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1.
Am J Hematol ; 99(6): 1066-1076, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38497679

RESUMO

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαß+/CD19+-depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34+ positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3+αß+/CD19+ depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαß+/CD19+ depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms.


Assuntos
Anemia Aplástica , Humanos , Criança , Estudos Retrospectivos , Masculino , Feminino , Pré-Escolar , Adolescente , Anemia Aplástica/terapia , Lactente , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transtornos da Insuficiência da Medula Óssea , Transplante Haploidêntico , Depleção Linfocítica , Condicionamento Pré-Transplante/métodos , Hemoglobinúria Paroxística/terapia , Anemia de Fanconi/terapia , Anemia de Fanconi/mortalidade , Doenças da Medula Óssea/terapia , Antígenos HLA/genética , Antígenos HLA/imunologia
2.
Clin Transplant ; 38(1): e15181, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37922213

RESUMO

INTRODUCTION: The data on post-transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo-HSCT are limited to case series. The present study aimed to assess the results of PTCy-based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo-HSCT. METHODS: A retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n = 28) for the study group, and calcineurin inhibitor (CNI) ± antimetabolite (n = 30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n = 42, 66.7%) or PTCy+CNI+sirolimus (n = 12, 19%). All patients (n = 69) in the control group received ATG+CNI+antimetabolite. RESULTS: After MUD allo-HSCT, the incidences of acute GVHD grade III-IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6% vs. 35.0% and 12.7% vs. 47.1%, respectively, p < .0001). Five-year GVHD-free, relapse-free survival (GRFS) after MUD allo-HSCT was higher in the PTCy group compared to control (35.1% vs. 7.3%, p < .0001). At the same time, there was no significant difference between both groups after MSD allo-HSCT. CONCLUSIONS: In pediatric acute leukemia, PTCy-based GVHD prophylaxis for MUD allo-HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG-based approach, PTCy provides better control of GVHD in children. In pediatric allo-HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Criança , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Doença Aguda , Inibidores de Calcineurina/uso terapêutico , Antimetabólitos/uso terapêutico , Doadores não Relacionados
3.
J Clin Immunol ; 43(6): 1241-1249, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37009957

RESUMO

PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) is an established therapy for many inborn errors of immunity (IEI). The indications for HSCT have expanded over the last decade. The study aimed to collect and analyze the data on HSCT activity in IEI in Russia. METHODS: The data were collected from the Russian Primary Immunodeficiency Registry and complemented with information from five Russian pediatric transplant centers. Patients diagnosed with IEI by the age of 18 years and who received allogeneic HSCT by the end of 2020 were included. RESULTS: From 1997 to 2020, 454 patients with IEI received 514 allogeneic HSCT. The median number of HSCTs per year has risen from 3 in 1997-2009 to 60 in 2015-2020. The most common groups of IEI were immunodeficiency affecting cellular and humoral immunity (26%), combined immunodeficiency with associated/syndromic features (28%), phagocyte defects (21%), and diseases of immune dysregulation (17%). The distribution of IEI diagnosis has changed: before 2012, the majority (65%) had severe combined immunodeficiency (SCID) and hemophagocytic lymphohistiocytosis (HLH), and after 2012, only 24% had SCID and HLH. Of 513 HSCTs, 48.5% were performed from matched-unrelated, 36.5% from mismatched-related (MMRD), and 15% from matched-related donors. In 349 transplants T-cell depletion was used: 325 TCRαß/CD19+ depletion, 39 post-transplant cyclophosphamide, and 27 other. The proportion of MMRD has risen over the recent years. CONCLUSION: The practice of HSCT in IEI has been changing in Russia. Expanding indications to HSCT and SCID newborn screening implementation may necessitate additional transplant beds for IEI in Russia.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Linfo-Histiocitose Hemofagocítica , Imunodeficiência Combinada Severa , Criança , Recém-Nascido , Humanos , Adolescente , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/terapia , Receptores de Antígenos de Linfócitos T alfa-beta , Imunodeficiência Combinada Severa/terapia , Linfo-Histiocitose Hemofagocítica/diagnóstico
4.
Materials (Basel) ; 16(8)2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37110037

