression. Using\ud immunohistochemistry, the expression of S100A6 was examined in benign (n ¼ 66), premalignant (n ¼ 10), malignant (n ¼ 66) and\ud metastatic prostate (n ¼ 5) tissues arranged in a tissue-microarray or whole sections as well as in prostate cancer cell lines. The\ud S100A6 immunostaining pattern in tissues was compared with that of cytokeratin 5 (a basal cell marker) and 18 (a benign luminal cell\ud marker). In all cases of benign epithelium, intense S100A6 expression was seen in the basal cell layer with absent staining in luminal\ud cells. In all cases of prostatic adenocarcinoma (matched), metastatic lesions and 3/10 high-grade prostatic intraepithelial neoplasia\ud lesions, an absence of S100A6 was seen. Western blotting and RT–PCR analysis of cell lines showed S100A6 expression to be\ud absent in LNCaP, LNCaP-LN3 and LNCaP-Pro5 but present in Du145, PC3, PC-3M and PC-3M-LN4. LNCaP cells treated with 5-\ud Azacytidine, caused re-expression of S100A6 mRNA. Sequencing of bisulphite modified DNA showed CpG methylation within the\ud S100A6 promoter region and exon 1 of LNCaP, LNCaP-LN3 and LNCaP-Pro5 cell lines but not in Du145 cells. Our data suggest\ud that loss of S100A6 protein expression is common in prostate cancer development and may occur at an early stage. The mechanism\ud of loss of expression may involve hypermethylation of CpG sites. The finding of intense S100A6 expression in the basal cells of benign\ud glands but loss of expression in cancer could be useful as a novel diagnostic marker for prostate cancer.
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- 2004
14. Differential Expression of Genes Related to Androgen and Estrogen Metabolism in Hereditary versus Sporadic Prostate Cancer
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Fromont, G., primary, Yacoub, M., additional, Valeri, A., additional, Mangin, P., additional, Vallancien, G., additional, Cancel-Tassin, G., additional, and Cussenot, O., additional
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- 2008
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15. Terminal urothelium differentiation of engineered neoureter after in vivo maturation in the "omental bioreactor"
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Baumert, H, primary, Mansouri, D, additional, Fromont, G, additional, Hekmati, M, additional, Simon, P, additional, Massoud, W, additional, Molinié, V, additional, and Malavaud, B, additional
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- 2007
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16. Effects of alimentary intact proteins and their oligopeptide hydrolysate on growth, nitrogen retention, and small bowel adaptation in inflammatory turpentine rat.
- Author
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UCL - MD/GYPE - Département de gynécologie, d'obstétrique et de pédiatrie, Zarrabian, S, Buts, Jean-Paul, Fromont, G, Tran, Trieu-Van, Macry, J, Mendy, F, Roger, L, Cèzard, J P, UCL - MD/GYPE - Département de gynécologie, d'obstétrique et de pédiatrie, Zarrabian, S, Buts, Jean-Paul, Fromont, G, Tran, Trieu-Van, Macry, J, Mendy, F, Roger, L, and Cèzard, J P
- Abstract
The effects of dietary proteins given as whole proteins (WP) or as a peptide hydrolysate (PH) on growth, nitrogen retention, and small bowel adaptation were assessed using two groups of male Wistar rats. Measurements were made 18, 42, and 66 h after acute inflammation induced by subcutaneous injections of 0.125 mL turpentine and in two control groups (n = 12). The two diets had the same caloric, nitrogen, vitamin, and mineral content. The WP diet resulted in better weight gain, nitrogen retention, and small intestinal adaptation by control rats than did the PH diet. Loss of body weight after 18 h of acute inflammation was significantly lower and nitrogen retention significantly higher in animals on the WP diet than in those on the PH diet. Small intestine morphology was maintained with the WP diet, whereas villus height was significantly lower after 66 h, and there were fewer mitoses per crypt in the rats on the PH diet. Glucoamylase activity at all times, and N-aminopeptidase activity at 18 h, were significantly higher in rats on the WP diet. The putrescine (at 42 h) and spermidine (at 18 h) concentrations in the mucosa were higher in the rats on the WP diet. These data suggest that synthetic diets should be tested for their nutritional value during acute inflammation before they are used in human nutrition.
- Published
- 1999
17. The status of CDKN2A alpha (p16INK4A) and beta (p14ARF) transcripts in thyroid tumour progression
- Author
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Ferru, A, primary, Fromont, G, additional, Gibelin, H, additional, Guilhot, J, additional, Savagner, F, additional, Tourani, J M, additional, Kraimps, J L, additional, Larsen, C J, additional, and Karayan-Tapon, L, additional
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- 2006
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18. Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 in serum and increased production of IL-1 beta mRNA in lymph nodes of patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome
- Author
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Gherardi, RK, primary, Belec, L, additional, Fromont, G, additional, Divine, M, additional, Malapert, D, additional, Gaulard, P, additional, and Degos, JD, additional
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- 1994
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19. Elevated Levels of Interleukin-1β(IL-1β) and IL-6 in Serum and Increased Production of IL-1βmRNA in Lymph Nodes of Patients With Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, and Skin Changes (POEMS) Syndrome
- Author
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Gherardi, R.K., Bélec, L, Fromont, G., Divine, M., Malapert, D., Gaulard, P., and Degos, J.-D.
- Abstract
To evaluate a possible implication of cytokines in the pathogenesis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome, we studied five consecutive patients with this condition, of which four had sclerotic bone lesions and four had multicentric Castleman’s disease, lnterleukin-1β(IL-1β) and IL-6 serum levels were determined in these patients (13 serum samples) and in patients with multiple myeloma (5) and Waldenström’s macroglobulinemia (5). In situ hybridization of the revelant mRNAs was performed on lymph node specimens of two patients with POEMS syndrome who had Castleman’s disease. Elevated serum levels of IL-1β(13/13 samples), and IL-6 (7/13 samples) were found in patients with POEMS syndrome. In the other patients, serum IL-1βwas undetectable or slightly increased and IL-6 was elevated in a single patient with Waldenström’s macroglobulinemia. Abundant IL-1βmRNA-producing cells were present in interfollicular spaces in the two tested patients, while IL-6 mRNA-producing cells were rare. We conclude that IL-1βand IL-6 serum levels may be chronically elevated in patients with POEMS syndrome, and that lymph node may be one site of IL-1βoverproduction. These results are in keeping with the hypothesis that cytokines mediate systemic manifestations of POEMS syndrome.
