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Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study

LANCET ONCOLOGY 2012年第8期13卷 817-826页

作者： Shen, Qiujin Fan, Jia Yang, Xin-Rong Tan, Yexiong Zhao, Weifeng Xu, Yang Wang, Ning Niu, Yongdong Wu, Zheng Zhou, Jian Qiu, Shuang-Jian Shi, Ying-Hong Yu, Bin Tang, Ning Chu, Wei Wang, Min Wu, Jinhua Zhang, Zhigang Yang, Shengli Gu, Jianren Wang, Hongyang Qin, Wenxin Shanghai Jiao Tong Univ State Key Lab Oncogenes & Related Genes Shanghai Canc Inst Renji HospSch Med Shanghai 200032 Peoples R China Fudan Univ Inst Biomed Sci Shanghai 200433 Peoples R China Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Shanghai Peoples R China Soochow Univ Affiliated Hosp 1 Dept Infect Dis Suzhou Peoples R China

Background Hepatocellular carcinoma (HCC) is prevalent worldwide and improvements in timely and effective diagnosis are needed. We assessed whether measurement of Dickkopf-1 (DKK1) in serum could improve diagnostic accuracy for HCC. Methods We analysed data for patients with HCC, chronic hepatitis B virus (HBV) infection, liver cirrhosis, and healthy controls, recruited from two Chinese centres between December, 2008, and July, 2009. A validation cohort matched for age and sex was recruited from another centre in China between July, 2010, and June, 2011. DKK1 was measured in serum by ELISA by independent researchers who had no access to patients' clinical information. We used receiver operating characteristics (ROC) to calculate diagnostic accuracy. Findings We assessed serum DKK1 in 831 participants: 424 with HCC, 98 with chronic HBV infection, 96 with cirrhosis, and 213 healthy controls. The validation cohort comprised 453 participants: 209 with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy controls. Levels of DKK1 in serum were significantly higher in patients with HCC than in all controls. ROC curves showed the optimum diagnostic cutoff was 2.153 ng/mL (area under curve [AUC] 0.848 [95% CI 0.820-0.875], sensitivity 69.1%, and specificity 90.6% in the test cohort;0.862 [0.825-0.899], 71.3%, and 87.2% in the validation cohort). Similar results were noted for early-stage HCC (0.865 [0.835-0.895], 70.9%, and 90.5% in the test cohort;0.896 [0.846-0.947], 73.8%, and 87.2% in the validation cohort). Furthermore, DKK1 maintained diagnostic accuracy for patients with HCC who were a-fetoprotein (AFP) negative (0.841 [0.801-0.882], 70.4%, and 90.0% in the test cohort;0.869 [0.815-0.923], 66.7%, and 87.2% in the validation cohort), including for patients with early-stage HCC (0.870 [0.829-0.911], 73.1%, and 90.0% in the test cohort;0.893 [0.804-0.983], 72.2%, and 87.2% in the validation cohort), compared with all controls. Raised concentrations of DK

关键词： diagnosis quality/standard cohort DKK1 gene Serum human-centered computing

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Optimal Measurement Modality and Method for Evaluation of Responses to Transarterial Chemoembolization of Hepatocellular Carcinoma Based on Enhancement Criteria

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2013年第3期24卷 316-325页

作者： Shim, Ju Hyun Han, Seungbong Shin, Yong Moon Yu, Eunsil Park, Wonhyeong Kim, Kang Mo Lim, Young-Suk Lee, Han Chu Univ Ulsan Coll Med Asan Med Ctr Dept GastroenterolAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept RadiolAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept PatholAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept Biostat Seoul 138736 South Korea

Purpose: To determine the usefulness of enhancement by iodized oil deposits on computed tomography (CT) following transarterial chemoembolization for hepatocellular carcinoma (HCC), and to compare the reliability of such CT imaging with that of magnetic, resonance (MR) imaging. Materials and Methods: Fifty-one patients for whom resected or explanted livers containing chemoembolized HCC lesions of at least 1 cm were available. Imaging responses were determined based on modified Response Evaluation Criteria In Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) criteria for 59 target tumors on CT and MR scans before surgery. CT-based evaluation was performed per mRECIST and EASL criteria, considering iodized oil retention as indicating necrosis and, alternatively, as enhancing viable tissue ("mRECIST-Lipiodol" and "EASL-Lipiodol"). Pathologic necrosis was graded as 100%, 50%-99%, or less than 50%. Results: Goodman-Kruskal gamma-values for radiologic-pathologic correlation were greater than 0.95 for mRECIST and EASL criteria on CT or MR imaging. However, mRECIST Lipiodol and EASL Lipiodol measurements showed weaker correlation with pathologic findings, with gamma-values of 0.797 and 0.846, respectively. With respect to intermethod agreement, weighted gamma-values for mRECIST by CT and MR, and for EASL criteria by CT and MR, both exceeded 0.80, whereas mRECIST Lipiodol and EASL Lipiodol showed only moderate levels of agreement with mRECIST/EASL criteria by CT or MR imaging, with gamma-values of 0.522-0.631. Conclusions: Response estimation based on measurement of iodized oil deposits as necrosis on CT when applying enhancement criteria after chemoembolization for HCC correlated well with actual pathologic class, and agreed with MR-based evaluation.