RESUMO

Composites with a copper matrix attract the attention of researchers due to their ability to combine high ductility, heat conductivity, and electrical conductivity of the matrix with the high hardness and strength of the reinforcing phases. In this paper, we present the results of studying the effect of thermal deformation processing of a Сu-Ti-C-B composite produced by self-propagating high-temperature synthesis (SHS) on its ability to deform plastically without failure. The composite consists of a copper matrix and reinforced particles of titanium carbide TiC (sized up to 1.0 µm) and titanium diboride TiB2 (sized up to 3.0 µm). The composite hardness is 60 HRC. Under uniaxial compression, the composite starts to deform plastically at a temperature of 700 °C and a pressure of 100 MPa. Temperatures ranging between 765 and 800 °C and an initial pressure of 150 MPa prove to be the most effective condition for composite deformation. These conditions enabled a true strain of 0.36 to be obtained without composite failure. Under higher strain, surface cracks appeared on the specimen surface. The EBSD analysis shows that dynamic recrystallization prevails at a deformation temperature of at least 765 °C; therefore, the composite can plastically deform. To increase the deformability of the composite, it is proposed to perform deformation under conditions of a favorable stress state. Based on the results of numerical modeling by the finite element method, the critical diameter of the steel shell is determined, which is sufficient for deformation of the composite with the most uniform distribution of the stress coefficient k. Composite deformation in a steel shell under a pressure of 150 MPa, at 800 °C, is experimentally implemented until a true strain of 0.53 is reached.

5.
Bone Marrow Transplant ; 58(5): 558-566, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36849806

RESUMO

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.


Assuntos
COVID-19 , Doenças Transmissíveis , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Criança , Feminino , Transplante Homólogo , Estudos Prospectivos , Medula Óssea , Teste para COVID-19 , Tosse/etiologia , COVID-19/etiologia , SARS-CoV-2 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco , Progressão da Doença , Doenças Transmissíveis/etiologia
6.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34451905

RESUMO

Chronic graft versus host disease (cGVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It significantly decreases survival and quality of life. The present study demonstrates retrospective data on extracorporeal photopheresis (ECP) in children with cGVHD. A total of 42 children with steroid-refractory cGVHD were enrolled in the study. The majority of patients had acute leukemia (n = 32, 76%). All patients received ECP as second (n = 18, 43%) or third (n = 24, 57%) line of therapy. Initial ECP schedule consisted of bimonthly regimen for two consecutive days with possibility of further tapering according to response. Any concurrent treatment administered before ECP could be continued if considered necessary. Complete response to ECP was registered in seven (17%) patients and partial response in 24 (57%). Overall response according to organ involvement was as follows: skin (n = 24, 75%), mucous membranes (n = 16, 73%), liver (n = 8, 80%), gut (n = 4, 80%), lungs (n = 2, 22%) and joints (n = 2, 67%). Five-year overall, progression-free and failure-free survival was 57%, 56% and 30%, respectively. Non-relapse mortality at 5 years was 14%. We didn't observe any clinically significant complications in children that could be attributed to the procedure. ECP remains important and safe treatment option in children with cGVHD.

7.
Transplant Cell Ther ; 27(3): 274.e1-274.e5, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781541

RESUMO

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.


Assuntos
Anemia Aplástica , Anemia de Diamond-Blackfan , Transplante de Células-Tronco Hematopoéticas , Anemia Aplástica/terapia , Anemia de Diamond-Blackfan/terapia , Medula Óssea , Criança , Humanos , Estudos Retrospectivos
8.
Oncotarget ; 6(42): 44905-26, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26636543

