<span style="font-family:Verdana;">Current humans, <span style="white-space:nowrap;"><i>Homo sapiens</i></span>, are genetically and epigenetically very heterogeneous,...<span style="font-family:Verdana;">Current humans, <span style="white-space:nowrap;"><i>Homo sapiens</i></span>, are genetically and epigenetically very heterogeneous, and subsequently also biologically and physiologically heterogeneous. Much of this heterogeneity likely arose during evolutionary processes, via various iterations of humanoid lineages, and interbreeding. While advantageous from a species perspective, the heterogeneity of humans poses serious challenges to researchers attempting to understand complex disease processes. While the use of inbred preclinical models makes the research effort more effective at some levels, the findings are often not translatable to the more heterogeneous human populations. This conundrum leads to considerable research activity with inbred preclinical models, but modest progress in understanding many complex human conditions and diseases. This article discusses several of the issues around human heterogeneity and the need to change some directions in preclinical model research. Using newer Artificial Intelligence and Machine Learning approaches can begin to deduce important elements from the complexity of human heterogeneity.</span>展开更多
Combined hepatocellular-cholangiocarcinoma（CHC） is a mixed tumor containing elements of both hepatocellular carcinoma（HCC） and cholangiocarcinoma（CC）. Its remarkable histological heterogeneity has been linked to...Combined hepatocellular-cholangiocarcinoma（CHC） is a mixed tumor containing elements of both hepatocellular carcinoma（HCC） and cholangiocarcinoma（CC）. Its remarkable histological heterogeneity has been linked to putative hepatic progenitor cell（HPC） origin. However, detailed histological or phenotypic description is rarely documented. In the present study, we reassessed 68 cases previously diagnosed as hepatitis B-related CHCs by immunohistochemistry and double-fluorescence immunostaining, focusing on HPC associated phenotypic observation of intermediate area of the tumor. It was found that tumor cells showed remarkable heterogeneity in intermediate area. Tumor cells with intermediate morphology between hepatocytes and cholangiocytes were oval-shaped and small with scant cytoplasm and hyperchromatic nuclei, arranging in solid nests mostly. By Keratin 7（K7） staining, it appeared that the nests of tumor cells represented a maturation process from the undifferentiated small cells to mature hepatocytes through the ＂transitional＂ cells. Then, these small cells were further confirmed with intermediate phenotype as HPC by exploring immature hepatocellular marker and HPC/biliary markers co-localization. In conclusion, the HPC associated trait in CHC can be interpreted by HPC origin or gain of ＂stemness＂ by dedifferentiation. It is still too soon to give a final word that it is innate or acquired signature of HPC associated trait in CHC.展开更多
By using cell cloning technique, 4 sublines (A,C,D,E) were isolated from a cell line of human lung giant cell carcinoma (PLA-801). After subcutaneous inoculation in T-cell deficient BALB/c nude mice, the incidence of ...By using cell cloning technique, 4 sublines (A,C,D,E) were isolated from a cell line of human lung giant cell carcinoma (PLA-801). After subcutaneous inoculation in T-cell deficient BALB/c nude mice, the incidence of tumor growth and spontaneous metastasis were the highest in subline D, moderate in sublines A and E, and lowest in subline C. Tumor cells of subline C also showed similar low tumorigenicity in another T-cell deficient 615/ PB1 nude mice.However, in 615/PB1 beige nude mice with con-genitally combined immune-deficiency in both T and NK cell activity, tumor cells of the rarely metastatic subline C do produce significantly high frequency of tumor growth and spontaneous metastasis.Morphological studies (light microscope, electron microscope and immunohistochemistry) showed rich microfilaments and Vimentin positive in the cytoplasm of metastatic tumor cells. This may imply a possibility that tumor cells differentiate towards the direction favourable to spreading and metastasis.展开更多
文摘<span style="font-family:Verdana;">Current humans, <span style="white-space:nowrap;"><i>Homo sapiens</i></span>, are genetically and epigenetically very heterogeneous, and subsequently also biologically and physiologically heterogeneous. Much of this heterogeneity likely arose during evolutionary processes, via various iterations of humanoid lineages, and interbreeding. While advantageous from a species perspective, the heterogeneity of humans poses serious challenges to researchers attempting to understand complex disease processes. While the use of inbred preclinical models makes the research effort more effective at some levels, the findings are often not translatable to the more heterogeneous human populations. This conundrum leads to considerable research activity with inbred preclinical models, but modest progress in understanding many complex human conditions and diseases. This article discusses several of the issues around human heterogeneity and the need to change some directions in preclinical model research. Using newer Artificial Intelligence and Machine Learning approaches can begin to deduce important elements from the complexity of human heterogeneity.</span>
基金supported by grants from National Natural Science Foundation of China(No.81302130)Military Medical Scientific Youth Cultivation Project(No.13QNP054)
文摘Combined hepatocellular-cholangiocarcinoma（CHC） is a mixed tumor containing elements of both hepatocellular carcinoma（HCC） and cholangiocarcinoma（CC）. Its remarkable histological heterogeneity has been linked to putative hepatic progenitor cell（HPC） origin. However, detailed histological or phenotypic description is rarely documented. In the present study, we reassessed 68 cases previously diagnosed as hepatitis B-related CHCs by immunohistochemistry and double-fluorescence immunostaining, focusing on HPC associated phenotypic observation of intermediate area of the tumor. It was found that tumor cells showed remarkable heterogeneity in intermediate area. Tumor cells with intermediate morphology between hepatocytes and cholangiocytes were oval-shaped and small with scant cytoplasm and hyperchromatic nuclei, arranging in solid nests mostly. By Keratin 7（K7） staining, it appeared that the nests of tumor cells represented a maturation process from the undifferentiated small cells to mature hepatocytes through the ＂transitional＂ cells. Then, these small cells were further confirmed with intermediate phenotype as HPC by exploring immature hepatocellular marker and HPC/biliary markers co-localization. In conclusion, the HPC associated trait in CHC can be interpreted by HPC origin or gain of ＂stemness＂ by dedifferentiation. It is still too soon to give a final word that it is innate or acquired signature of HPC associated trait in CHC.
文摘By using cell cloning technique, 4 sublines (A,C,D,E) were isolated from a cell line of human lung giant cell carcinoma (PLA-801). After subcutaneous inoculation in T-cell deficient BALB/c nude mice, the incidence of tumor growth and spontaneous metastasis were the highest in subline D, moderate in sublines A and E, and lowest in subline C. Tumor cells of subline C also showed similar low tumorigenicity in another T-cell deficient 615/ PB1 nude mice.However, in 615/PB1 beige nude mice with con-genitally combined immune-deficiency in both T and NK cell activity, tumor cells of the rarely metastatic subline C do produce significantly high frequency of tumor growth and spontaneous metastasis.Morphological studies (light microscope, electron microscope and immunohistochemistry) showed rich microfilaments and Vimentin positive in the cytoplasm of metastatic tumor cells. This may imply a possibility that tumor cells differentiate towards the direction favourable to spreading and metastasis.
