The People's Hospital of Guangxi Zhuang Autonomous Region

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

BACKGROUND: Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis. METHODS: In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9. RESULTS: During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period. CONCLUSIONS: In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).

IMPORTANCE: This study demonstrates that tislelizumab in combination with chemotherapy is associated with improved progression-free survival (PFS) in patients with advanced squamous non-small-cell lung cancer (sq-NSCLC). OBJECTIVE: To assess the efficacy and safety/tolerability of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for patients with advanced sq-NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 3 clinical trial was conducted at 46 sites in China between July 2018 and June 2019 and included patients with treatment-naive, histologically confirmed stage IIIB/IV sq-NSCLC. The data cutoff for these analyses was December 6, 2019; data extraction occurred on January 7, 2020. INTERVENTIONS: Patients were randomized (1:1:1) to receive 1 of the following regimens intravenously on a 21-day cycle: tislelizumab (200 mg, day 1) plus paclitaxel (175 mg/m2, day 1) and carboplatin (area under the concentration of 5, day 1) (arm A); tislelizumab plus nab-paclitaxel (100 mg/m2, days 1, 8, and 15) and carboplatin (arm B); and paclitaxel and carboplatin (arm C). Patients were stratified by disease stage and tumor programmed cell death 1 ligand 1 (PD-L1) expression (<1% vs 1%-49% vs ≥50%). MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary end points included overall survival, investigator-assessed (INV) PFS, IRC-assessed objective response rate (ORR), and IRC-assessed duration of response, as well as the incidence and severity of adverse events (AEs). RESULTS: Overall, 355 patients (median [range] age, 62 [34-74] years; 330 men [91.7%]) with sq-NSCLC received treatment. After a median study follow-up of 8.6 months (95% CI, 8.1-9.0 months), IRC-assessed PFS was significantly improved with tislelizumab plus chemotherapy (arm A, 7.6 months; arm B, 7.6 months) vs chemotherapy alone (arm C, 5.5 months; hazard ratios were 0.524 (95% CI, 0.370-0.742; P < .001 [A vs C]) and 0.478 (95% CI, 0.336-0.679; P < .001 [B vs C]). Higher IRC-assessed ORR and longer IRC-assessed duration of response were observed in arms A (72.5%; 8.2 months) and B (74.8%; 8.6 months) vs C (49.6%; 4.2 months). No association was observed between PD-L1 expression and IRC-assessed PFS or ORR. Discontinuation of any treatment because of AEs was reported in 15 (12.5%; arm A), 35 (29.7%; arm B), and 18 (15.4%; arm C) patients. In each arm, the most common grade of 3 or greater AE was decreased neutrophil levels, which aligned with known chemotherapy toxic effects. Six treatment-related AEs leading to death occurred; however, no deaths were solely attributed to tislelizumab. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, adding tislelizumab to chemotherapy was associated with significantly prolonged IRC-assessed PFS, higher IRC-assessed ORRs, and a manageable safety/tolerability profile in patients with advanced sq-NSCLC, regardless of PD-L1 expression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03594747.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Checkpoint inhibitors are effective in recurrent/metastatic nasopharyngeal cancer (R/M NPC). RATIONALE-309 (NCT03924986) randomized 263 treatment-naive R/M NPC patients to tislelizumab or placebo every 3 weeks (Q3W), plus chemotherapy (Q3W for 4–6 cycles). At interim analysis, progression-free survival (PFS) was significantly longer with tislelizumab-chemotherapy versus placebo-chemotherapy (hazard ratio: 0.52; 95% confidence interval: 0.38, 0.73; p < 0.0001). PFS benefit for tislelizumab-chemotherapy versus placebo-chemotherapy was observed regardless of programmed death-ligand 1 expression. PFS after next line of treatment and overall survival showed favorable trends for tislelizumab-chemotherapy versus placebo-chemotherapy. The safety profile was similar between arms. Gene expression profiling (GEP) identified immunologically “hot” tumors, and showed an activated dendritic cell (DC) signature was associated with tislelizumab-chemotherapy PFS benefit. Our results support that tislelizumab-chemotherapy should be considered as first-line treatment for R/M NPC, and GEP and activated DC signature results may help identify patients who might benefit most from immunochemotherapy treatment.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI3NGEwOGMxYzJkMDU0Y2NkNTkyM2E0Y2ZlODJjMTZiMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjg3NTI4NzE1fQ.JYBUikARIghjsloAprCtibsNgBaFKynYiv7xF44UnarQBvkRp8F_LrATRQs-M79ABt8dcRz98RJJHXeAYZp2Ci2a1b-PM2l-W4B8vQIBCFUcX7ndwxGU28aNqowl-a8PLMUS58iAGwDidhzuOggXajX9cwc8Gjcz-b0WIlVFuhZ53fmkpqDUrDKw7NTJz2kXWrMSoeQzHy3b0C7wZUdXDZv_GInNVIPem_EEZVPmzuLl2wgouRHkmftSZt0LFvTpeNcRmCg0XvYR3GceXvbK2rmb_Lb-tl4mirHuuk6V-r-KLjBorpz4ZGr4xo1im9tnwXJuXSULDzETkEhu8GPevQ(mp4, (256.46 MB) Download video