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- 1994
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20. Elevated Levels of Interleukin-1β (IL-1β) and IL-6 in Serum and Increased Production of IL-1β mRNA in Lymph Nodes of Patients With Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, and Skin Changes (POEMS) Syndrome
- Author
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Gherardi, R.K., Bélec, L, Fromont, G., Divine, M., Malapert, D., Gaulard, P., and Degos, J.-D.
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- 1994
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21. PARP inhibitors in prostate cancers, is it time for combinations?
- Author
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Teyssonneau D, Dariane C, Barret E, Beauval JB, Brureau L, Fiard G, Fromont G, Créhange G, Gauthé M, Ruffion A, Renard-Penna R, Mathieu R, Sargos P, Rouprêt M, Ploussard G, and Roubaud G
- Abstract
Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2 . More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)
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- 2024
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22. Endogenous ether lipids differentially promote tumor aggressiveness by regulating the SK3 channel.
- Author
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Papin M, Fontaine D, Goupille C, Figiel S, Domingo I, Pinault M, Guimaraes C, Guyon N, Cartron PF, Emond P, Lefevre A, Gueguinou M, Crottès D, Jaffrès PA, Ouldamer L, Maheo K, Fromont G, Potier-Cartereau M, Bougnoux P, Chantôme A, and Vandier C
- Subjects
- Humans, Cell Movement, MicroRNAs metabolism, MicroRNAs genetics, Lipids chemistry, Cell Line, Tumor, Neoplasm Invasiveness, Neoplasms metabolism, Neoplasms pathology, Neoplasms genetics, Small-Conductance Calcium-Activated Potassium Channels metabolism, Small-Conductance Calcium-Activated Potassium Channels genetics
- Abstract
SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9-dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests with the contents of article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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- View/download PDF
23. Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.
- Author
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de Vries-Brilland M, Rioux-Leclercq N, Meylan M, Dauvé J, Passot C, Spirina-Menand E, Flippot R, Fromont G, Gravis G, Geoffrois L, Chevreau C, Rolland F, Blanc E, Lefort F, Ravaud A, Gross-Goupil M, Escudier B, Negrier S, and Albiges L
- Subjects
- Humans, Prospective Studies, Tumor Microenvironment, Gene Expression Profiling methods, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Kidney Neoplasms drug therapy, Kidney Neoplasms genetics
- Abstract
Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets., Methods: We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort., Results: Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations., Conclusion: For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies., Trial Registration Number: NCT02489695., Competing Interests: Competing interests: MdV-B: Research Grant: Ipsen. Board: AstraZeneca, AAA, BMS, Astellas. Travel expense: Pfizer. NR-L: Board: Ipsen, BMS, AstraZeneca. RF: Honoraria: Merck, Pfizer, Ipsen, MSD, Bayer. Board: Janssen, Merck, Pfizer. Expert: Ipsen, Janssen, Astellas. GG: Speaker bureau: Janssen, Amgen, BMS, Ipsen, AAA, AstraZeneca, Bayer, Pfizer, Merck, Astellas. Recipient my institution. Board: Janssen, Amgen, BMS, Curium, Bayer, Pfizer, Merck. Recipient my institution. Expert: BMS, Bayer, Pfizer, Merck. Recipient my institution. Travel expense: Janssen, BMS, AstraZeneca, Bayer, Pfizer Merck. Recipient: me. LG: Consulting or advisory role: BMS, MSD, Novartis, Ipsen, Janssen. CC: Consulting or advisory role: Pfizer, Novartis, BMS. FR: Consulting: Pfizer, Ipsen, BMS, MSD. AR: Consulting or advisory role: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen. Travel expenses: Pfizer, BMS, AstraZeneca, Roche, MSD, Ipsen ; Institutional Grant: Pfizer. MG-G: Honoraria and travel expenses: Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche and Sanofi. BE: Advisory role: BMS, Pfizer, Novartis, Oncorena, Immunicum. Research grants: BMS, Novartis, Aveo. SN: Honoraria: Pfizer, Ipsen, MSD, BMS, Eisaï. Travel expenses: Pfizer, Ipsen, MSD. Research grant (institution): Pfizer, Ipsen. LA: Advisory role (Institution): BMS, MSD, Pfizer, Novartis, Amgen, Astellas, Ipsen, Roche, Merck, AstraZeneca, Exelixis, Peloton therapeutics, Corvus pharmaceuticals, Janssen, Eisai, 4D Pharma. Travel expenses: Merck/Pfizer. MM, JD, CP, ES-M, GF, EB, FL: no conflict., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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24. Persistent organochlorine pesticides in periprostatic adipose tissue from men with prostate cancer: Ethno-geographic variations, association with disease aggressiveness.
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Antignac JP, Figiel S, Pinault M, Blanchet P, Bruyère F, Mathieu R, Lebdai S, Fournier G, Rigaud J, Mahéo K, Marchand P, Guiffard I, Bichon E, le Bizec B, Multigner L, and Fromont G
- Subjects
- Male, Humans, Mirex, Adipose Tissue chemistry, Hydrocarbons, Chlorinated analysis, Pesticides analysis, Prostatic Neoplasms
- Abstract
Although several studies have examined the relationship between organochlorine pesticides (OCPs) and prostate cancer (PCa) risk, no data are available concerning the association between OCPs concentrations in periprostatic adipose tissue (PPAT), which reflects cumulative exposure, and PCa aggressiveness. Moreover, no previous study has compared OCPs exposure in two distinct ethno-geographical populations. The objectives were to analyze OCPs in PPAT of PCa patients from either Mainland France or French West Indies in correlation with features of tumor aggressiveness, after adjusting for potential confounders such age, BMI, and polyunsaturated fatty acid (PUFA) content of PPAT. PPAT was analyzed in 160 patients (110 Caucasians and 50 African-Caribbeans), 80 with an indolent tumor (ISUP group 1 + pT2), and 80 with an aggressive tumor (ISUP group more than 3 + pT3). The concentrations of 29 OCPs were measured in PPAT concomitantly with the characterization of PUFA content. Exposure patterns of OCPs differed according to the ethno-geographical origin. Most OCPs were found at higher concentration in Caucasian patients, whereas pp'-DDE content was twice as high in African-Caribbeans. Chlordecone was only detected in PPAT from African-Caribbean patients. Most OCP concentrations were positively correlated with age, and some with BMI. After adjusting for age, BMI, and PUFA composition of PPAT, no significant association was found between OCPs content and risk of aggressive disease, except of mirex which appeared inversely associated with aggressive features of PCa in Caucasian patients. These results highlight a significant ethno-geographic variation in internal exposure to OCPs, which likely reflects differences in consumption patterns. The inverse relationship observed between mirex concentration and markers of PCa aggressiveness need to be further investigated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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25. Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario.
