Objection： To study the relationship between different doses and biological effect of 32p-glass microspheres （32P-GMS） by percutaneous intra-tumor injection at different times and provide proofs of theory for clini...Objection： To study the relationship between different doses and biological effect of 32p-glass microspheres （32P-GMS） by percutaneous intra-tumor injection at different times and provide proofs of theory for clinical therapy. Methods： 36 Zealand rabbits and Vx-2 were used to establish the animal model of liver tumor. Six groups were randomly designed. The suspension of different radiative doses of 32p-GMS combined with lipiodol-ultrafluid （0.1 mL） was respectively injected by percutaneous intra-tumor. The tumor tissues were examined by light microscope. MRI examination of liver tumors were performed before and after the injection. Results： C and D groups were observed that the tumor volume was decreased and the rate of restrained tumor was gradually increased after injection of 32p-GMS. The living tumor tissues of E group completely disappeared after the injection for two weeks. MRI examination showed that the tumor signal of E group was equal as T2 as the signal of normal liver parenchyma. The living tumor tissues were not found in F group after the injection for three weeks. Conclusion： 111 MBq was the best radiative dose of ~2p-GMS for treatment of 1 cm liver cancer by percutaneous intra-tumor injection. MRI examination was very valuable to evaluate the result and follow up after the injection to treat liver cancer.展开更多
Aim:Current cancer treatments are challenged by the plasticity of cancer cells,largely influenced by chromosomal instability(CIN)leading to variations in karyotype known as tumor-specific aneuploidy,which in turn,lead...Aim:Current cancer treatments are challenged by the plasticity of cancer cells,largely influenced by chromosomal instability(CIN)leading to variations in karyotype known as tumor-specific aneuploidy,which in turn,leads to intra-tumor cellular heterogeneity(TH).Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors.Modulation of the CIN rate seems to reside within the tumor itself.In an attempt to develop a therapy targeting cancer plasticity,we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.Methods:Chr7-fluorescence in situ hybridization was applied on various grades of gliomas,in vitro cultures and intracranial xenografts of two syngeneic glioma lines(U251 and U251-NS)derived from various cell-inoculating densities,with or without EFEMP1 overexpression.Results:A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas.A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.Conclusion:Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells,and EFEMP1 is one of these factors.展开更多
T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy ...T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy and associated with poor outcome.Here,we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GTG)-banding.However,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic heterogeneity.In addition,homozygous loss of CDKN2A,as well as amplification of oncogene TLX1(HOX11)were detected.Actually,NUP214-ABL1 fusion gene replicated autonomously in this case as episomes.Overall,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.展开更多
The presence of heritable differences among cancer cells within a tumor, called intra-tumor genetic heterogeneity, has long been suspected of playing a role in poor responses to therapy. Research over the past decade ...The presence of heritable differences among cancer cells within a tumor, called intra-tumor genetic heterogeneity, has long been suspected of playing a role in poor responses to therapy. Research over the past decade has documented the existence of such heterogene-ity within tumors of individual patients and documented its potential clinical significance. The research methods for identifying this heterogeneity were not, however, readily adaptable to widespread clinical application. After a brief review of this background, we describe the devel-opment of a measure of intra-tumor genetic heterogeneity, based on whole-exome sequencing of individual tumor samples, that could be applied to biopsy specimens in a clinical setting. This measure has now been used in head and neck squamous cell carcinoma (HNSCC) to docu-ment, for the first time, a relation of high intra-tumor genetic heterogeneity to shorter overall survival in a large, multi-institutional study. The implications of heterogeneity for research and clinical care thus now need to be addressed. Copyright a 2016 Chinese Medical Association. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).展开更多
Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this ...Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes.In addition,accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects.This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.Methods:ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes,i.e.,complex single gene variance(CSGV).Results:CSGV was identified in the androgen receptor genes in all breast tumors examined.Conclusion:Evidence of CSGV suggests that a selection-as opposed to a mutation-centric hypothesis could better explain carcinogenesis.Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations.Thus,the role of selection pressures,such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.展开更多
Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell reso...Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.展开更多
BACKGROUND: Non-operative therapy takes an impor- tant position in comprehensive therapy of liver cancer. De- spite some effects by using ethanol, acetic acid and heat sa- line for intra-tumor injection in the treatme...BACKGROUND: Non-operative therapy takes an impor- tant position in comprehensive therapy of liver cancer. De- spite some effects by using ethanol, acetic acid and heat sa- line for intra-tumor injection in the treatment of liver canc- er, it is difficult to attain a complete cure but bring about injury to the liver to some extent. Hence, searching for other drugs for the local treatment of liver tumor is an im- portant option. This study was designed to set up rat mo- dels of transplanted liver cancer, intra-tumor injection of Kang-Lai-Te (KLT), and negative control (saline) and positive control (ethanol). The effect of intra-tumor injec- tion of KLT in treating transplanted hepatoma in rats and its advantages and disadvantages were assessed and the pos- sibility of its use in treating patients with liver cancer was evaluated. METHODS: Forty rats were divided into 4 groups ( G1, G2, G3 and G4, 10 rats in each group). Different drugs were injected into their implanted hepatoma (G1 with 0.2 ml saline as control, G2 with 10 mg KLT, G3 with 20 mg KLT, G4 with 0.2 ml ethanol). After 3 and 8 days, the hepa- toma volume (HV), the serum levels of albumin, alanine aminotransferase(ALT), aspartate aminotransferase alkaline phosphatase( ALP) and creatinine, as well as the expression of proliferation cell nuclear antigen (PCNA) in hepatoma were detected. RESULTS: After 3 days, the HVs were smaller in G3 and G4 than in G1 (P <0.05), the serum levels of albumin were higher in G2 and G3 than in Gl and G4 (P <0.05), the se- rum levels of ALT and AST were lower in G2 and G3 than in G4 (P<0.05), the serum levels of ALP was lower in G2 and G3 than in Gl and G4 (P <0. 05), the PCNA labeling indexes (PCNA LI) were lower in G2 and G3 than in Gl and GA (P <0.05). After 8 days, the HVs were smaller in G2, G3 and G4 than in Gl (P <0.05), and the differences of HVs among G2, G3 and G4 were not significant. The serum levels of ALP were lower in G1, G2 and G3 than in G4 (P <0.05), and the PCNA LI were lower in G3 than in Gl andG4 (P<0.05). CONCLUSION: Intra-tumor injection of KLT into implan- ted hepatoma is evidently effective, but it is less effective than ethanol. The effect of KLT on liver function is markedly lower than that of ethanol.展开更多
基金a grant from the Tianjin Municipal Commission of Science and Technology(No.003607111)
文摘Objection： To study the relationship between different doses and biological effect of 32p-glass microspheres （32P-GMS） by percutaneous intra-tumor injection at different times and provide proofs of theory for clinical therapy. Methods： 36 Zealand rabbits and Vx-2 were used to establish the animal model of liver tumor. Six groups were randomly designed. The suspension of different radiative doses of 32p-GMS combined with lipiodol-ultrafluid （0.1 mL） was respectively injected by percutaneous intra-tumor. The tumor tissues were examined by light microscope. MRI examination of liver tumors were performed before and after the injection. Results： C and D groups were observed that the tumor volume was decreased and the rate of restrained tumor was gradually increased after injection of 32p-GMS. The living tumor tissues of E group completely disappeared after the injection for two weeks. MRI examination showed that the tumor signal of E group was equal as T2 as the signal of normal liver parenchyma. The living tumor tissues were not found in F group after the injection for three weeks. Conclusion： 111 MBq was the best radiative dose of ~2p-GMS for treatment of 1 cm liver cancer by percutaneous intra-tumor injection. MRI examination was very valuable to evaluate the result and follow up after the injection to treat liver cancer.
文摘Aim:Current cancer treatments are challenged by the plasticity of cancer cells,largely influenced by chromosomal instability(CIN)leading to variations in karyotype known as tumor-specific aneuploidy,which in turn,leads to intra-tumor cellular heterogeneity(TH).Cells with certain chromosomal defects often survive treatment and the growth-associated states of TH persist in recurrent tumors.Modulation of the CIN rate seems to reside within the tumor itself.In an attempt to develop a therapy targeting cancer plasticity,we studied the possible extracellular control of CIN rate in Chr7-defined TH in gliomas.Methods:Chr7-fluorescence in situ hybridization was applied on various grades of gliomas,in vitro cultures and intracranial xenografts of two syngeneic glioma lines(U251 and U251-NS)derived from various cell-inoculating densities,with or without EFEMP1 overexpression.Results:A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas.A negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by EFEMP1 overexpression.Conclusion:Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be controlled by extracellular factors derived from normal and tumor cells,and EFEMP1 is one of these factors.