// Ningning Liu 1,2,* , Xiaofen Li 1,* , Hongbiao Huang 1,* , Chong Zhao 1,* , Siyan Liao 1,* , Changshan Yang 1,* , Shouting Liu 1,* , Wenbin Song 1 , Xiaoyu Lu 1 , Xiaoying Lan 1 , Xin Chen 1 , Songgang Yi 1 , Li Xu 1,3 , Lili Jiang 1 , Canguo Zhao 1 , Xiaoxian Dong 1 , Ping Zhou 1 , Shujue Li 1,4 , Shunqing Wang 1 , Xianping Shi 1 , Ping Q. Dou 1,5 , Xuejun Wang 1,6 , and Jinbao Liu 1 1 State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong, China 2 Guangzhou Research Institute of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People&rsquo;s Republic of China 3 Department of Hematology, The People&rsquo;s Hospital of Guangxi Autonomous Region, Nanning, Guangxi, People&rsquo;s Republic of China 4 Guangzhou Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People&rsquo;s Republic of China 5 The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA 6 Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota, USA * These Authors contributed equally to this work Correspondence: Jinbao Liu, email: // Keywords : cancer, deubiquitinase, proteasome, auranofin Received : April 7, 2014 Accepted : June 17, 2014 Published : June 18, 2014 Abstract Proteasomes are attractive emerging targets for anti-cancer therapies. Auranofin (Aur), a gold-containing compound clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer but its anti-cancer mechanism is poorly understood. Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome-associated DUBs is required for Aur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients. This study provides important novel insight into understanding the proteasome-inhibiting property of metal-containing compounds. Although several DUB inhibitors were reported, this study uncovers the first drug already used in clinic that can inhibit proteasome-associated DUBs with promising anti-tumor effects.

OBJECTIVE: To evaluate the clinical treatment effects of orthokeratology to slow the progression of myopia. METHODS: Several well-designed controlled studies have investigated the effects of orthokeratology in school-aged children. We conducted this meta-analysis to better evaluate the existing evidence. Relevant studies were identified in the Medline and Embase database without language limitations. The main outcomes included axial length and vitreous chamber depth reported as the mean ± standard deviation. The results were pooled and assessed with a fixed-effects model analysis. Subgroup analyses were performed according to geographical location and study design. RESULTS: Of the seven eligible studies, all reported axial length changes after 2 years, while two studies reported vitreous chamber depth changes. The pooled estimates indicated that change in axial length in the ortho-k group was 0.27 mm (95% confidence interval [CI]: 0.22, 0.32) less than the control group. Myopic progression was reduced by approximately 45%. The combined results revealed that the difference in vitreous chamber depth between the two groups was 0.22 mm (95% confidence interval [CI]: 0.14, 0.31). None of the studies reported severe adverse events. CONCLUSION: The overall findings suggest that ortho-k can slow myopia progression in school-aged children.

Photoluminescent carbon dots derived from sugarcane molasses were investigated<italic>via</italic>cellular imaging and sensing for Fe³⁺or sunset yellow. The underlying mechanism of fluorescence quenching in the C-dots/sunset yellow system was also studied.