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Cancel M, Pouillot W, Mahéo K, Fontaine A, Crottès D, and Fromont G
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- Adipokines, Adiponectin, Adipose Tissue pathology, Fatty Acids, Unsaturated, Humans, Lipids, Male, Tumor Microenvironment, Environmental Pollutants, Prostatic Neoplasms pathology
- Abstract
Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.
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- 2022
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26. Vasectomy and Risk of Prostate Cancer: A Systematic Review and Meta-analysis.
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Baboudjian M, Rajwa P, Barret E, Beauval JB, Brureau L, Créhange G, Dariane C, Fiard G, Fromont G, Gauthé M, Mathieu R, Renard-Penna R, Roubaud G, Ruffion A, Sargos P, Rouprêt M, and Ploussard G
- Abstract
Context: Previous reports have shown an association between vasectomy and prostate cancer (PCa). However, there exist significant discrepancies between studies and systematic reviews due to a lack of strong causal association and residual confounding factors such as prostate-specific antigen (PSA) screening., Objective: To assess the association between vasectomy and PCa, in both unadjusted and PSA screen-adjusted studies., Evidence Acquisition: We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses. The PubMed, Scopus, and Web of Science databases were searched in January 2022 for studies that analyzed the association between vasectomy and PCa., Evidence Synthesis: A total of 37 studies including 16 931 805 patients met our inclusion criteria. A pooled analysis from all studies showed a significant association between vasectomy and any-grade PCa (odds ratio [OR] 1.23; 95% confidence interval [CI], 1.10-1.37; p < 0.001; I
2 = 96%), localized PCa (OR 1.08; 95% CI, 1.06-1.11; p < 0.00001; I2 = 31%), or advanced PCa (OR 1.07; 95% CI, 1.02-1.13; p = 0.006; I2 = 0%). The association with PCa remained significant when the analyses were restricted to studies with a low risk of bias (OR 1.06; 95% CI, 1.02-1.10; p = 0.02; I2 = 48%) or cohort studies (OR 1.09; 95% CI, 1.04-1.13; p < 0.0001; I2 = 64%). Among studies adjusted for PSA screening, the association with localized PCa (OR 1.06; 95% CI, 1.03-1.09; p < 0.001; I2 = 0%) remained significant. Conversely, vasectomy was no longer associated with localized high-grade ( p = 0.19), advanced ( p = 0.22), and lethal ( p = 0.42) PCa., Conclusions: Our meta-analysis found an association between vasectomy and any, mainly localized, PCa. However, the effect estimates of the association were increasingly close to null when examining studies of robust design and high quality. On exploratory analyses including studies, which adjusted for PSA screening, the association for aggressive and/or advanced PCa diminished., Patient Summary: In this study, we found an association between vasectomy and the risk of developing localized prostate cancer without being able to determine whether the procedure leads to a higher prostate cancer incidence., (© 2022 The Author(s).)- Published
- 2022
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27. Development of a High-Performance Thin-Layer Chromatography Method for the Quantification of Alkyl Glycerolipids and Alkenyl Glycerolipids from Shark and Chimera Oils and Tissues.
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Papin M, Guimaraes C, Pierre-Aue B, Fontaine D, Pardessus J, Couthon H, Fromont G, Mahéo K, Chantôme A, Vandier C, and Pinault M
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- Animals, Chromatography, Thin Layer, Ether, Ethers, Glycerol, Plant Oils, Fish Oils, Sharks, Lipids analysis
- Abstract
Ether lipids are composed of alkyl lipids with an ether bond at the sn-1 position of a glycerol backbone and alkenyl lipids, which possess a vinyl ether bond at the sn-1 position of the glycerol. These ether glycerolipids are present either as polar glycerophospholipids or neutral glycerolipids. Before studying the biological role of molecular species of ether glycerolipids, there is a need to separate and quantify total alkyl and alkenyl glycerolipids from biological samples in order to determine any variation depending on tissue or physiopathological conditions. Here, we detail the development of the first high-performance thin-layer chromatography method for the quantification of total alkyl and alkenyl glycerolipids thanks to the separation of their corresponding alkyl and alkenyl glycerols. This method starts with a reduction of all lipids after extraction, resulting in the reduction of neutral and polar ether glycerolipids into alkyl and alkenyl glycerols, followed by an appropriate purification and, finally, the linearly ascending development of alkyl and alkenyl glycerols on high-performance thin-layer chromatography plates, staining, carbonization and densitometric analysis. Calibration curves were obtained with commercial alkyl and alkenyl glycerol standards, enabling the quantification of alkyl and alkenyl glycerols in samples and thus directly obtaining the quantity of alkyl and alkenyl lipids present in the samples. Interestingly, we found a differential quantity of these lipids in shark liver oil compared to chimera. We quantified alkyl and alkenyl glycerolipids in periprostatic adipose tissues from human prostate cancer and showed the feasibility of this method in other biological matrices (muscle, tumor).
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- 2022
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28. PARP Inhibitors as Monotherapy in Daily Practice for Advanced Prostate Cancers.