关键词： complete response CR EASL European Association for the Study of the Liver HBV HCC hepatitis B virus hepatocellular carcinoma modified Response Evaluation Criteria In Solid Tumors mRECIST RECIST Response Evaluation Criteria In Solid Tumors WHO World Health Organization Hepatocellular Cancer chemoembolization Complete Remission X-Ray Computed Tomography Iodized Oil Hepatitis B virus Response Evaluation Criteria in Solid Tumors Necrosis World Health Organisation human-centered computing

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Contrast-enhanced ultrasound for characterisation of hepatic lesions appearing non-hypervascular on CT in chronic liver diseases

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BRITISH JOURNAL OF RADIOLOGY 2012年第1012期85卷 351-357页

作者： Maruyama, H. Takahashi, M. Ishibashi, H. Yoshikawa, M. Yokosuka, O. Chiba Univ Grad Sch Med Dept Med & Clin Oncol Chuou ku Chiba 2608670 Japan

Objectives: The purpose of this prospective study was to elucidate the efficacy of using contrast-enhanced ultrasound to characterise focal hepatic lesions appearing non-hypervascular on contrast-enhanced CT in chronic liver diseases. Methods: The study population included 22 patients with cirrhosis or chronic hepatitis, who between them had 27 focal hepatic lesions smaller than 20 mm (mean 13.9 +/- 3.4) that appeared non-hypervascular on contrast-enhanced CT. Contrast-enhanced ultrasound with perflubutane microbubble agent (Sonazoid, 0.0075 ml kg(-1)) was performed prior to ultrasound-guided needle biopsy, and intensity analysis was done for hepatic lesions in the early phase (-60 s) and late phase (600 s post injection). Results: All seven early-phase hyperenhanced lesions were hepatocellular carcinoma (HCC). 20 lesions iso- or hypoenhanced during the early phase consisted of 11 regenerative nodules (RNs) and 9 HCCs. HCC was more frequent in early-phase hyperenhanced lesions than in iso- or hypoenhanced lesions (p=0.0108). Both late-phase hypoenhanced lesions were HCCs, whereas 25 late-phase isoenhanced lesions consisted of 11 RNs and 14 HCCs. The enhancement patterns of the 11 RNs included isoenhanced appearance in both the early and late phases in 8 lesions, and early-phase hypoenhancement combined with late-phase isoenhancement in the remaining 3. Both of these enhancement patterns (i.e. either iso-iso or hypo-iso) were found in 9 malignant lesions, 9 (75%) of the 12 well-differentiated HCCs. Conclusion: Hypervascularity on contrast-enhanced ultrasound with Sonazoid strongly suggested HCC regardless of non-hypervascularity on CT, and late-phase hypoenhancement was another possible finding of HCC. However, characterisation of hepatic lesions with other enhancement patterns was difficult using our technique.

关键词： Hepatic Organ System X-Ray Computed Tomography chronic liver disease Lesions intensity analysis Liver Diseases perfluorobutane human-centered computing Puncture Biopsy contrast-enhanced ultrasound

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Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro

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JOURNAL OF CELLULAR PHYSIOLOGY 2013年第6期228卷 1344-1350页

作者： Carr, Brian I. D'Alessandro, Rosalba Refolo, Maria G. Iacovazzi, Palma A. Lippolis, Catia Messa, Caterina Cavallini, Aldo Correale, Mario Di Carlo, Antonio IRCCS S de Bellis Natl Inst Digest Dis Biochem Lab I-70013 Castellana Grotte BA Italy IRCCS S de Bellis Natl Inst Digest Dis Clin Pathol Lab I-70013 Castellana Grotte BA Italy

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.11 mu M drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multikinase inhibitor concentrations thus modulate several aspects of HCC cell biology. J. Cell. Physiol. 228: 13441350, 2013. (c) 2012 Wiley Periodicals, Inc.