The activation of both the SA and JA/ETsignalling pathways may lead to more efficient general and broad resistance to Pst DC3000 by non-pathogenic rhizobacteria. However, the mechanisms that govern this simultaneous activation are unclear. Using Arabidopsis as a model system, two transcription factors, WRKY11 and WRKY70, were identified as important regulators involved in Induced Systemic Resistance (ISR) triggered by Bacillus cereus AR156. The results revealed that AR156 treatment significantly stimulated the transcription of WRKY70, but suppressed that of WRKY11 in Arabidopsis leaves. Furthermore, they were shown to be required for AR156 enhancing the activation of cellular defence responses and the transcription level of the plant defence response gene. Overexpression of the two transcription factors in Arabidopsis also showed that they were essential for AR156 to elicit ISR. AR156-triggered ISR was completely abolished in the double mutant of the two transcription factors, but still partially retained in the single mutants, indicating that the regulation of the two transcription factors depend on two different pathways. The target genes of the two transcription factors and epistasis analysis suggested that WRKY11 regulated AR156-triggered ISR through activating the JA signalling pathway, and WRKY70 regulated the ISR through activating the SA signalling pathway. In addition, both WRKY11 and WRKY70 modulated AR156-triggered ISR in a NPR1-dependent manner. In conclusion, WRKY11 and WRKY70 played an important role in regulating the signalling transduction pathways involved in AR156-triggered ISR. This study is the first to illustrate the mechanism by which a single rhizobacterium elicits ISR by simultaneously activating both the SA and JA/ET signalling pathways.

Zebra Chip (ZC) is an emerging plant disease that causes aboveground decline of potato shoots and generally results in unusable tubers. This disease has led to multi-million dollar losses for growers in the central and western United States over the past decade and impacts the livelihood of potato farmers in Mexico and New Zealand. ZC is associated with 'Candidatus Liberibacter solanacearum', a fastidious alpha-proteobacterium that is transmitted by a phloem-feeding psyllid vector, Bactericera cockerelli Sulc. Research on this disease has been hampered by a lack of robust culture methods and paucity of genome sequence information for 'Ca. L. solanacearum'. Here we present the sequence of the 1.26 Mbp metagenome of 'Ca. L. solanacearum', based on DNA isolated from potato psyllids. The coding inventory of the 'Ca. L. solanacearum' genome was analyzed and compared to related Rhizobiaceae to better understand 'Ca. L. solanacearum' physiology and identify potential targets to develop improved treatment strategies. This analysis revealed a number of unique transporters and pathways, all potentially contributing to ZC pathogenesis. Some of these factors may have been acquired through horizontal gene transfer. Taxonomically, 'Ca. L. solanacearum' is related to 'Ca. L. asiaticus', a suspected causative agent of citrus huanglongbing, yet many genome rearrangements and several gene gains/losses are evident when comparing these two Liberibacter. species. Relative to 'Ca. L. asiaticus', 'Ca. L. solanacearum' probably has reduced capacity for nucleic acid modification, increased amino acid and vitamin biosynthesis functionalities, and gained a high-affinity iron transport system characteristic of several pathogenic microbes.

