International Journal of Radiation Oncology*Biology*Physics, 2014
Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in p... more Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
Partial hepatectomy (PH) and some tumor-promoting agents stimulate hepatocyte cell proliferation,... more Partial hepatectomy (PH) and some tumor-promoting agents stimulate hepatocyte cell proliferation, but each treatment acts through distinct transcription factors. We compared mouse immediate-early gene expression changes after PH with those induced by 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene (TCPOBOP), a tumor-promoting liver mitogen. PH activates nuclear factor B (NF-B) and Stat3, whereas TCPOBOP is a ligand for the nuclear receptor, constitutive androstane receptor (CAR). RNA from 1 and 3 hours after each treatment was hybridized to a 9,000 complementary DNA (cDNA) microarray. Of about 6,000 messenger RNAs that had detectable expression, 127 showed reproducible up-regulation or down-regulation at a significant level. The TCPOBOP response was more discrete than the PH response; they amounted to 1% and 1.9% of positive hybridizations, respectively. Twenty-three genes were regulated only by TCPOBOP, 57 only by PH, and 59 by both treatments. More detailed analysis defined 16 clusters with common patterns of expression. These patterns and quantification of hybridization levels on the array were confirmed by Northern blots. TCPOBOP selectively activated expression of a number of detoxification enzymes. In conclusion, the genes that were regulated by both treatments suggest downregulation of apoptosis, altered signal transduction, and early biogenesis of critical cell components. (HEPATOLOGY 2003;38:314-325.)
American Journal of Clinical Pathology, Aug 1, 1989
This study presents the clinical and laboratory observations on posttransplant lymphoproliferativ... more This study presents the clinical and laboratory observations on posttransplant lymphoproliferative disorders (PTLDs) occurring in 5 of 53 heart-lung transplantation recipients. Cervical lymph nodes, tonsils, lungs, and gastrointestinal tract were the common sites of involvement by PTLDs. The histopathologic findings showed a spectrum of lymphoid and immunoblastic proliferation ranging from diffuse hyperplasia to malignant lymphoma, immunoblastic or large cell type. All cases were associated with a primary Epstein-Barr virus infection, and viral DNA was demonstrated within the lesional tissue in three cases. Immunohistochemical and immunoglobulin gene rearrangement studies revealed a B-cell proliferation that was monoclonal in three cases and polyclonal in two cases. Compared with PTLDs arising in other organ transplant recipients, this series is remarkable for a high incidence of PTLDs (9.4%), a short interval to tumor diagnosis (2.2 months, mean), involvement of the primary allograft in three cases (60%), and the frequent development of bronchiolitis obliterans. Possible reasons for this distinct clinicopathologic profile are discussed.
A variety ofgene analyses were performed on lymphoid tumors from transplant patients who received... more A variety ofgene analyses were performed on lymphoid tumors from transplant patients who received cyclosporine A for immunosuppression. Epstein-Barr virus DNA was detected in the tumors, and the structure of circular episomal virus DNA was used as a measure ofcell clonality. This analysis was correlated with clonality determined by study of immunoglobulin gene rearrangement. Some ofthe tumors had DNA rearrangements near the c-myc gene. Analysis suggested thepathogenesis ofthe tumors and indicatedfour categories oflymphoproliferation, three neoplastic and one reactive. (AmJPathol 1989, 135:977-987) Tumors of B lymphocytes commonly arise in immunosuppressed patients.1-7 These '"post-transplant lymphoproliferations" (PTLs) range from benign hyperplasias to malignant lymphomas, and are closely associated with Epstein-Barr viral (EBV) infection.2'4'7'813 PTLs differ in clinical behavior, but it is difficult to discriminate morphologically hyperplastic from malignant lesions.27 Some tumors consist of a monomorphic cell population whereas others contain "polymorphic" maturing B cell populations, ranging from large cells to plasmacytoid cells. The morphology of the latter may resemble hyperplasia. Conversely, both monomorphic and polymorphic malignant tumors probably arise in hyperplasias. Many patients have multiple tumors in different locations. These could represent multiple neoplastic transformations, metastatic spread, or hyperplasia that is incorrectly called neoplasia.
Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 198... more Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 1981. Posttransplant lymphoproliferative disorders (PTLD) have occurred in 131 patients, at a frequency of 2.2%. The majority of cases manifest within 6 months following allograft, but individual lesions may arise several years thereafter. From 1981 to 1989, cyclosporine-A (CsA) served as the primary immunosuppressant in this population. In March of 1989, FK506 was introduced for clinical trials. Since that time, 1421 patients have received FK506 either for primary immunosuppression or as rescue therapy. The frequency of PTLD in this subpopulation is 1.5%. PTLD arising under FK506-containing regimens have clinicopathologic features similar to those arising with CsA immunosuppression. The frequency of PTLD at this point in time is approximately 1% in kidney allograft patients, 2.7% in liver, 3.3% in heart and 3.8% in heart/lung or lung recipients. An understanding of the range of histologic appearance is important for the diagnosis of PTLD, especially when it involves the allograft itself. Immunoglobulin heavy chain gene analysis shows that lesions with no rearrangements or with a rearrangement in only a small proportion of cells are more likely to respond to reduced immunosuppression than are those with clonal rearrangement involving a high proportion of cells. However, this distinction is not absolute, and a trial of reduced immunosuppression appears to be indicated regardless of clonal status.
To refine the analysis ofgene amplification in breast cancer, the authors have developed sensitiv... more To refine the analysis ofgene amplification in breast cancer, the authors have developed sensitive methods that can be used to screen nucleic acidpreparedfrom a variety of sources, In their analysis, Southern hybridization and DNA dot-blot analysis were used to screen 49 breast cancer DNAs for Myc, Neu, and Int-2 gene amplification. The analysis detected minimal (one extra gene copy) as well as expanded (two or more extra gene copies) gene amplifications, and in addition, distinguished between gene amplification and aneuploidy as the cause of extra gene copies These quantitative methods were adapted to patient specimens routinely available in the anatomic pathology laboratory, including fresh tumor tissue, tumor nuclei discarded during estrogen receptor analysis and paraffin blocks One minimal gene amplification was found in three cases of intraductal cancer. Of25 cases of nonmetastatic invasive cancer, 28% had at least one extra Myc gene, whereas 24% had Neu, and 21% had Int-2 gene amplification. Of 21 cases of metastatic invasive cancer, 43% had Myc, 43% had Neu, and 40% had Int-2 gene amplification. Among the nonmetastatic cancers, 47% had one, 12% had two, and 4% had three amplified genes Within the metastatic cancers 48% had one, 28% had two, and 5% had three amplified genes Our data suggest relationships between tumorprogression and both incidence and size of Myc, Net; and Int-2 gene amplification. (AmJ Pathol 1991, 138:835-845) Breast cancer, the most common cause of cancer death in women, results from the complex interaction of genetic, physiologic, and environmental factors. In each case, the ability to predict the clinical outcome, determine the probability of recurrence, and make decisions on adjuvant chemotherapy or radiotherapy relies on tumor staging using several independent prognostic indicators. Those most commonly used include node status,1 steroid receptor status,2 histopathology,3 histologic grade,4 DNA ploidy, and percentage of cells in S phase.56 These characteristics predict, with a certain probability, the behavior of breast cancer. Within each group, however, there appear to be subcategories of tumor with different clinical outcomes. For example, although negative node status is correlated with a decreased probability of tumor recurrence, in fact, only 70% of women will remain disease free after 5 years.
Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) t... more Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) that results in the fusion of the retinoic acid receptor alpha (RAR alpha) gene with a transcription factor gene called PML. Several cases of APML with t(11;17) have recently been described, involving fusion of the RAR alpha gene with a new zinc finger gene named PLZF. We report here a second non-classical translocation, t(5;17), with a rearranged RAR alpha gene in a child with APML. Based on restriction endonuclease analysis, the rearrangement of RAR alpha occurred within the second intron, the common breakpoint site for t(15;17). The leukemic cells in the bone marrow aspirate were a mixture of hypergranular and hypogranular bilobed promyelocytes. Although less than 1% abnormal promyelocytes were identified after induction therapy, cytogenetics revealed persistent t(5;17). Therefore, the child was treated with all-trans-retinoic acid (ATRA). There was no disease progression, and one marrow was interpreted as remission, with confirmation by cytogenetics which failed to reveal the translocation. However, disease reoccurred shortly after completion of ATRA. This poor response to ATRA may be an additional characteristic associated with non-classical translocations in APML. The identification of a second variant translocation involving the RAR alpha gene in APML suggests yet another RAR alpha rearrangement related to neoplastic myelopoiesis.
Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R2... more Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R21, and R22), congenic (Y0.1U.grc+, Y0.1U.grc+/Y0.1L.grc, and Y0.1L.grc) and inbred rats has been performed to examine the restriction fragment length polymorphisms of class I genes. After digestion with Xba I or Eco RI, the genomic DNA was resolved on agarose gels, was transferred to nitrocellulose membranes, and was hybridized with murine H-2 cDNA probes. Eighteen to 25 bands of varying intensities could be clearly resolved in any given strain. Analysis of these hybridization patterns detected restriction fragment length polymorphisms that permitted the assignment of 17 specific fragments to regions within the major histocompatibility complex: RT1.A, RT1.B/D, and the RT1.E-grc-T1 alpha region. Fragments have been identified that are specific for grc, grc+, and RT1.E, and mark the junction sites between these loci. In addition, several markers identify the region around the sites of recombination in some strains. The hybridization pattern of the R18 recombinant had a unique band that specified a point of recombination within the grc. The recombinant R11 presented a unique restriction pattern unrelated to either of the parental strains or other related strains. This result suggests that R11 arose from a recombination event(s) undetected by conventional serologic methods.
The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, anal... more The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA ...
Mature adult parenchymal hepatocytes, typically of restricted capacity to proliferate in culture,... more Mature adult parenchymal hepatocytes, typically of restricted capacity to proliferate in culture, can now enter into clonal growth under the influence of hepatocyte growth factor (scatter factor) (HGF/SF), epidermal growth factor (EGF), and transforming growth factor et (TGFo 0 in the presence of a new chemically defined medium (HGM). The expanding populations of hepatocytes lose expression of hepatocyte specific genes (albumin, cytochrome P450 IIB1), acquire expression of markers expressed by bile duct epithelium (cytokeratin 19), produce TGFot and acidic FGF and assume a very simplified morphologic phenotype by electron microscopy. A major change associated with this transition is the decrease in ratio between transcription factors C/EBPo~ and C/EBP[3, as well as the emergence in the proliferating hepatocytes of transcription factors AP1, NFKB. The liver associated transcription factors HNF1, HNF3, and HNF4 are preserved throughout this process.
International Journal of Radiation Oncology*Biology*Physics, 2014
Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in p... more Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.
Partial hepatectomy (PH) and some tumor-promoting agents stimulate hepatocyte cell proliferation,... more Partial hepatectomy (PH) and some tumor-promoting agents stimulate hepatocyte cell proliferation, but each treatment acts through distinct transcription factors. We compared mouse immediate-early gene expression changes after PH with those induced by 1,4-bis[2-(3,5-dichoropyridyloxy)]benzene (TCPOBOP), a tumor-promoting liver mitogen. PH activates nuclear factor B (NF-B) and Stat3, whereas TCPOBOP is a ligand for the nuclear receptor, constitutive androstane receptor (CAR). RNA from 1 and 3 hours after each treatment was hybridized to a 9,000 complementary DNA (cDNA) microarray. Of about 6,000 messenger RNAs that had detectable expression, 127 showed reproducible up-regulation or down-regulation at a significant level. The TCPOBOP response was more discrete than the PH response; they amounted to 1% and 1.9% of positive hybridizations, respectively. Twenty-three genes were regulated only by TCPOBOP, 57 only by PH, and 59 by both treatments. More detailed analysis defined 16 clusters with common patterns of expression. These patterns and quantification of hybridization levels on the array were confirmed by Northern blots. TCPOBOP selectively activated expression of a number of detoxification enzymes. In conclusion, the genes that were regulated by both treatments suggest downregulation of apoptosis, altered signal transduction, and early biogenesis of critical cell components. (HEPATOLOGY 2003;38:314-325.)
American Journal of Clinical Pathology, Aug 1, 1989
This study presents the clinical and laboratory observations on posttransplant lymphoproliferativ... more This study presents the clinical and laboratory observations on posttransplant lymphoproliferative disorders (PTLDs) occurring in 5 of 53 heart-lung transplantation recipients. Cervical lymph nodes, tonsils, lungs, and gastrointestinal tract were the common sites of involvement by PTLDs. The histopathologic findings showed a spectrum of lymphoid and immunoblastic proliferation ranging from diffuse hyperplasia to malignant lymphoma, immunoblastic or large cell type. All cases were associated with a primary Epstein-Barr virus infection, and viral DNA was demonstrated within the lesional tissue in three cases. Immunohistochemical and immunoglobulin gene rearrangement studies revealed a B-cell proliferation that was monoclonal in three cases and polyclonal in two cases. Compared with PTLDs arising in other organ transplant recipients, this series is remarkable for a high incidence of PTLDs (9.4%), a short interval to tumor diagnosis (2.2 months, mean), involvement of the primary allograft in three cases (60%), and the frequent development of bronchiolitis obliterans. Possible reasons for this distinct clinicopathologic profile are discussed.