关键词： Cell Growth Drug Exposure Invasions sorafenib blood drug concentration low concentrations human-centered computing regorafenib cell invasion

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EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma

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EUROPEAN JOURNAL OF CANCER 2012年第5期48卷 599-641页

作者： European Assoc Study Liver EASL Off CH-1205 Geneva Switzerland

EASL-EORTC Clinical Practice Guidelines (CPG) on the management of hepatocellular carcinoma (HCC) define the use of surveillance, diagnosis and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001. Several clinical and scientific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed.

关键词： Hepatocellular Cancer Patient type European organisation Cancer human-centered computing European association

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Comparative Analysis of the Safety and Efficacy of Transcatheter Arterial Chemoembolization and Yttrium-90 Radioembolization in Patients with Unresectable Hepatocellular Carcinoma

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2011年第12期22卷 1697-1705页

作者： Lance, Craig McLennan, Gordon Obuchowski, Nancy Cheah, Grace Levitin, Abraham Sands, Mark Spain, James Srinivas, Shyam Shrikanthan, Sankaran Aucejo, Federico N. Kim, Richard Menon, K. V. Narayanan Cleveland Clin Fdn Inst Digest Dis Imaging Inst Cleveland OH 44195 USA Cleveland Clin Fdn Inst Digest Dis Dept Transplant Surg Cleveland OH 44195 USA Case Western Reserve Univ Sch Med Cleveland OH USA Cleveland Clin Fdn Inst Digest Dis Div Vasc & Intervent Radiol Cleveland OH 44195 USA Cleveland Clin Fdn Inst Digest Dis Dept Quantitat Hlth Sci Cleveland OH 44195 USA

Purpose: To compare retrospectively the safety and efficacy of yttrium-90 ((90)Y) radioembolization with the safety and efficacy of chemoembolization in patients with unresectable hepatocellular carcinoma (HCC). Materials and Methods: Survival and complication rates were evaluated for patients with HCC who underwent chemoembolization or radioembolization at a single institution between August 2007 and April 2010. Complications were graded according to a standardized grading system for embolization procedures. Survival was determined via the Kaplan-Meier method, and multivariable analysis for factors affecting survival was performed. Results: This study included 73 patients with HCC who underwent index embolization with radioembolization (n = 38;52.1%) or chemoembolization (n = 35;47.9%). The two patient populations were similar in terms of demographics, etiology of cirrhosis, functional status, tumor characteristics, Child-Pugh class, previous liver-directed therapy, and number of patients with bilirubin > 2.0 mg/dL. There was no significant difference in survival between the radioembolization (median 8.0 months) and chemoembolization (median 10.3 months) cohorts (P = .33). Postembolization syndrome was significantly more severe in patients who underwent chemoembolization, which led to increased total hospitalization rates in these patients. The rates of other complications and rehospitalization were similar between groups. Increased age, Child-Pugh class B, hepatitis seropositivity, bilobar tumor distribution, tumor vascular invasion, and presence of extrahepatic metastases were associated with reduced patient survival. Conclusions: Patients treated with radioembolization did not show a survival advantage over patients treated with chemoembolization. However, patients who underwent chemoembolization had significantly higher rates of hospitalization as a result of postembolization syndrome.

关键词： 90Y AFP alpha-fetoprotein CI confidence interval Eastern Cooperative Oncology Group ECOG HCC hepatocellular carcinoma yttrium-90 chemoembolization Hepatocellular Cancer Yttrium 90 human-centered computing Electrocorticography Patients

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Predictors for Microinvasion of Small Hepatocellular Carcinoma ≤2 cm

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ANNALS OF SURGICAL ONCOLOGY 2012年第6期19卷 2027-2034页

作者： Yamashita, Yo-ichi Tsuijita, Eiji Takeishi, Kazuki Fujiwara, Megumu Kira, Shinsuke Mori, Masaki Aishima, Shinichi Taketomi, Akinobu Shirabe, Ken Ishida, Terutoshi Maehara, Yoshihiko Hiroshima Red Cross Hosp Dept Surg Hiroshima Japan Atom Bomb Survivors Hosp Hiroshima Japan Kyushu Univ Grad Sch Med Sci Dept Surg & Sci Fukuoka 812 Japan Hiroshima Red Cross Hosp Dept Pathol Hiroshima Japan Hiroshima Red Cross Hosp Dept Internal Med Liver Hiroshima Japan Hiroshima Red Cross Hosp Dept Radiol Hiroshima Japan Kyushu Univ Grad Sch Med Sci Dept Anat Pathol Fukuoka 812 Japan