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Teyssonneau D, Thiery-Vuillemin A, Dariane C, Barret E, Beauval JB, Brureau L, Créhange G, Fiard G, Fromont G, Gauthé M, Ruffion A, Renard-Penna R, Mathieu R, Sargos P, Rouprêt M, Ploussard G, Roubaud G, and On Behalf Of The Cc-Afu Cancerology Committee Of The Association Française d'Urologie
- Abstract
Despite recent improvements in survival, metastatic castration-resistant prostate cancers (mCRPCs) remain lethal. Alterations in genes involved in the homologous recombination repair (HRR) pathway are associated with poor prognosis. Poly-ADP-ribose polymerase (PARP) inhibitors (PARPis) have demonstrated anti-tumoral effects by synthetic lethality in patients with mCRPCs harboring HRR gene alterations, in particular BRCA2 . While both olaparib and rucaparib have obtained government approvals for use, the selection of eligible patients as well as the prescription of these treatments within the clinical urology community are challenging. This review proposes a brief review of the rationale and outcomes of PARPi treatment, then a pragmatic vision of PARPi use in terms of prescription and the selection of patients based on molecular screening, which can involve potential genetic counseling in the case of associated germinal alterations.
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- 2022
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29. The Hepatokine FGF21 Increases the Human Spermatozoa Motility.
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Bourdon G, Estienne A, Chevaleyre C, Ramé C, Guérif F, Brun JS, Vasseur C, Fromont G, Plotton I, Dufour-Rainfray D, Caldas-Silveira E, Dupont J, Froment P, and Ducluzeau PH
- Subjects
- Humans, Male, Phosphatidylinositol 3-Kinases, Spermatozoa, Diabetes Mellitus, Type 2, Fibroblast Growth Factors genetics, Sperm Motility
- Abstract
Lifestyle, environment and excess body weight are not only associated with an increased risk of metabolic disorders, such as type 2 diabetes, but also to other pathological processes, such as infertility. A hormone produced mainly by the liver called fibroblast growth factor 21 (FGF21) is closely linked to the energy status and is increased in patients suffering from obesity or insulin resistance. Recently, FGF21 has been shown to be associated with female fertility disorders, but no or few data about the role of FGF21 on human male fertility has been described. In the present study, FGF21 was measured in the seminal fluid at a lower level in comparison to the blood level. Thus, in the present in vitro study, we aimed to decipher the FGF21 system in human semen. To evaluate the putative role of FGF21 on spermatozoa function, we incubated human spermatozoa with increasing concentrations of recombinant human FGF21. The FGF21 in seminal fluid is potentially produced by male reproductive tract tissues. In spermatozoa, the FGF21 signal was transduced by the two main receptors FGFR1-c and FGFR3 and the cofactor β-klotho, which are colocalized in the middle piece of spermatozoa and stimulated the PI3K/Akt and MAPK pathways. Finally, in vitro treatment by FGF21 significantly increased sperm motility and ATP levels. Concomitantly, exposure to FGF21 improved the oxidative stress, as a lower ROS level was observed. Overall, these results seem to indicate that the metabolic factor, FGF21, positively modifies the activity and quality of the parameters of human spermatozoa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bourdon, Estienne, Chevaleyre, Ramé, Guérif, Brun, Vasseur, Fromont, Plotton, Dufour-Rainfray, Caldas-Silveira, Dupont, Froment and Ducluzeau.)
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- 2022
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30. HSP110 as a Diagnostic but Not a Prognostic Biomarker in Colorectal Cancer With Microsatellite Instability.
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Tachon G, Chong-Si-Tsaon A, Lecomte T, Junca A, Frouin É, Miquelestorena-Standley E, Godet J, Evrard C, Randrian V, Chautard R, Auriault ML, Moulin V, Guyetant S, Fromont G, Karayan-Tapon L, and Tougeron D
- Abstract
Determination of microsatellite instability (MSI) using molecular test and deficient mismatch repair (dMMR) using immunohistochemistry (IHC) has major implications on colorectal cancer (CRC) management. The HSP110 T
17 microsatellite has been reported to be more monomorphic than the common markers used for MSI determination. Large deletion of HSP110 T17 has been associated with efficacy of adjuvant chemotherapy in dMMR/MSI CRCs. The aim of this study was to evaluate the interest of HSP110 deletion/expression as a diagnostic tool of dMMR/MSI CRCs and a predictive tool of adjuvant chemotherapy efficacy. All patients with MSI CRC classified by molecular testing were included in this multicenter prospective cohort ( n = 381). IHC of the 4 MMR proteins was carried out. HSP110 expression was carried out by IHC ( n = 343), and the size of HSP110 T17 deletion was determined by PCR (n = 327). In the 293 MSI CRCs with both tests, a strong correlation was found between the expression of HSP110 protein and the size of HSP110 T17 deletion. Only 5.8% of MSI CRCs had no HSP110 T17 deletion ( n = 19/327). HSP110 T17 deletion helped to re-classify 4 of the 9 pMMR/MSI discordance cases as pMMR/MSS cases. We did not observe any correlation between HSP110 expression or HSP110 T17 deletion size with time to recurrence in patients with stage II and III CRC, treated with or without adjuvant chemotherapy. HSP110 is neither a robust prognosis marker nor a predictor tool of adjuvant chemotherapy efficacy in dMMR/MSI CRC. However, HSP110 T17 is an interesting marker, which may be combined with the other pentaplex markers to identify discordant cases between MMR IHC and MSI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tachon, Chong-Si-Tsaon, Lecomte, Junca, Frouin, Miquelestorena-Standley, Godet, Evrard, Randrian, Chautard, Auriault, Moulin, Guyetant, Fromont, Karayan-Tapon and Tougeron.)- Published
- 2022
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31. Overview of the Development and Use of Akt Inhibitors in Prostate Cancer.
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Gasmi A, Roubaud G, Dariane C, Barret E, Beauval JB, Brureau L, Créhange G, Fiard G, Fromont G, Gauthé M, Ruffion A, Renard-Penna R, Sargos P, Rouprêt M, Ploussard G, and Mathieu R
- Abstract
Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.
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- 2021
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32. Same-day-discharge Robot-assisted Radical Prostatectomy: An Annual Countrywide Analysis.