A variety ofgene analyses were performed on lymphoid tumors from transplant patients who received... more A variety ofgene analyses were performed on lymphoid tumors from transplant patients who received cyclosporine A for immunosuppression. Epstein-Barr virus DNA was detected in the tumors, and the structure of circular episomal virus DNA was used as a measure ofcell clonality. This analysis was correlated with clonality determined by study of immunoglobulin gene rearrangement. Some ofthe tumors had DNA rearrangements near the c-myc gene. Analysis suggested thepathogenesis ofthe tumors and indicatedfour categories oflymphoproliferation, three neoplastic and one reactive. (AmJPathol 1989, 135:977-987) Tumors of B lymphocytes commonly arise in immunosuppressed patients.1-7 These '"post-transplant lymphoproliferations" (PTLs) range from benign hyperplasias to malignant lymphomas, and are closely associated with Epstein-Barr viral (EBV) infection.2'4'7'813 PTLs differ in clinical behavior, but it is difficult to discriminate morphologically hyperplastic from malignant lesions.27 Some tumors consist of a monomorphic cell population whereas others contain "polymorphic" maturing B cell populations, ranging from large cells to plasmacytoid cells. The morphology of the latter may resemble hyperplasia. Conversely, both monomorphic and polymorphic malignant tumors probably arise in hyperplasias. Many patients have multiple tumors in different locations. These could represent multiple neoplastic transformations, metastatic spread, or hyperplasia that is incorrectly called neoplasia.
Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 198... more Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 1981. Posttransplant lymphoproliferative disorders (PTLD) have occurred in 131 patients, at a frequency of 2.2%. The majority of cases manifest within 6 months following allograft, but individual lesions may arise several years thereafter. From 1981 to 1989, cyclosporine-A (CsA) served as the primary immunosuppressant in this population. In March of 1989, FK506 was introduced for clinical trials. Since that time, 1421 patients have received FK506 either for primary immunosuppression or as rescue therapy. The frequency of PTLD in this subpopulation is 1.5%. PTLD arising under FK506-containing regimens have clinicopathologic features similar to those arising with CsA immunosuppression. The frequency of PTLD at this point in time is approximately 1% in kidney allograft patients, 2.7% in liver, 3.3% in heart and 3.8% in heart/lung or lung recipients. An understanding of the range of histologic appearance is important for the diagnosis of PTLD, especially when it involves the allograft itself. Immunoglobulin heavy chain gene analysis shows that lesions with no rearrangements or with a rearrangement in only a small proportion of cells are more likely to respond to reduced immunosuppression than are those with clonal rearrangement involving a high proportion of cells. However, this distinction is not absolute, and a trial of reduced immunosuppression appears to be indicated regardless of clonal status.
To refine the analysis ofgene amplification in breast cancer, the authors have developed sensitiv... more To refine the analysis ofgene amplification in breast cancer, the authors have developed sensitive methods that can be used to screen nucleic acidpreparedfrom a variety of sources, In their analysis, Southern hybridization and DNA dot-blot analysis were used to screen 49 breast cancer DNAs for Myc, Neu, and Int-2 gene amplification. The analysis detected minimal (one extra gene copy) as well as expanded (two or more extra gene copies) gene amplifications, and in addition, distinguished between gene amplification and aneuploidy as the cause of extra gene copies These quantitative methods were adapted to patient specimens routinely available in the anatomic pathology laboratory, including fresh tumor tissue, tumor nuclei discarded during estrogen receptor analysis and paraffin blocks One minimal gene amplification was found in three cases of intraductal cancer. Of25 cases of nonmetastatic invasive cancer, 28% had at least one extra Myc gene, whereas 24% had Neu, and 21% had Int-2 gene amplification. Of 21 cases of metastatic invasive cancer, 43% had Myc, 43% had Neu, and 40% had Int-2 gene amplification. Among the nonmetastatic cancers, 47% had one, 12% had two, and 4% had three amplified genes Within the metastatic cancers 48% had one, 28% had two, and 5% had three amplified genes Our data suggest relationships between tumorprogression and both incidence and size of Myc, Net; and Int-2 gene amplification. (AmJ Pathol 1991, 138:835-845) Breast cancer, the most common cause of cancer death in women, results from the complex interaction of genetic, physiologic, and environmental factors. In each case, the ability to predict the clinical outcome, determine the probability of recurrence, and make decisions on adjuvant chemotherapy or radiotherapy relies on tumor staging using several independent prognostic indicators. Those most commonly used include node status,1 steroid receptor status,2 histopathology,3 histologic grade,4 DNA ploidy, and percentage of cells in S phase.56 These characteristics predict, with a certain probability, the behavior of breast cancer. Within each group, however, there appear to be subcategories of tumor with different clinical outcomes. For example, although negative node status is correlated with a decreased probability of tumor recurrence, in fact, only 70% of women will remain disease free after 5 years.
Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) t... more Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) that results in the fusion of the retinoic acid receptor alpha (RAR alpha) gene with a transcription factor gene called PML. Several cases of APML with t(11;17) have recently been described, involving fusion of the RAR alpha gene with a new zinc finger gene named PLZF. We report here a second non-classical translocation, t(5;17), with a rearranged RAR alpha gene in a child with APML. Based on restriction endonuclease analysis, the rearrangement of RAR alpha occurred within the second intron, the common breakpoint site for t(15;17). The leukemic cells in the bone marrow aspirate were a mixture of hypergranular and hypogranular bilobed promyelocytes. Although less than 1% abnormal promyelocytes were identified after induction therapy, cytogenetics revealed persistent t(5;17). Therefore, the child was treated with all-trans-retinoic acid (ATRA). There was no disease progression, and one marrow was interpreted as remission, with confirmation by cytogenetics which failed to reveal the translocation. However, disease reoccurred shortly after completion of ATRA. This poor response to ATRA may be an additional characteristic associated with non-classical translocations in APML. The identification of a second variant translocation involving the RAR alpha gene in APML suggests yet another RAR alpha rearrangement related to neoplastic myelopoiesis.
Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R2... more Southern blot analysis with liver DNA from a unique series of recombinant (R10, R11, R16, R18, R21, and R22), congenic (Y0.1U.grc+, Y0.1U.grc+/Y0.1L.grc, and Y0.1L.grc) and inbred rats has been performed to examine the restriction fragment length polymorphisms of class I genes. After digestion with Xba I or Eco RI, the genomic DNA was resolved on agarose gels, was transferred to nitrocellulose membranes, and was hybridized with murine H-2 cDNA probes. Eighteen to 25 bands of varying intensities could be clearly resolved in any given strain. Analysis of these hybridization patterns detected restriction fragment length polymorphisms that permitted the assignment of 17 specific fragments to regions within the major histocompatibility complex: RT1.A, RT1.B/D, and the RT1.E-grc-T1 alpha region. Fragments have been identified that are specific for grc, grc+, and RT1.E, and mark the junction sites between these loci. In addition, several markers identify the region around the sites of recombination in some strains. The hybridization pattern of the R18 recombinant had a unique band that specified a point of recombination within the grc. The recombinant R11 presented a unique restriction pattern unrelated to either of the parental strains or other related strains. This result suggests that R11 arose from a recombination event(s) undetected by conventional serologic methods.
The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, anal... more The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA ...
Mature adult parenchymal hepatocytes, typically of restricted capacity to proliferate in culture,... more Mature adult parenchymal hepatocytes, typically of restricted capacity to proliferate in culture, can now enter into clonal growth under the influence of hepatocyte growth factor (scatter factor) (HGF/SF), epidermal growth factor (EGF), and transforming growth factor et (TGFo 0 in the presence of a new chemically defined medium (HGM). The expanding populations of hepatocytes lose expression of hepatocyte specific genes (albumin, cytochrome P450 IIB1), acquire expression of markers expressed by bile duct epithelium (cytokeratin 19), produce TGFot and acidic FGF and assume a very simplified morphologic phenotype by electron microscopy. A major change associated with this transition is the decrease in ratio between transcription factors C/EBPo~ and C/EBP[3, as well as the emergence in the proliferating hepatocytes of transcription factors AP1, NFKB. The liver associated transcription factors HNF1, HNF3, and HNF4 are preserved throughout this process.
Uploads
Papers by Joseph Locker