文摘T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy and associated with poor outcome.Here,we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GTG)-banding.However,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic heterogeneity.In addition,homozygous loss of CDKN2A,as well as amplification of oncogene TLX1(HOX11)were detected.Actually,NUP214-ABL1 fusion gene replicated autonomously in this case as episomes.Overall,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.
文摘The presence of heritable differences among cancer cells within a tumor, called intra-tumor genetic heterogeneity, has long been suspected of playing a role in poor responses to therapy. Research over the past decade has documented the existence of such heterogene-ity within tumors of individual patients and documented its potential clinical significance. The research methods for identifying this heterogeneity were not, however, readily adaptable to widespread clinical application. After a brief review of this background, we describe the devel-opment of a measure of intra-tumor genetic heterogeneity, based on whole-exome sequencing of individual tumor samples, that could be applied to biopsy specimens in a clinical setting. This measure has now been used in head and neck squamous cell carcinoma (HNSCC) to docu-ment, for the first time, a relation of high intra-tumor genetic heterogeneity to shorter overall survival in a large, multi-institutional study. The implications of heterogeneity for research and clinical care thus now need to be addressed. Copyright a 2016 Chinese Medical Association. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
基金This study was supported by a grant to BG from the Weekend to End Breast Cancer Fund of the Jewish General Hospital,Montreal,Quebec,Canada.
文摘Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes.In addition,accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects.This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.Methods:ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes,i.e.,complex single gene variance(CSGV).Results:CSGV was identified in the androgen receptor genes in all breast tumors examined.Conclusion:Evidence of CSGV suggests that a selection-as opposed to a mutation-centric hypothesis could better explain carcinogenesis.Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations.Thus,the role of selection pressures,such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.
基金funded by Beijing Hope Run Special Fund of Cancer Foundation of China (No.LC2020A19)。
文摘Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.
基金The study was supported by a grant from the Science Foundation of the Health Department of Shandong Province (No 1998CA1CKA3)
文摘BACKGROUND: Non-operative therapy takes an impor- tant position in comprehensive therapy of liver cancer. De- spite some effects by using ethanol, acetic acid and heat sa- line for intra-tumor injection in the treatment of liver canc- er, it is difficult to attain a complete cure but bring about injury to the liver to some extent. Hence, searching for other drugs for the local treatment of liver tumor is an im- portant option. This study was designed to set up rat mo- dels of transplanted liver cancer, intra-tumor injection of Kang-Lai-Te (KLT), and negative control (saline) and positive control (ethanol). The effect of intra-tumor injec- tion of KLT in treating transplanted hepatoma in rats and its advantages and disadvantages were assessed and the pos- sibility of its use in treating patients with liver cancer was evaluated. METHODS: Forty rats were divided into 4 groups ( G1, G2, G3 and G4, 10 rats in each group). Different drugs were injected into their implanted hepatoma (G1 with 0.2 ml saline as control, G2 with 10 mg KLT, G3 with 20 mg KLT, G4 with 0.2 ml ethanol). After 3 and 8 days, the hepa- toma volume (HV), the serum levels of albumin, alanine aminotransferase(ALT), aspartate aminotransferase alkaline phosphatase( ALP) and creatinine, as well as the expression of proliferation cell nuclear antigen (PCNA) in hepatoma were detected. RESULTS: After 3 days, the HVs were smaller in G3 and G4 than in G1 (P <0.05), the serum levels of albumin were higher in G2 and G3 than in Gl and G4 (P <0.05), the se- rum levels of ALT and AST were lower in G2 and G3 than in G4 (P<0.05), the serum levels of ALP was lower in G2 and G3 than in Gl and G4 (P <0. 05), the PCNA labeling indexes (PCNA LI) were lower in G2 and G3 than in Gl and GA (P <0.05). After 8 days, the HVs were smaller in G2, G3 and G4 than in Gl (P <0.05), and the differences of HVs among G2, G3 and G4 were not significant. The serum levels of ALP were lower in G1, G2 and G3 than in G4 (P <0.05), and the PCNA LI were lower in G3 than in Gl andG4 (P<0.05). CONCLUSION: Intra-tumor injection of KLT into implan- ted hepatoma is evidently effective, but it is less effective than ethanol. The effect of KLT on liver function is markedly lower than that of ethanol.