BACKGROUND: Medical artificial intelligence (AI) has entered the clinical implementation phase, although real-world performance of deep-learning systems (DLSs) for screening fundus disease remains unsatisfactory. Our study aimed to train a clinically applicable DLS for fundus diseases using data derived from the real world, and externally test the model using fundus photographs collected prospectively from the settings in which the model would most likely be adopted. METHODS: In this national real-world evidence study, we trained a DLS, the Comprehensive AI Retinal Expert (CARE) system, to identify the 14 most common retinal abnormalities using 207 228 colour fundus photographs derived from 16 clinical settings with different disease distributions. CARE was internally validated using 21 867 photographs and externally tested using 18 136 photographs prospectively collected from 35 real-world settings across China where CARE might be adopted, including eight tertiary hospitals, six community hospitals, and 21 physical examination centres. The performance of CARE was further compared with that of 16 ophthalmologists and tested using datasets with non-Chinese ethnicities and previously unused camera types. This study was registered with ClinicalTrials.gov, NCT04213430, and is currently closed. FINDINGS: The area under the receiver operating characteristic curve (AUC) in the internal validation set was 0·955 (SD 0·046). AUC values in the external test set were 0·965 (0·035) in tertiary hospitals, 0·983 (0·031) in community hospitals, and 0·953 (0·042) in physical examination centres. The performance of CARE was similar to that of ophthalmologists. Large variations in sensitivity were observed among the ophthalmologists in different regions and with varying experience. The system retained strong identification performance when tested using the non-Chinese dataset (AUC 0·960, 95% CI 0·957-0·964 in referable diabetic retinopathy). INTERPRETATION: Our DLS (CARE) showed satisfactory performance for screening multiple retinal abnormalities in real-world settings using prospectively collected fundus photographs, and so could allow the system to be implemented and adopted for clinical care. FUNDING: This study was funded by the National Key R&D Programme of China, the Science and Technology Planning Projects of Guangdong Province, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Fundamental Research Funds for the Central Universities. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Recent studies suggest that cuproptosis, a novel mode of cell death, may be associated with the development of cancer. However, no studies are showing its role in tumorigenesis, progression, and prognosis. In the present study, we comprehensively analyzed the expression difference, gene variation and methylation modification of cuproptosis-related genes (CRGs) in pan-cancer. Then, Single sample gene set enrichment analysis (ssGSEA) was used to calculate individual cuproptosis scores (CS). The association of CS with copy number variation, clinical features, immune-related genes, TMB, MSI, and tumor immune dysfunction and exclusion (TIDE) was comprehensively assessed. Single-cell transcriptome sequencing (scRNA-seq) to analyze the activation of cuproptosis in the tumor microenvironment. Immunohistochemistry (IHC) were used to validate the expression of cuproptosis hub-gene. Our study shows that CRGs were significantly expressed in a variety of tumors, and CDKN2A had the highest mutation frequency (49%) in all tumors. A significant increase in the CS was observed in most cancers and were associated with poor prognosis in the majority of tumors. CS was significantly negatively correlated with tumor microenvironment scores in more than 10 tumors and positively correlated with PD-L1 in 11 tumors, suggesting involvement in tumor immune escape. scRNA-seq suggests that CRG scores significantly increased in the cancer cells. This study opens avenues for further research on the role of cuproptosis in the occurrence and development of cancer and the development of targeted therapies based on cuproptosis.

Background/objectives The assessment of nutritional status and the quality of life in patients with gastric cancer has become one of the important goals of current clinical treatment. The purpose of this study was to assess the nutritional status in hospitalized gastric cancer patients by using patient-generated subjective global assessment (PG-SGA) and to analyze the influence of nutritional status on the patients' quality of life (QOL). Methods We reviewed the pathological diagnosis of gastric cancer for 2322 hospitalized patients using PG-SGA to assess their nutritional status and collected data on clinical symptoms, the anthropometric parameters (height, weight, body mass index (BMI), mid-arm circumference (MAC), triceps skin-fold thickness (TSF), and hand-grip strength (HGS). We also collected laboratory data (prealbumin, albumin, hemoglobin) within 48 h after the patient was admitted to the hospital. The 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) was used for QOL assessment in all patients.