RESUMO

mTOR is a critical target for controlling cell cycle progression, senescence and cell death in mammalian cancer cells. Here we studied the role of mTOR-dependent autophagy in implementating the antiprolifrative effect of mTORC1-specific inhibitor rapamycin and ATP-competitive mTOR kinase inhibitor pp242. We carried out a comprehensive analysis of pp242- and rapamycin-induced autophagy in ERas tumor cells. Rapamycin exerts cytostatic effect on ERas tumor cells, thus causing a temporary and reversible cell cycle arrest, activation of non-selective autophagy not accompanied by cell death. The rapamycin-treated cells are able to continue proliferation after drug removal. The ATP-competitive mTORC1/mTORC2 kinase inhibitor pp242 is highly cytotoxic by suppressing the function of mTORC1-4EBP1 axis and mTORC1-dependent phosphorylation of mTORC1 target--ULK1-Ser757 (Atg1). In contrast to rapamycin, pp242 activates the selective autophagy targeting mitochondria (mitophagy). The pp242-induced mitophagy is accompanied by accumulation of LC3 and conversion of LC3-I form to LC3-II. However reduced degradation of p62/SQSTM indicates abnormal flux of autophagic process. According to transmission electron microscopy data, short-term pp242-treated ERas cells exhibit numerous heavily damaged mitochondria, which are included in single membrane-bound autophagic/autolysophagic vacuoles (mitophagy). Despite the lack of typical for apoptosis features, ERas-treated cells with induced mitophagy revealed the activation of caspase 3, 9 and nucleosomal DNA fragmentation. Thus, pp242 activates autophagy with suppressed later stages, leading to impaired recycling and accumulation of dysfunctional mitochondria and cell death. Better understanding of how autophagy determines the fate of a cell--survival or cell death, can help to development of new strategy for cancer therapy.


Assuntos
Proteínas E1A de Adenovirus/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Purinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas E1A de Adenovirus/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/ultraestrutura , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Transfecção
9.
Cell Cycle ; 13(9): 1424-39, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24626185

RESUMO

Cells respond to genotoxic stress by activating the DNA damage response (DDR). When injury is severe or irreparable, cells induce apoptosis or cellular senescence to prevent transmission of the lesions to the daughter cells upon cell division. Resistance to apoptosis is a hallmark of cancer that challenges the efficacy of cancer therapy. In this work, the effects of ionizing radiation on apoptosis-resistant E1A + E1B transformed cells were investigated to ascertain whether the activation of cellular senescence could provide an alternative tumor suppressor mechanism. We show that irradiated cells arrest cell cycle at G 2/M phase and resume DNA replication in the absence of cell division followed by formation of giant polyploid cells. Permanent activation of DDR signaling due to impaired DNA repair results in the induction of cellular senescence in E1A + E1B cells. However, irradiated cells bypass senescence and restore the population by dividing cells, which have near normal size and ploidy and do not express senescence markers. Reversion of senescence and appearance of proliferating cells were associated with downregulation of mTOR, activation of autophagy, mitigation of DDR signaling, and expression of stem cell markers.


Assuntos
Apoptose/fisiologia , Senescência Celular/fisiologia , Dano ao DNA , Células-Tronco/efeitos da radiação , Serina-Treonina Quinases TOR/metabolismo , Proteínas E1A de Adenovirus/genética , Proteínas E1B de Adenovirus/genética , Autofagia , Biomarcadores/metabolismo , Linhagem Celular Transformada , Proliferação de Células , Reparo do DNA , Replicação do DNA , Regulação para Baixo , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco/metabolismo , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/metabolismo
10.
Cell Cycle ; 12(24): 3841-51, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24296616

RESUMO

Primary rodent cells undergo replicative senescence, independent from telomere shortening. We have recently shown that treatment with rapamycin during passages 3-7 suppressed replicative senescence in rat embryonic fibroblasts (REFs), which otherwise occurred by 10-14 passages. Here, we further investigated rapamycin-primed cells for an extended number of passages. Rapamycin-primed cells continued to proliferate without accumulation of senescent markers. Importantly, these cells retained the ability to undergo serum starvation- and etoposide-induced cell cycle arrest. The p53/p21 pathway was functional. This indicates that rapamycin did not cause either transformation or loss of cell cycle checkpoints. We found that rapamycin activated transcription of pluripotent genes, oct-4, sox-2, nanog, as well as further upregulated telomerase (tert) gene. The rapamycin-derived cells have mostly non-rearranged, near-normal karyotype. Still, when cultivated for a higher number of passages, these cells acquired a chromosomal marker within the chromosome 3. We conclude that suppression mTORC1 activity may prevent replicative senescence without transformation of rodent cells.