Hepatocellular carcinoma (HCC) a parts per thousand currency sign2 cm in diameter is considered to have a low potential for malignancy. A retrospective review was undertaken of 149 patients with primary solitary HCC a parts per thousand currency sign2 cm who underwent initial hepatic resection between 1994 and 2010. The independent predictors of the microinvasion (MI) such as portal venous, hepatic vein, or bile duct infiltration and/or intrahepatic metastasis were identified by multivariate analysis. Prognosis of patients with HCC a parts per thousand currency sign2 cm accompanied by MI was compared to that of patients with HCC a parts per thousand currency sign2 cm without MI. Forty-three patients with HCC a parts per thousand currency sign2 cm had MI in patients (28.9%). Three independent predictors of the MI were revealed: invasive gross type (simple nodular type with extranodular growth or confluent multinodular type), des-gamma-carboxy prothrombin (DCP) > 100 mAU/ml, and poorly differentiated. Disease-free survival rates of patients with HCC a parts per thousand currency sign2 cm with MI (3 year 44%) were significantly worse than those for HCC a parts per thousand currency sign2 cm without MI (3 year 72%). This disadvantage of disease-free survival rate of patients with HCC a parts per thousand currency sign2 cm with MI could be dissolved by hepatic resection with a wide tumor margin of a parts per thousand yen5 mm ( = 0.04). Even in cases of HCC a parts per thousand currency sign2 cm, patients who are suspected of having invasive gross type tumors in preoperative imaging diagnosis or who have a high DCP level (> 100 mAU/ml) are at risk for MI. Therefore, in such patients, hepatic resection with a wide tumor margin should be recommended.

关键词： image diagnosis Hepatic Organ System At-risk ectomy Tumor margin status Data collection platform Tumours Even number human-centered computing

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Enhanced Detection of Early Hepatocellular Carcinoma by Serum SELDI-TOF Proteomic Signature Combined with Alpha-Fetoprotein Marker

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ANNALS OF SURGICAL ONCOLOGY 2010年第9期17卷 2518-2525页

作者： Chen, Lei Ho, David W. Y. Lee, Nikki P. Y. Sun, Stella Lam, Brian Wong, Kwong-Fai Yi, Xin Lau, George K. Ng, Eddy W. Y. Poon, Terence C. W. Lai, Paul B. S. Cai, Zongwei Peng, Jirun Leng, Xisheng Poon, Ronnie T. P. Luk, John M. Univ Hong Kong Queen Mary Hosp Dept Surg Hong Kong Hong Kong Peoples R China Univ Hong Kong Queen Mary Hosp Dept Med Hong Kong Hong Kong Peoples R China Peking Univ Peoples Hosp Dept Hepatobiliary Surg Beijing 100871 Peoples R China Univ Cambridge Metab Res Labs Inst Metab Sci Addenbrookes Hosp NHS Turst Cambridge England Chinese Univ Hong Kong Dept Med & Therapeut Hong Kong Hong Kong Peoples R China Hong Kong Baptist Univ Dept Chem Hong Kong Hong Kong Peoples R China Natl Univ Singapore Dept Pharmacol Singapore 117548 Singapore Natl Univ Singapore Dept Surg Singapore 117548 Singapore

Background. Biomarkers for accurate diagnosis of early hepatocellular carcinoma (HCC) are limited in number and clinical validation. We applied SELDI-TOF-MS Protein-Chip technology to identify serum profile for distinguishing HCC and liver cirrhosis (LC) and to compare the accuracy of SELDI-TOF-MS profile and alpha-fetoprotein (AFP) level in HCC diagnosis. Patients and Methods. Serum samples were obtained from 120 HCC and 120 LC patients for biomarker discovery and validation studies. Protein Chip technology was employed for generating SELDI-TOF proteomic features and analyzing serum proteins/peptides. Results. A diagnostic model was established by CART algorithm, which is based on 5 proteomic peaks with m/z values at 3324, 3994, 4665, 4795, and 5152. In the training set, the CART algorithm could differentiate HCC from LC subjects with a sensitivity and specificity of 98% and 95%, respectively. The results were assessed in blind validation using separate cohorts of 60 HCC and 60 LC patients, with an accuracy of 83% for HCC and 92% for LC patients. The diagnostic odd ratio (DOR) indicated that SELDI-TOF proteomic signature could achieve better diagnostic performance than serum AFP level at a cutoff of 20 ng/mL (AFP(20)) (92.72 vs 9.11), particularly superior for early-stage HCC (87% vs 54%). Importantly, a combined use of both tests could enhance the detection of HCC (sensitivity, 95%;specificity, 98%;DOR, 931). Conclusion. Serum SELDI-TOF proteomic signature, alone or in combination with AFP marker, promises to be a good tool for early diagnosis and/screening of HCC in at-risk population with liver cirrhosis.