STUDY QUESTION: Can a reconstructed ovary using decellularized human ovarian tissue (DCT) support survival of pre-antral stage follicles? SUMMARY ANSWER: We have demonstrated an effective protocol for decellularization of human ovarian tissues and successful recellularization with isolated human ovarian cells and pre-antral follicles. WHAT IS KNOWN ALREADY: Survivors of leukemia or ovarian cancer run a risk of reintroducing malignancy when cryopreserved ovarian tissue is transplanted to restore fertility. A reconstructed ovary free of malignant cells could provide a safe alternative. Decellularization of ovarian tissue removes all cells from the extracellular matrix (ECM) including possible malignancies and leaves behind a physiological scaffold. The ECM offers the complex milieu that facilitates the necessary interaction between ovarian follicles and their surroundings to ensure their growth and development. Previous studies have shown that decellularized bovine ovarian scaffolds supported murine follicle growth and restoration of ovarian function in ovariectomized mice. STUDY DESIGN, SIZE, DURATION: Optimizing a decellularization protocol for human ovarian tissues and testing biofunctionality of the decellularized scaffolds in vitro and in vivo by reseeding with both murine and human pre-antral follicles and ovarian cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Donated human ovarian tissue and isolated pre-antral follicles were obtained from women undergoing ovarian tissue cryopreservation for fertility preservation. Ovarian cortical and medullary tissues were decellularized using 0.1% sodium dodecyl sulfate (SDS) for 3, 6, 18 and 24 hours followed by 24 hours of 1 mg/mL DNase treatment and washing. Decellularization of ovarian tissues and preservation of ECM were characterized by morphological evaluation using Periodic Acid-Schiff (PAS) staining, DNA quantification, histochemical quantification of collagen content and immunofluorescence analysis for collagen IA, laminin, fibronectin and DNA. Human ovarian stromal cells and isolated human pre-antral follicles were reseeded on the DCT and cultured in vitro. Isolated murine (N = 241) and human (N = 20) pre-antral follicles were reseeded on decellularized scaffolds and grafted subcutaneously to immunodeficient mice for 3 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: Incubation in 0.1% SDS for 18-24 hours adequately decellularized both human ovarian medullary and cortical tissue by eliminating all cells and leaving the ECM intact. DNA content in DCT was decreased by >90% compared to native tissue samples. Histological examination using PAS staining confirmed that the cortical and medullary tissues were completely decellularized, and no visible nuclear material was found within the decellularized sections. DCT also stained positive for collagen I and collagen quantities in DCT constituted 88-98% of the individual baselines for native samples. Human ovarian stroma cells were able to recellularize the DCT and isolated human pre-antral follicles remained viable in co-culture. Xenotransplantation of DCT reseeded with human or murine pre-antral follicles showed, that the DCT was able to support survival of human follicles and growth of murine follicles, of which 39% grew to antral stages. The follicular recovery rates after three weeks grafting were low but similar for both human (25%) and murine follicles (21%). LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Further studies are needed to increase recovery and survival of the reseeded follicles. Longer grafting periods should be evaluated to determine the developmental potential of human follicles. Survival of the follicles might be impaired by the lack of stroma cells. WIDER IMPLICATIONS OF THE FINDINGS: This is the first time that isolated human follicles have survived in a decellularized human scaffold. Therefore, this proof-of-concept could be a potential new strategy to eliminate the risk of malignant cell re-occurrence in former cancer patients having cryopreserved ovarian tissue transplanted for fertility restoration. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. Furthermore, Project ITN REP-BIOTECH 675526 funded by the European Union, European Joint Doctorate in Biology and Technology of the Reproductive Health, the Research Pools of Rigshospitalet, the Danish Cancer Foundation and Dagmar Marshalls Foundation are thanked for having funded this study. The funders had no role in the study design, data collection and interpretation, or in the decision to submit the work for publication.

(-)-Epigallocatechin-3-O-gallate(EGCG), the highest catechins from green tea, has promisingly been found to sensitize the efficacy of several chemotherapy agents like doxorubicin (DOX) in hepatocellular carcinoma (HCC) treatment. However, the detailed mechanisms by which EGCG augments the chemotherapeutic efficacy remain unclear. Herein, this study was designed to determine the synergistic impacts of EGCG and DOX on hepatoma cells and particularly to reveal whether the autophagic flux is involved in this combination strategy for the HCC. Electron microscopy and fluorescent microscopy confirmed that DOX significantly increased autophagic vesicles in hepatoma Hep3B cells. Western blot and trypan blue assay showed that the increasing autophagy flux by DOX impaired about 45% of DOX-induced cell death in these cells. Conversely, both qRT-PCR and western blotting showed that EGCG played dose-dependently inhibitory role in autophagy signaling, and that markedly promoted cellular growth inhibition. Amazingly, the combined treatment caused a synergistic effect with 40 to 60% increment on cell death and about 45% augmentation on apoptosis versus monotherapy pattern. The DOX-induced autophagy was abolished by this combination therapy. Rapamycin, an autophagic agonist, substantially impaired the anticancer effect of either DOX or combination with EGCG treatment. On the other hand, using small interference RNA targeting chloroquine autophagy-related gene Atg5 and beclin1 to inhibit autophagy signal, hepatoma cell death was dramatically enhanced. Furthermore, in the established subcutaneous Hep3B cells xenograft tumor model, about 25% reduction in tumor growth as well as 50% increment of apoptotic cells were found in combination therapy compared with DOX alone. In addition, immunohistochemistry analysis indicated that the suppressed tendency of autophagic hallmark microtubule-associated protein light chain 3 (LC3) expressions was consistent with thus combined usage in vitro. Taken together, the current study suggested that EGCG emerges as a chemotherapeutic augmenter and synergistically enhances DOX anticancer effects involving autophagy inhibition in HCC.