Assuntos
Senescência Celular/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição SOXB1/genética , Sirolimo/farmacologia , Telomerase/genética , Animais , Autofagia , Técnicas de Cultura de Células , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Proteínas de Homeodomínio/metabolismo , Cariótipo , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/metabolismo , Ratos , Fatores de Transcrição SOXB1/metabolismo , Telomerase/metabolismo
11.
Cell Cycle ; 11(12): 2402-7, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22672902

RESUMO

The TOR (target of rapamycin) pathway is involved in aging in diverse organisms from yeast to mammals. We have previously demonstrated in human and rodent cells that mTOR converts stress-induced cell cycle arrest to irreversible senescence (geroconversion), whereas rapamycin decelerates or suppresses geroconversion during cell cycle arrest. Here, we investigated whether rapamycin can suppress replicative senescence of rodent cells. Mouse embryonic fibroblasts (MEFs) gradually acquired senescent morphology and ceased proliferation. Rapamycin decreased cellular hypertrophy, and SA-ß-Gal staining otherwise developed by 4-6 passages, but it blocked cell proliferation, masking its effects on replicative lifespan. We determined that rapamycin inhibited pS6 at 100-300 pM and inhibited proliferation with IC(50) around 30 pM. At 30 pM, rapamycin partially suppressed senescence. However, the gerosuppressive effect was balanced by the cytostatic effect, making it difficult to suppress senescence without causing quiescence. We also investigated rat embryonic fibroblasts (REFs), which exhibited markers of senescence at passage 7, yet were able to slowly proliferate until 12-14 passages. REFs grew in size, acquired a large, flat cell morphology, SA-ß-Gal staining and components of DNA damage response (DDR), in particular, γH2AX/53BP1 foci. Incubation of REFs with rapamycin (from passage 7 to passage 10) allowed REFs to overcome the replicative senescence crisis. Following rapamycin treatment and removal, a fraction of proliferating REFs gradually increased and senescent phenotype disappeared completely by passage 24.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Sirolimo/farmacologia , Animais , Proteínas Reguladoras de Apoptose , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Proteínas de Choque Térmico/metabolismo , Histonas/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Fosforilação , Ratos , Proteínas Quinases S6 Ribossômicas/metabolismo
12.
Biochimie ; 93(9): 1408-14, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21554922

RESUMO

Cyclin-dependent kinase inhibitor p21(Waf1) is known to have alternative functions associated with positive regulation of proliferation, actin cytoskeleton remodeling and suppression of apoptosis. The goal of the present study was to assess the role of p21(Waf1) in the establishment of the transformed phenotype of mouse embryo fibroblasts with stable expression of E1Aad5 and c-Ha-ras complementary oncogenes. Herein, we demonstrate that E1A/c-Ha-Ras-transformed p21(Waf1)-null fibroblasts possess some characteristic features of transformed cells, such as loss of contact inhibition, high saturation density, shortened cell cycle, inability to undergo cell-cycle arrest after DNA damage and serum deprivation, but, at the same time, they are not completely transformed in that they are unable to proliferate at clonal density, are anchorage-dependent, retain a fibroblast-like morphology with pronounced actin cytoskeleton and show reduced migration and invasion. Our data support the concept of p21(Waf1) "tumor suppressor" having alternative oncogenic functions in the cytoplasm and for the first time indicate that p21(Waf1) can be indispensable for complete oncogenic transformation.


Assuntos
Proteínas E1A de Adenovirus/metabolismo , Transformação Celular Neoplásica/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Fibroblastos/citologia , Oncogenes , Proteínas E1A de Adenovirus/genética , Animais , Apoptose , Ciclo Celular , Linhagem Celular Transformada , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/patologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Citoplasma/metabolismo , Fibroblastos/metabolismo , Genes ras , Camundongos , Transdução Genética
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