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Ploussard G, Grabia A, Barret E, Beauval JB, Brureau L, Créhange G, Dariane C, Fiard G, Fromont G, Gauthé M, Mathieu R, Renard-Penna R, Roubaud G, Ruffion A, Sargos P, Rouprêt M, and Lequeu CE
- Abstract
There are no countrywide data regarding the utilization of same-day-discharge (SDD) surgery for robot-assisted radical prostatectomy (RARP). We aimed to evaluate the annual number of SDD RARP procedures in France and to compare postoperative outcomes in SDD versus non-SDD centers. Data for all 9651 patients undergoing RARP in France in 2020 were extracted from the central database of the national healthcare system. Endpoints were length of hospital stay, patient age, center volume, lymph node dissection, and the hospital readmission rate. Overall, 184 SDD cases (1.9%) were reported in 14.2% of RARP centers. The annual RARP and SDD RARP caseload ranged from 41 to 485, and from one to 47, respectively, in SDD centers. SDD was significantly associated with higher-volume centers ( p < 0.001). No difference in readmission rate (7.9% vs 5.1%; p = 0.141) was observed for SDD versus non-SDD centers. Direct stay costs were estimated at €1457 in SDD centers compared to €2021 in non-SDD centers. The main limitation is the lack of detailed patient characteristics and readmission causes. This annual nationwide analysis suggests that SDD RARP remains infrequently used in routine practice in France despite being associated with comparable short-term outcomes after RARP and potential cost benefits., Patient Summary: We evaluated the use of robot-assisted removal of the prostate (RARP) with same-day hospital discharge in France for men with prostate cancer. In 2020, only 1.9% of the 9651 RARP procedures involved same-day discharge, even though the data show that this approach has lower costs and comparable safety., (© 2021 The Author(s).)
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- 2021
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33. A 5-Year Contemporary Nationwide Evolution of the Radical Prostatectomy Landscape.
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Ploussard G, Grabia A, Beauval JB, Barret E, Brureau L, Dariane C, Fiard G, Fromont G, Gauthé M, Mathieu R, Renard-Penna R, Roubaud G, Ruffion A, Sargos P, Rozet F, Lequeu CE, and Rouprêt M
- Abstract
The evolution in the past decade of recommendations for prostate cancer (PCa) management, from screening to surgical treatment, may have affected the radical prostatectomy (RP) landscape. However, comprehensive data at a national level remain scarce. We extracted 5-yr data for RP patients in France from the central database of the national health care system. The primary endpoints were surgical approach (open [ORP], laparoscopic [LRP], and robot-assisted RP [RARP]), length of stay (LOS), and complication and readmission rates. The annual number of RPs was stable during the study period. The proportion of RARPs increased from 39.8% in 2015 to 52.6% in 2019, whereas the proportion of ORPs decreased from 34.4% to 24.5%. LOS continuously decreased over time irrespective of the surgical approach. The proportion of centres in the highest quartile of hospital volume increased from 22.0% to 28.3% ( p = 0.006). LOS and complication and readmission rates were significantly lower ( p < 0.001) in the LRP cohort at each time point. National trends confirmed that RARP progressively replaced ORP, with a stable number of annual RPs over time. Greater centralisation and better early postoperative outcomes were observed with laparoscopy., Patient Summary: We reviewed French data for patients undergoing removal of the prostate for prostate cancer between 2015 and 2019. We found that robot-assisted minimally invasive surgery has increased over time and the length of hospital stays has decreased. Rates of complications and readmission were lower with minimally invasive surgery., (© 2021 The Author(s).)
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- 2021
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34. Biomarker in Active Surveillance for Prostate Cancer: A Systematic Review.
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Manceau C, Fromont G, Beauval JB, Barret E, Brureau L, Créhange G, Dariane C, Fiard G, Gauthé M, Mathieu R, Renard-Penna R, Roubaud G, Ruffion A, Sargos P, Rouprêt M, Ploussard G, and On Behalf Of The Cc-Afu Cancerology Committee Of The Association Française d'Urologie
- Abstract
Active surveillance (AS) in prostate cancer (PCa) represents a curative alternative for men with localised low-risk PCa. Continuous improvement of AS patient's selection and surveillance modalities aims at reducing misclassification, simplifying modalities of surveillance and decreasing need for invasive procedures such repeated biopsies. Biomarkers represent interesting tools to evaluate PCa diagnosis and prognosis, of which many are readily available or under evaluation. The aim of this review is to investigate the biomarker performance for AS selection and patient outcome prediction. Blood, urinary and tissue biomarkers were studied and a brief description of use was proposed along with a summary of major findings. Biomarkers represent promising tools which could be part of a more tailored risk AS strategy aiming to offer personalized medicine and to individualize the treatment and monitoring of each patient. The usefulness of biomarkers has mainly been suggested for AS selection, whereas few studies have investigated their role during the monitoring phase. Randomized prospective studies dealing with imaging are needed as well as larger prospective studies with long-term follow-up and strong oncologic endpoints.
- Published
- 2021
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35. PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1.
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Matheux A, Gassiot M, Fromont G, Leenhardt F, Boulahtouf A, Fabbrizio E, Marchive C, Garcin A, Agherbi H, Combès E, Evrard A, Houédé N, Balaguer P, Gongora C, Mbatchi LC, and Pourquier P
- Abstract
Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.
- Published
- 2021
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36. Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation.
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Bery F, Cancel M, Guéguinou M, Potier-Cartereau M, Vandier C, Chantôme A, Guibon R, Bruyère F, Fromont G, and Mahéo K
- Abstract
Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes.
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- 2021
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37. The Chemokine Receptor CCR3 Is Potentially Involved in the Homing of Prostate Cancer Cells to Bone: Implication of Bone-Marrow Adipocytes.
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Guérard A, Laurent V, Fromont G, Estève D, Gilhodes J, Bonnelye E, Le Gonidec S, Valet P, Malavaud B, Reina N, Attané C, and Muller C
- Subjects
- Aging pathology, Bone Marrow drug effects, Bone and Bones drug effects, Cell Line, Tumor, Chemokine CCL7 metabolism, Chemotaxis drug effects, Culture Media, Conditioned pharmacology, Humans, Male, Neoplasm Metastasis, Obesity complications, Prostatic Neoplasms complications, Adipocytes metabolism, Adipocytes pathology, Bone Marrow pathology, Bone and Bones pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, CCR3 metabolism
- Abstract
Bone metastasis remains the most frequent and the deadliest complication of prostate cancer (PCa). Mechanisms leading to the homing of tumor cells to bone remain poorly characterized. Role of chemokines in providing navigational cues to migrating cancer cells bearing specific receptors is well established. Bone is an adipocyte-rich organ since 50 to 70% of the adult bone marrow (BM) volume comprise bone marrow adipocytes (BM-Ads), which are likely to produce chemokines within the bone microenvironment. Using in vitro migration assays, we demonstrated that soluble factors released by human primary BM-Ads are able to support the directed migration of PCa cells in a CCR3-dependent manner. In addition, we showed that CCL7, a chemokine previously involved in the CCR3-dependent migration of PCa cells outside of the prostate gland, is released by human BM-Ads. These effects are amplified by obesity and ageing, two clinical conditions known to promote aggressive and metastatic PCa. In human tumors, we found an enrichment of CCR3 in bone metastasis vs. primary tumors at mRNA levels using Oncomine microarray database. In addition, immunohistochemistry experiments demonstrated overexpression of CCR3 in bone versus visceral metastases. These results underline the potential importance of BM-Ads in the bone metastatic process and imply a CCR3/CCL7 axis whose pharmacological interest needs to be evaluated.
