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| 1 | Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis显示文摘The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention. | Xuezhen Zeng Jingying Zhou Zhewen Xiong Hanyong Sun Weiqin Yang Myth T.S.Mok Jing Wang Jingqing Li Man Liu Wenshu Tang Yu Feng Hector Kwong-Sang W ang Shun-Wa Tsang King-Lau Chow Philip Chun Yeung John Wong Paul Bo-San Lai Anthony Wing-Hung Chan Ka Fai To Stephen Lam Chan Qiang Xia Jing Xue Xiao Chen Jun Yu Sui Peng Joseph Jao-Yiu Sung Ming Kuang Alfred Sze-Lok Cheng | 2021 | Cellular & Molecular Immunology2021，18，4： | 5 |
| 2 | Clinical significance of hepatic derangement in severe acute respiratory syndrome显示文摘AIM: Elevation of alanine aminotransferase (ALT) level is commonly seen among patients suffering from severe acute respiratory syndrome (SARS). We report the progression and clinical significance of liver derangement in a large cohort of SARS patient.METHODS: Serial assay of serum ALT was followed in patients who fulfilled the WHO criteria of SARS. Those with elevated ALT were compared with those with normal liver functions for clinical outcome. Serology for hepatitis B virus (HBV) infection was checked. Adverse outcomes were defined as oxygen desaturation, need of intensive care unit (ICU) and mechanical ventilation and death.RESULTS: Two hundred and ninety-four patients were included in this study. Seventy (24%) patients had elevated serum ALT on admission and 204 (69%) patients had elevated ALT during the subsequent course of illness. Using peak ALT >5×ULN as a cut-off and after adjusting for potential confounding factors, the odds ratio of peak ALT>5x ULN for oxygen desaturation was 3.24 (95%CI 1.23-8.59, P = 0.018), ICU care was 3.70 (95% CI 1.38-9.89, P = 0.009), mechanical ventilation was 6.64 (95%CI 2.22-19.81, P = 0.001) and death was 7.34(95%CI 2.28-24.89, P = 0.001). Ninety-three percent of the survived patients had ALT levels normalized or were on the improving trend during follow-up. Chronic hepatitis B was not associated with worse clinical outcomes.CONCLUSION: Reactive hepatitis is a common complication of SARS-coronavirus infection. Those patients with severe hepatitis had worse clinical outcome. | Henry Lik-Yuen Chan Ambrose Chi-Pong Kwan Ka-Fai To Sik-To Lai Paul Kay-Sheung Chan Wai-Keung Leung Nelson Lee Alan Wu Joseph Jao-Yiu Sung | 2005 | World Journal of Gastroenterology2005，11，14： | 4 |
| 3 | Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver显示文摘Obesity is a major risk factor for cancers including hepatocellular carcinoma(HCC)that develops from a background of non-alcoholic fatty liver disease(NAFLD).Hypercholesterolemia is a common comorbidity of obesity.Although cholesterol biosynthesis mainly occurs in the liver,its role in HCC development of obese people remains obscure.Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models,we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T(NKT)cell-mediated antitumor immunosurveillance.Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients.Notably,cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development.Moreover,suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin(mTOR)inhibitor vistusertib preceded tumor regression,which was abolished by NKT inactivation but not CD8^(+)T cell depletion.Mechanistically,sterol regulatory element-binding protein 2(SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells,which were supported by findings in people with obesity,NAFLD and NAFLD-HCC.This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment,providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic. | Wenshu Tang Jingying Zhou Weiqin Yang Yu Feng Haoran Wu Myth T.S.Mok Lingyun Zhang Zhixian Liang Xiaoyu Liu Zhewen Xiong Xuezhen Zeng Jing Wang Jiahuan Lu Jingqing Li Hanyong Sun Xiaoyu Tian Philip Chun Yeung Yong Hou Heung Man Lee Candice C.H.Lam Howard H.W.Leung Anthony W.H.Chan Ka Fai To John Wong Paul B.S.Lai Kelvin K.C.Ng Simon K.H.Wong Vincent W.S.Wong Alice P.S.Kong Joseph J.Y.Sung Alfred S.L.Cheng | 2022 | Cellular & Molecular Immunology2022，19，7： | 3 |