关键词： Protein Array Analysis Liver Cirrhosis line controller proteomics surface enhanced laser desorption ionization time of flight mass spectrometry Serum AFP Population at Risk human-centered computing alpha-Fetoproteins

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Evolution of prognostic factors in hepatocellular carcinoma in Japan

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2010年第3期31卷 407-414页

作者： Nouso, K. Kobayashi, Y. Nakamura, S. Kobayashi, S. Toshimori, J. Kuwaki, K. Hagihara, H. Onishi, H. Miyake, Y. Ikeda, F. Shiraha, H. Takaki, A. Iwasaki, Y. Kobashi, H. Yamamoto, K. Okayama Univ Dept Mol Hepatol Grad Sch Med Dent & Pharmaceut Sci Okayama 7008558 Japan Okayama Univ Dept Gastroenterol & Hepatol Grad Sch Med Dent & Pharmaceut Sci Okayama 7008558 Japan

P>Background The surveillance of hepatocellular carcinoma (HCC) has become prevalent, and the modalities for its treatment have improved. Aim To understand the changes that occur in the characteristics and prognostic factors of HCC with time. Methods Newly diagnosed HCC patients were divided into two groups;patients treated before 31 December 2000 (n = 504), and after 1 January 2001 (n = 746), and their clinical backgrounds and prognostic factors were analysed. Results The number of patients negative for both Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody (HCVAb) increased with time (NBNC-HCC). The size of HCC decreased in patients who were positive for HBsAg (B-HCC) or HCVAb (C-HCC), whereas no difference was observed in NBNC-HCC. The patient survival of C-HCC improved;however, no difference was detected for NBNC-HCC. In multivariate analysis, low albumin, high aspartate aminotransferase (AST), ascites, large tumour size, multiple tumour number and high alpha-fetoprotein were risk factors for survival before 2000, whereas the presence of HBsAg was additionally selected as a good prognostic factor and AST was excluded after 2001. Conclusions The prognostic factors as well as clinical background of HCC changed with time, and the presence of HBsAg was found to be an additional good prognostic factor after 2001.

关键词： Hepatitis C Antibodies Prognostic Factors Risk Factors Number of tumors AST human-centered computing Hepatitis B Surface Antigens Patients

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Clinicopathological Significance of ZEB1 Protein in Patients with Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2012年第5期19卷 1700-1706页

作者： Zhou, Yan-Ming Cao, Lu Li, Bin Zhang, Rui-Xiu Sui, Cheng-Jun Yin, Zheng-Feng Yang, Jia-Mei Xiamen Univ Affiliated Hosp 1 Dept Hepatobiliary Pancreato Vasc Surg Xiamen Peoples R China Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Dept Special Treatment Shanghai Peoples R China Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Dept Mol Oncol Shanghai Peoples R China

ZEB1, a member of the ZFH family of proteins (zinc-finger E-box binding homeobox), plays a central role in epithelial-mesenchymal transition (EMT) during carcinogenesis. In this study, we investigated the expression of ZEB1 in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms. Expression levels of ZEB1 were assessed by Western blot in 5 HCC cell lines and in paired cancerous and noncancerous tissues from 110 patients with HCC. Short-hairpin RNA (shRNA) interference for ZEB1 was performed in MHCC-97H cell line. ZEB1 protein was detected at a relatively high level in metastatic human HCC cell lines (MHCC-97L and MHCC-97H) when compared with that in nonmetastatic HCC cell lines (Hep3B, PLC and Huh-7). ZEB1 was expressed at high levels in 72 of 110 HCC patients (65.4%) and correlated with advanced TNM stage, tumor size > 5 cm, intrahepatic metastasis, vascular invasion, and frequent early recurrence. The results of multivariate analysis revealed that ZEB1 high expression was a significant prognostic factor for poor overall and disease-free survivals. Silencing ZEB1 resulted in significant suppression of motility of MHCC-97H cell line, which was accompanied with increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers N-cadherin and vimentin. Furthermore, silencing ZEB1 prevented the spread of intrahepatic metastasis and increased overall survival in mouse orthotopic tumor models. This study shows that ZEB1 high expression was correlated with HCC malignant progression and subsequent poor patient survival by induction of EMT changes.

关键词： Hepatocellular Cancer Zinc Finger E-box-Binding Homeobox 1 Disease-Free Survival human-centered computing Cell Line

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