- Published
- 2021
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38. Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression.
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Bery F, Figiel S, Kouba S, Fontaine D, Guéguinou M, Potier-Cartereau M, Vandier C, Guibon R, Bruyère F, Fromont G, and Mahéo K
- Subjects
- Cell Line, Tumor, Cell Movement, Eicosapentaenoic Acid pharmacology, Glycolipids pharmacology, Humans, Linoleic Acid pharmacology, Male, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Small-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors, Epithelial-Mesenchymal Transition, Hypoxia physiopathology, Prostatic Neoplasms pathology, Small-Conductance Calcium-Activated Potassium Channels metabolism, Tumor Microenvironment, Zinc Finger E-box-Binding Homeobox 1 metabolism
- Abstract
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca
2+ -activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes.- Published
- 2020
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39. A comparative study of the capacity of mesenchymal stromal cell lines to form spheroids.
- Author
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Deynoux M, Sunter N, Ducrocq E, Dakik H, Guibon R, Burlaud-Gaillard J, Brisson L, Rouleux-Bonnin F, le Nail LR, Hérault O, Domenech J, Roingeard P, Fromont G, and Mazurier F
- Subjects
- Animals, Cell Aggregation, Cell Death, Cell Dedifferentiation, Cell Hypoxia, Cell Line, Cell Proliferation, Humans, Mice, Oxidative Stress, Mesenchymal Stem Cells cytology, Spheroids, Cellular cytology
- Abstract
Mesenchymal stem cells (MSC)-spheroid models favor maintenance of stemness, ex vivo expansion and transplantation efficacy. Spheroids may also be considered as useful surrogate models of the hematopoietic niche. However, accessibility to primary cells, from bone marrow (BM) or adipose tissues, may limit their experimental use and the lack of consistency in methods to form spheroids may affect data interpretation. In this study, we aimed to create a simple model by examining the ability of cell lines, from human (HS-27a and HS-5) and murine (MS-5) BM origins, to form spheroids, compared to primary human MSCs (hMSCs). Our protocol efficiently allowed the spheroid formation from all cell types within 24 hours. Whilst hMSC-spheroids began to shrink after 24 hours, the size of spheroids from cell lines remained constant during three weeks. The difference was partially explained by the balance between proliferation and cell death, which could be triggered by hypoxia and induced oxidative stress. Our results demonstrate that, like hMSCs, MSC cell lines make reproductible spheroids that are easily handled. Thus, this model could help in understanding mechanisms involved in MSC functions and may provide a simple model by which to study cell interactions in the BM niche., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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40. Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease.
- Author
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Fontaine D, Figiel S, Félix R, Kouba S, Fromont G, Mahéo K, Potier-Cartereau M, Chantôme A, and Vandier C
- Subjects
- Animals, Humans, Ether chemistry, Fatty Acids, Unsaturated metabolism, Ion Channels metabolism
- Abstract
Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage [i.e., plasmalogens (Pls)] at the sn 1 position of the glycerol backbone, and they are enriched in PUFAs at the sn 2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs) and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions., (Copyright © 2020 Fontaine et al.)
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- 2020
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41. Apolipoprotein-mediated regulation of lipid metabolism induces distinctive effects in different types of breast cancer cells.
- Author
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Ben Hassen C, Gutierrez-Pajares JL, Guimaraes C, Guibon R, Pinault M, Fromont G, and Frank PG
- Subjects
- Animals, Breast Neoplasms classification, Cell Line, Tumor, Cell Movement, Databases, Genetic, Epithelial-Mesenchymal Transition, Female, Humans, Mice, Mice, Nude, Survival Rate, Xenograft Model Antitumor Assays, Apolipoprotein A-I metabolism, Apolipoproteins E metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation, Cholesterol metabolism, Lipid Metabolism
- Abstract
Background: The highest incidence of breast cancer is in the Western world. Several aspects of the Western lifestyle are known risk factors for breast cancer. In particular, previous studies have shown that cholesterol levels can play an important role in the regulation of tumor progression., Methods: In the present study, we modulated cholesterol metabolism in the human breast cancer cell lines MCF-7 and MDA-MB-231 using a genetic approach. Apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) were expressed in these cell lines to modulate cholesterol metabolism. The effects of these apolipoproteins on cancer cell properties were examined., Results: Our results show that both apolipoproteins can regulate cholesterol metabolism and can control the epithelial-to-mesenchymal transition process. However, these effects were different depending on the cell type. We show that expressing apoA-I or apoE stimulates proliferation, migration, and tumor growth of MCF-7 cells. However, apoA-I or apoE reduces proliferation and migration of MDA-MB-231 cells., Conclusions: These data suggest that modulating sterol metabolism may be most effective at limiting tumor progression in models of triple-negative cancers.
- Published
- 2020
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42. The Calcium-Sensing Receptor is A Marker and Potential Driver of Neuroendocrine Differentiation in Prostate Cancer.