| 4 | Viral-Human Chimeric Transcript Predisposes Risk to Liver Cancer Development and Progression显示文摘 | Chi-Chiu Lau Tingting Sun Arthur K.K. Ching Mian He Jing-Woei Li Alissa M. Wong Ngai Na Co Anthony W.H. Chan Pik-Shan Li Raymond W.M. Lung Joanna H.M. Tong Paul B.S. Lai Henry L.Y. Chan Ka-Fai To Ting-Fung Chan Nathalie Wong | 2014 | Cancer Cell2014，，3： | 2 |
| 5 | miR-130b Promotes CD133 + Liver Tumor-Initiating Cell Growth and Self-Renewal via Tumor Protein 53-Induced Nuclear Protein 1显示文摘 | Stephanie Ma Kwan Ho Tang Yuen Piu Chan Terence K. Lee Pak Shing Kwan Antonia Castilho Irene Ng Kwan Man Nathalie Wong Ka-Fai To Bo-Jian Zheng Paul B.S. Lai Chung Mau Lo Kwok Wah Chan Xin-Yuan Guan | 2010 | Cell Stem Cell2010，，： | 2 |
| 6 | Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention显示文摘 | Shepherd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，： | 1 |
| 7 | Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention 显示文摘 | Paul TO Shepherd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，： | 1 |
| 8 | Congential vadolarimal duct obstyuction: natygal history and the timing of optimal intorvention显示文摘 | Paul TO shepyerd R | 1994 | J Pe- diatr Ophthalmol Strabismus1994，31，6： | 1 |
| 9 | Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention显示文摘 | Paul TO Shepherd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，6： | 1 |
| 10 | Congenital duct obstruction: natural history and the timing of optimal intervention显示文摘 | Paul TO Shepherd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，6： | 1 |
| 11 | Congenital nasolacrimal duct obstruction:natural history and the timing of opt- imal intervention显示文摘 | Paul To shepherd R | 1994 | J Pediatric Ophthalmol Stra- bismus1994，31，6： | 1 |
| 12 | Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma显示文摘 | Tian Yuan Wong Vincent W.S. Wong Grace L.H. Yang Weiqin Sun Hanyong Shen Jiayun Tong Joanna H.M. Go Minnie Y.Y. Cheung Yue S. Lai Paul B.S. Zhou Mingyan Xu Gang Huang Tim H.M. Yu Jun To Ka F. Cheng Alfred S.L. Chan Henry L.Y | 2015 | Cancer Research2015，，22： | 1 |
| 13 | Syndesmosis injuries in athletes显示文摘 | Clanton TO Paul P | 2002 | Foot Ankle Clin North Am2002，7，： | 1 |
| 14 | Simultaneous in Vitro Measurement of Patellofemoral Kinematics and Forces显示文摘 | Amy BZ Paul TO Andrew JP | 2004 | Journal of Biomechanical Engineering2004，126，3： | 1 |
| 15 | Congential vadolarimal duct obstyuction:natygal history and the tining of optimal intervention显示文摘 | Paul TO shepyerd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，6： | 1 |
| 16 | Congenital vasolarimal duct obstruction:natual history and the tinting of optimal intervention显示文摘 | paul TO Shepherd R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，： | 1 |
| 17 | MicroRNA-223 Is Commonly Repressed in Hepatocellular Carcinoma and Potentiates Expression of Stathmin1显示文摘 | Queenie W.–L. Wong Raymond W.–M. Lung Priscilla T.–Y. Law Paul B.–S. Lai Kathy Y.–Y. Chan Ka–Fai To Nathalie Wong | 2008 | Gastroenterology2008，，1： | 1 |
| 18 | Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives [Beta]-catenin/T cell factor-dependent hepatocarcinogenesis显示文摘 | Feng Hai Cheng Alfred S L Tsang Daisy P Li May S Go Minnie Y Cheung Yue S Zhao Gui-jun Ng Samuel S Lin Marie C Yu Jun Lai Paul B To Ka F Sung Joseph J Y | 2011 | Journal of Clinical Investigation2011，，8： | 1 |
| 19 | Congential Vadolarimal duct obstyuetion: natygal history and the timingof optimal intorvention 显示文摘 | Paul To shepyed R | 1994 | J Pediatr Ophthalmol Strabismus1994，31，： | 1 |
| 20 | Syndesmosis injuries in athletes显示文摘 | Clanton TO Paul P | 2002 | Foot Ankle Clinics2002，7，3： | 1 |
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