Summary Background Multidrug-resistant tuberculosis (MDR-TB) is a significant threat to tuberculosis elimination worldwide. Understanding the transmission pattern is crucial for its control. We used a genomic epidemiological approach to assess the recent transmission of MDR-TB and potential risk factors for transmission. Methods In a population-based retrospective study, we performed variable-number-of-tandem-repeat (VNTR) genotyping, followed by whole-genome sequencing (WGS) of isolates from all MDR-TB patients in Shanghai, China, 2009-2012. We measured strain diversity within and between genomically clustered patients. Genomic and epidemiologic data were combined to construct transmission networks. Findings 367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance. Interpretation Recent transmission of MDR strains, with increasing drug-resistance, helps drive the MDR-TB epidemic in Shanghai, China. WGS provides a measure of the heterogeneity of drug-resistant mutations within and between hosts and enhances our ability to determine the transmission patterns of MDR-TB. Funding National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.
Human hepatocellular carcinoma (HCC) is one of the most common types of tumour, especially in Asia and Africa (Anderson et al, 1992;Okuda, 1992;Parkin et al, 1993). HCC is characterized by extensive carcinoma cell infiltration and metastasis. Although advances have been made in liver cancer therapies, most cancer deaths still result from metastatic disease, so metastasis has been the greatest obstacle to successful tumour treatment. The poor understanding of the molecular mechanisms responsible for the disseminated metastasis, which would be partly due to the lack of ideal samples and models for study, has hindered the development of effective antimetastatic therapies. Although several reports of the establishment of HCC cell lines were available (Chen, 1963;Alexander et al, 1976;Dong et al, 1980), none have demonstrated prominent metastatic potential. The human cell line with a metastatic potential from primary tumour or metastatic lesions would permit metastatic mechanisms to be studied further. However, the cancer cells from the surgical samples or metastatic lesions can only be maintained in primary culture for a short time before cellular senescence occurs. The aim of this study was to establish a human HCC cell line with a metastatic potential. We successfully established a new HCC cell line with a highly metastatic potential derived from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) (Sun et al, 1996) by improving the conventional method of establishing a cell line -alternating cell culture in vivo and growth in nude mice. In this paper the processes of establishing a new human HCC cell line MHCC97 and some characteristics, including observation of some factors associated with metastasis, are reported. MATERIALS AND METHODS Specimens and in vitro cultureSeventy-eight primary cultures were taken from subcutaneous or intrahepatic xenografts of LCI-D20 nude mouse models. The model was developed by orthotopic inoculation of an intact tumour tissue of an intrahepatic disseminated lesion from a 39-year-old Chinese male patient with HCC (Zhong-Shan Hospital, Shanghai Medical University). Abnormal alpha-fetoprotein (AFP) and HBsAg were found in serum from this patient. The LCI-D20 model represents 100% metastases to the lungs, lymph nodes and intrahepatic spreading (Sun, 1996). These xenografts were removed and used for primary culture in vitro by different culture methods (tissue fragments or single-cell Summary A new human hepatocellular carcinoma (HCC) cell line with a highly metastatic potential was established from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) by means of alternating cell culture in vitro and growth in nude mice. The line, designated MHCC97, has been cultivated for 18 months and subcultured for more than 90 passages. The line was showed to be of human origin by karyotype analysis. The cells were either grown as compact colonies (in clusters) or as a monolayered sheet with about 31 h of population-doubling time, exhibited ty...
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