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Bery F, Cancel M, Chantôme A, Guibon R, Bruyère F, Rozet F, Mahéo K, and Fromont G
- Abstract
The mechanisms underlying neuroendocrine (NE) differentiation in prostate cancer (PCa) remain mostly uncharacterized. Since a deregulated calcium homeostasis has been reported in neuroendocrine prostate cancer (NEPC), we explored herein the link between NE differentiation and the calcium-sensing receptor (CaSR). CaSR expression was evaluated by immunohistochemistry-together with NE markers-on tissue microarrays containing samples of normal prostate, localized PCa, metastatic castration resistant PCa (MCRPC) and NEPC. In prostate tissues, we observed a strong association between CaSR and chromogranin expression. Both markers were strongly expressed in all cases of NEPC and co-expression was confirmed by double immunostaining. In MCRPC, the expression of CaSR was significantly associated with shorter overall survival. The involvement of CaSR in NE differentiation was evaluated in PCa cell lines. Inhibition of CaSR led to decrease the expression of neuronal (NSE, βtubulinIII) and NE (chromogranin, synaptophysin) markers in the NE PCa cell line NCI-H660. A decrease of neuronal and NE markers was also observed in siCaSR-transfected PC3 and 22RV1 cells, respectively, whereas CaSR activation increased both NSE and synaptophysin expression in PC3 cells. These results strongly suggest that CaSR is a marker and a driver of NE differentiation in PCa and emphasize the potential of CaSR directed therapy for NEPC patients.
- Published
- 2020
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43. A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy.
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Figiel S, Bery F, Chantôme A, Fontaine D, Pasqualin C, Maupoil V, Domingo I, Guibon R, Bruyère F, Potier-Cartereau M, Vandier C, Fromont G, and Mahéo K
- Abstract
The composition of periprostatic adipose tissue (PPAT) has been shown to play a role in prostate cancer (PCa) progression. We recently reported an inverse association between PCa aggressiveness and elevated PPAT linoleic acid (LA) and eicosapentaenoic acid (EPA) content. In the present study, we identified a new signaling pathway with a positive feedback loop between the epithelial-to-mesenchymal transition (EMT) transcription factor Zeb1 and the Ca
2+ -activated K+ channel SK3, which leads to an amplification of Ca2+ entry and cellular migration. Using in vitro experiments and ex vivo cultures of human PCa slices, we demonstrated that LA and EPA exert anticancer effects, by modulating Ca2+ entry, which was involved in Zeb1 regulation and cancer cellular migration. This functional approach using human prostate tumors highlights the clinical relevance of our observations, and may allow us to consider the possibility of targeting cancer spread by altering the lipid microenvironment., Competing Interests: The authors declare no conflicts of interest.- Published
- 2019
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44. Morphologic and immunophenotypical features distinguishing Merkel cell polyomavirus-positive and negative Merkel cell carcinoma.
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Kervarrec T, Tallet A, Miquelestorena-Standley E, Houben R, Schrama D, Gambichler T, Berthon P, Le Corre Y, Hainaut-Wierzbicka E, Aubin F, Bens G, Tabareau-Delalande F, Beneton N, Fromont G, Arbion F, Leteurtre E, Herfs M, Touzé A, Samimi M, and Guyétant S
- Subjects
- Aged, Aged, 80 and over, Carcinoma, Merkel Cell virology, Female, Humans, Immunophenotyping, Male, Merkel cell polyomavirus, Polyomavirus Infections complications, Polyomavirus Infections virology, Skin Neoplasms virology, Tumor Virus Infections pathology, Tumor Virus Infections virology, 12E7 Antigen biosynthesis, Biomarkers, Tumor analysis, Carcinoma, Merkel Cell pathology, Polyomavirus Infections pathology, Skin Neoplasms pathology
- Abstract
In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei-similar to the spindle-shape variant of small cell lung cancer-were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p = 0.005). Moreover, virus-negative cases more frequently displayed a "large-cell neuroendocrine carcinoma" phenotype with larger cell size (p = 0.0026), abundant cytoplasm (p = 4×10
-7 ) and prominent nucleoli (p = 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.- Published
- 2019
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45. TRPM8-androgen receptor association within lipid rafts promotes prostate cancer cell migration.
- Author
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Grolez GP, Gordiendko DV, Clarisse M, Hammadi M, Desruelles E, Fromont G, Prevarskaya N, Slomianny C, and Gkika D
- Subjects
- Biotinylation, Blotting, Western, Cell Movement genetics, Gene Silencing physiology, Humans, Immunoprecipitation, Male, PC-3 Cells, Prostatic Neoplasms genetics, Receptors, Androgen genetics, Time-Lapse Imaging, Tissue Array Analysis, Cell Movement physiology, Membrane Microdomains metabolism, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism, TRPM Cation Channels metabolism
- Abstract
In prostate carcinogenesis, androgens are known to control the expression of the transient receptor potential melastatin 8 (TRPM8) protein via activation of androgen receptor (AR). Overexpression and/or activity of TRPM8 channel was shown to suppress prostate cancer (PCa) cell migration. Here we report that at certain concentrations androgens facilitate PCa cell migration. We show that underlying mechanism is inhibition of TRPM8 by activated AR which interacts with the channel within lipid rafts microdomains of the plasma membrane. Thus, our study has identified an additional nongenomic mechanism of the TRPM8 channel regulation by androgens that should be taken into account upon the development of novel therapeutic strategies.
- Published
- 2019
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46. Stimulation of murine P2Y11-like purinoreceptor protects against hypoxia/reoxygenation injury and decreases heart graft rejection lesions.