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.

BACKGROUND: As effective medication to treat COVID-19 is currently unavailable, preventive remedies may be particularly important. OBJECTIVE: To examine the relationship between serum 25-hydroxy vitamin D (25(OH)D) level and COVID-19 infection, its severity, and its clinical case characteristics. METHODS: This case-control study compared serum 25(OH)D levels and rates of vitamin D deficiency (VDD) between 80 healthy controls and 62 patients diagnosed with COVID-19 and admitted to Guangxi People's Hospital, China, 2/16/2020-3/16/2020. Cases were categorized into asymptomatic, mild/moderate, and severe/critical disease. Logistic regression analysis was conducted to examine the associations between 25(OH)D level, or VDD, and case status/severity of COVID-19 while controlling for demographics and comorbidities. A threshold level of vitamin D for conveying COVID-19 risk was estimated. RESULTS: Severe/critical COVID-19 cases were significantly older and had higher percentages of comorbidity (renal failure) compared to mild cases. The serum 25(OH)D concentration in COVID-19 patient was much lower than that in healthy control. And 25(OH)D level was the lowest in severe/critical cases, compared with mild cases. In further, significantly higher rates of VDD were found in COVID-19 cases (41.9%) compared to healthy controls (11.1%). And VDD was the greatest in severe/critical cases (80%), compared with mild cases (36%). These statistically significant associations remained even after controlling for demographics and comorbidities. A potential threshold of 25(OH)D (41.19 nmol/L) to protect against COVID-19 was identified. CONCLUSION: Elderly and people with comorbidities were susceptible to severe COVID-19 infection. VDD was a risk factor for COVID-19, especially for severe/critical cases. While further confirmation is needed, vitamin D supplementation may have prevention or treatment potential for COVID-19 disease.

PURPOSE: Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. EXPERIMENTAL DESIGN: CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of gambogic acid and its combination with imatinib was also assessed with nude xenografts. RESULTS: Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for gambogic acid-induced Bcr-Abl downregulation and apoptotic cell death. CONCLUSIONS: These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy.

Abstract Ovarian cancer have a poor overall survival rate in patients, and late disease presentation and chemoresistance are the main factors that lead to the mortality of ovarian cancer. Cancer stem cells (CSCs), a small subpopulation of cancer cells, have been associated with resistance to chemo- and radio-therapy in cancer treatment. Hypoxia is a common characteristic of many malignant tumors, and increased HIF-1α expression predicts the poor prognosis of ovarian cancer. In this study, we reported the relationship between hypoxia and cancer stem cells-like properties in human ovarian cancer cell lines SKOV3 and HO8910, we found that hypoxia induced cancer stem cells-like properties in ovarian cancer cells. Moreover, SIRT1 was found to be the downstream target gene of HIF-1α, which was involved in the promotion of cancer stem cells-like features in ovarian cancer cells by hypoxia, and NF-κB signaling pathway was involved in hypoxia-induced SIRT1 up-regulation. Our results hinted that HIF1α and SIRT1 might serve as potential therapeutic targets for ovarian cancer.

In this study we provide the first report of the characteristics, comorbidities,<br/>laboratory and x-ray findings, and clinical outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with pre-existing liver cirrhosis. The cause of death in most patients was respiratory failure rather than progression of liver disease. Lower numbers of blood lymphocytes and platelets, and higher bilirubin levels might represent indicators of poor outcome in this patient population.<br/><br/><br/><br/><br/><br/>