Ratti, F. (Francesca)

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    An international retrospective observational study of liver functional deterioration after repeat liver resection for patients with hepatocellular carcinoma
    (2022) Otsuka, Y. (Yuichiro); Buell, J.F. (Joseph F.); Dagher, I. (Ibrahim); Briceño, J. (Javier); Ohmura, Y. (Yoshiaki); Wilson, G.C. (Gregory C.); Wakabayashi, G. (Go); Morise, Z. (Zenichi); Rotellar, F. (Fernando); Seyama, Y. (Yasuji); Okamura, Y. (Yukiyasu); Alzoubi, M. (Mohammad); Belli, A. (Andrea); Ueno, M. (Masaki); Fuks, D. (David); Gayet, B. (Brice); Monden, K. (Kazuteru); Kawamoto, K. (Kazuyuki); Kaizu, T. (Takashi); Troisi, R.I. (Roberto I.); Kumamoto, Y. (Yusuke); Lewin, J. (Joel); Laurent, A. (Alexis); Lin, C.C.W. (Charles Chung-Wei); Cheung, T.T. (Tan To); Yasunaga, M. (Masafumi); Cherqui, D. (Daniel); Edwin, B. (Bjorn); Kato, Y. (Yutaro); Tanabe, M. (Minoru); Ome, Y. (Yusuke); Belli, G. (Giulio); Ciria-Bru, R. (Rubén); Suh, K.S. (Kyung Suk); O’Rourke, N. (Nicholas); Tanaka, S. (Shogo); Chen, K. (KuoHsin); Abu-Hilal, M. (Mohammed); Kaneko, H. (Hironori); Hashida, K. (Kazuki); Yoh, T. (Tomoaki); Shinoda, M. (Masahiro); Ekmekcigil, E. (Ela); Cho, H.D. (Hwui-Dong); Halim, N.A. (Nasser Abdul); Aldrighetti, L. (Luca); Kubo, S. (Shoji); Sadamori, H. (Hiroshi); Gotohda, N. (Naoto); Soubrane, O. (Olivier); Abe, Y. (Yuta); Lo, C.M. (Chung Mau); Geller, D.A. (David A.); Han, H.S. (Ho-Seong); Kanazawa, A. (Akishige); Ogura, T. (Toshiro); Kim, K.H. (Ki Hun); Ratti, F. (Francesca); Nitta, H. (Hiroyuki); Takeda, Y. (Yutaka); Berardi, G. (Giammauro); Sugioka, A. (Atsushi); Uesaka, K. (Katsuhiko)
    Simple Summary For 657 cases of segment or less repeat liver resection with results of plasma albumin and bilirubin levels and platelet counts before and 3 months after surgery, the indicators were compared before and after surgery. There were 268 open repeat after open and 224 cases laparoscopic repeat after laparoscopic liver resection. The background factors and liver functional indicators before and after surgery, and the changes were compared between both groups. Plasma levels of albumin (p = 0.006) and total bilirubin (p = 0.01) were decreased, and ALBI score (p = 0.001) indicated worse liver function after surgery. Though laparoscopic group had poorer performance status and liver function, changes of the values and overall survivals were similar between both groups. Plasma levels of albumin and bilirubin and ALBI score could be the liver functional indicators for liver functional deterioration after liver resection. The laparoscopic group with poorer conditions showed a similar deterioration of liver function and overall survival to the open group. Whether albumin and bilirubin levels, platelet counts, ALBI, and ALPlat scores could be useful for the assessment of permanent liver functional deterioration after repeat liver resection was examined, and the deterioration after laparoscopic procedure was evaluated. For 657 patients with liver resection of segment or less in whom results of plasma albumin and bilirubin levels and platelet counts before and 3 months after surgery could be retrieved, liver functional indicators were compared before and after surgery. There were 268 patients who underwent open repeat after previous open liver resection, and 224 patients who underwent laparoscopic repeat after laparoscopic liver resection. The background factors, liver functional indicators before and after surgery and their changes were compared between both groups. Plasma levels of albumin (p = 0.006) and total bilirubin (p = 0.01) were decreased, and ALBI score (p = 0.001) indicated worse liver function after surgery. Laparoscopic group had poorer preoperative performance status and liver function. Changes of liver functional values before and after surgery and overall survivals were similar between laparoscopic and open groups. Plasma levels of albumin and bilirubin and ALBI score could be the indicators for permanent liver functional deterioration after liver resection. Laparoscopic group with poorer conditions showed the similar deterioration of liver function and overall survivals to open group.
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    Identification of PRMT5 as a therapeutic target in cholangiocarcinoma
    (BMJ, 2024) Elurbide, J. (Jasmin); Colyn, L. (Leticia); Latasa, M.U. (María Ujué); Uriarte, I. (Iker); Mariani, S. (Stefano); Lopez-Pascual, A. (Amaya); Valbuena, E. (Emiliana); Castelló-Uribe, B. (Borja); Arnes-Benito, R. (Robert); Adán-Villaescusa, E. (Elena); Martínez-Pérez, L. (L.); Azkargorta, M. (Mikel); Elortza, F. (Felix); Wu, H. (Hanghang); Krawczyk, M. (Marcin); Schneider, K.M. (Kai Markus); Sangro, B. (Bruno); Aldrighetti, L. (Luca); Ratti, F. (Francesca); Casadei-Gardini, A. (Andrea); Marin, J.J.G (Jose J.G.); Amat, I. (Irene); Urman, J.M. (Jesús M.); Arechederra, M. (María); Martinez-Chantar, M.L. (María Luz); Trautwein, C. (Christian); Huch, M. (Meritxell); Cubero, F.J. (Francisco Javier); Berasain, C. (Carmen); Fernández-Barrena, M.G. (Maite G.); Avila, M.A. (Matías Antonio)
    Background: Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. Objective: We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. Design: We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. Results: PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. Conclusion: PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.