- Author
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Bourguignon T, Benoist L, Chadet S, Miquelestorena-Standley E, Fromont G, Ivanes F, and Angoulvant D
- Subjects
- Animals, Apoptosis drug effects, Caspases metabolism, Cell Line, Cytokines metabolism, Disease Models, Animal, Female, Graft Rejection metabolism, Graft Rejection pathology, Graft Survival drug effects, Mice, Inbred BALB C, Mice, Inbred C57BL, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Rats, Receptors, Purinergic P2 metabolism, Signal Transduction drug effects, Time Factors, Diphosphonates pharmacology, Graft Rejection prevention & control, Heart Transplantation adverse effects, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Naphthalenesulfonates pharmacology, Purinergic P2 Receptor Agonists pharmacology, Receptors, Purinergic P2 drug effects
- Abstract
Objective: Myocardial ischemia reperfusion is a major cause of cell injury during cardiac transplantation and is responsible for increased graft rejection. Several in vitro studies demonstrated the protective effect of P2Y11-like purinoreceptor stimulation in the context of myocardial ischemia/reperfusion. In this study, we hypothesized a possible cardioprotective role of P2Y11R stimulation against ischemia/reperfusion lesions and validated its clinical effect in vivo in a heart transplantation model., Methods: We subjected H9c2 rat cardiomyocyte-derived cell line to 5 hours of hypoxia and 1 hour of reoxygenation. P2Y11R selective agonist NF546 and antagonist NF340 were added at the onset of reoxygenation. Cell injuries were assessed by microculture tetrazolium reduction and intracellular adenosine triphosphate level. Clinical effect of P2Y11R stimulation was further investigated in vivo. Hearts from BALB/c mice were transplanted intra-abdominally into allogenic C57BL/6 mice (n = 104). Recipient mice were injected with P2Y11R agonist. Mice in the sham group were injected with saline solution. In the control group, hearts from C57BL/6 were transplanted into syngeneic C57BL/6 mice. Rejection lesions were investigated using histology and immunohistochemistry at days 3, 5, and 7 after transplantation. We measured caspase activities to quantify apoptosis. Production of proinflammatory and anti-inflammatory cytokines was investigated., Results: P2Y11R stimulation at the onset of reoxygenation significantly reduced in vitro hypoxia/reoxygenation injuries. This protection was suppressed with P2Y11R antagonist. In vivo, cardiac allograft survival was significantly prolonged after P2Y11R stimulation. Rejection lesions, classified according to the International Society of Heart Lung Transplantation guidelines and quantified using the mean number of inflammatory cells per field, were significantly reduced in the treated group. At day 5 after transplantation, P2Y11R agonist pretreated allografts also demonstrated less apoptotic lesions., Conclusions: Our data suggest a novel cardioprotective role of P2Y11R at the onset of reoxygenation/reperfusion against reperfusion injuries. Pharmacologic conditioning using P2Y11 agonist may be beneficial after cardiac transplantation in improving myocardial ischemia/reperfusion outcomes and decreasing graft rejection lesions., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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47. Transient Receptor Potential Channel Expression Signatures in Tumor-Derived Endothelial Cells: Functional Roles in Prostate Cancer Angiogenesis.
- Author
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Bernardini M, Brossa A, Chinigo G, Grolez GP, Trimaglio G, Allart L, Hulot A, Marot G, Genova T, Joshi A, Mattot V, Fromont G, Munaron L, Bussolati B, Prevarskaya N, Fiorio Pla A, and Gkika D
- Abstract
Background : Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the ' prostate-associated ' channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results : We identified three ' prostate-associated ' genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions : We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets.
- Published
- 2019
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48. Functional Organotypic Cultures of Prostate Tissues: A Relevant Preclinical Model that Preserves Hypoxia Sensitivity and Calcium Signaling.
- Author
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Figiel S, Pasqualin C, Bery F, Maupoil V, Vandier C, Potier-Cartereau M, Domingo I, Guibon R, Bruyere F, Maheo K, and Fromont G
- Subjects
- Aged, Antigens, Neoplasm metabolism, Carbonic Anhydrase IX metabolism, Cell Hypoxia, Humans, Kallikreins metabolism, Male, Middle Aged, Neoplasm Proteins metabolism, Prostate-Specific Antigen metabolism, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Tissue Culture Techniques, Transcriptional Regulator ERG metabolism, Zinc Finger E-box-Binding Homeobox 1 metabolism, Calcium metabolism, Calcium Signaling, Models, Biological, Prostatic Neoplasms metabolism, Tumor Microenvironment
- Abstract
In prostate cancer research, there is a lack of valuable preclinical models. Tumor cell heterogeneity and sensitivity to microenvironment signals, such as hypoxia or extracellular calcium concentration, are difficult to reproduce. Here, we developed and characterized an ex vivo tissue culture model preserving these properties. Prostate tissue slices from 26 patients were maintained ex vivo under optimized culture conditions. The expression of markers associated with proliferation, androgen-receptor signaling, and hypoxia was assessed by immunostaining. A macroscope was used to achieve real-time calcium fluorescence optical imaging. Tissue morphology was maintained successfully without necrosis for 5 days. Compared with native tumors and tissue cultured with androgens, androgen deprivation in the medium led to decreased expression of both androgen receptor and its target gene products, prostate specific antigen (PSA) and ETS-related gene (ERG). Ex vivo cultured slices also were sensitive to hypoxia because carbonic anhydrase IX and zinc finger E-box binding homeobox 1 (Zeb1) protein levels increased in 1% oxygen. Exposure of slices to supraphysiological extracellular Ca
2+ concentration induced a robust and rapid Ca2+ entry, with a greater response in tumor compared with nontumor tissue. This ex vivo model reproduces the morphologic and functional characteristics of human prostate cancer, including sensitivity to androgen deprivation and induced response to hypoxia and extracellular Ca2+ . It therefore could become an attractive tool for drug response prediction studies., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
49. Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas.
- Author
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Kervarrec T, Tallet A, Miquelestorena-Standley E, Houben R, Schrama D, Gambichler T, Berthon P, Le Corre Y, Hainaut-Wierzbicka E, Aubin F, Bens G, Tabareau-Delalande F, Beneton N, Fromont G, Arbion F, Leteurtre E, Touzé A, Samimi M, and Guyétant S
- Subjects
- Aged, Aged, 80 and over, Diagnosis, Differential, Female, Humans, Immunohistochemistry methods, Male, Middle Aged, Biomarkers, Tumor analysis, Carcinoma, Merkel Cell diagnosis, Carcinoma, Neuroendocrine diagnosis, Skin Neoplasms diagnosis
- Abstract
Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.
- Published
- 2019
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50. Phosphorylation of NHERF1 S279 and S301 differentially regulates breast cancer cell phenotype and metastatic organotropism.
- Author
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Greco MR, Bon E, Rubino R, Guerra L, Bernabe-Garcia M, Cannone S, Cayuela ML, Ciaccia L, Marionneau-Lambot S, Oullier T, Fromont G, Guibon R, Roger S, Reshkin SJ, and Cardone RA
- Subjects
- Animals, Breast Neoplasms pathology, Cell Line, Tumor, Disease Models, Animal, Female, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Mice, Mutant Proteins metabolism, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphoproteins genetics, Phosphorylation, Signal Transduction, Sodium-Hydrogen Exchanger 1 metabolism, Sodium-Hydrogen Exchangers genetics, Xenograft Model Antitumor Assays, Zebrafish, Breast Neoplasms metabolism, Phenotype, Phosphoproteins metabolism, Sodium-Hydrogen Exchangers metabolism
- Abstract
Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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