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1.
Clin Colorectal Cancer ; 15(2): 135-40, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26553578

RESUMO

BACKGROUND: The treatment of patients with metastatic colorectal cancer (mCRC) has evolved during the past 2 decades, and patient survival has increased. Consequently, patients are exposed to more chemotherapeutic agents and regimens. Little is known about therapeutic drug sequencing and the factors influencing these choices. MATERIALS AND METHODS: An observational, retrospective medical record review was conducted of patients with newly diagnosed adult mCRC from January 2002 to September 2013 identified in the McGill University-Jewish General Hospital's local tumor registry. All patients presented with mCRC (stage IV) and received ≥ 2 cycles and/or ≥ 28 days of first-line chemotherapy. The patient demographics, CRC characteristics, treatment patterns, and outcomes were recorded. The reason for changing or halting therapy was also reported. RESULTS: Of the 215 patients who underwent treatment, 74.4% received second-line, 36% third-line, and 16.3% fourth-line treatment. In total, 88% received ≥ 3 classes of cytotoxic chemotherapy and 80% received ≥ 1 biologic agent. The most common first-line treatment was FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) (47.4%) or CAPOX (capecitabine, oxaliplatin) (28.8%), and more than one half received bevacizumab (56%). Among the second- and third-line treatments, FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) was the most common (40.3% and 30.3%, respectively), and bevacizumab was the most frequently used biologic agent (48.1% and 39.2%, respectively). For fourth-line treatment and beyond, most patients participated in clinical trials (45.7%) or received panitumumab monotherapy (31.4%). Across the first 4 therapy lines, disease progression was the primary motive for discontinuation (39.5%, 53.8%, 58.2%, and 37.1%). CONCLUSION: FOLFOX was the most common first-line and FOLFIRI the most common second- and third-line mCRC therapy. Bevacizumab was the most frequently used targeted therapy across all 3 treatment lines. Therapy discontinuation was primarily due to disease progression.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Terapia de Salvação/estatística & dados numéricos , Adulto Jovem
2.
Cancer Res ; 75(20): 4351-63, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26297734

RESUMO

The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor-α (ERα)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERα, including Split Ends (SPEN), a transcriptional corepressor. Here, we demonstrate a role for SPEN in ERα-expressing breast cancers. SPEN nonsense mutations were detectable in the ERα-expressing breast cancer cell line T47D and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3% to 4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor to regulate cell proliferation, tumor growth, and survival. We also found that SPEN binds ERα in a ligand-independent manner and negatively regulates the transcription of ERα targets. Moreover, we demonstrate that SPEN overexpression sensitizes hormone receptor-positive breast cancer cells to the apoptotic effects of tamoxifen, but has no effect on responsiveness to fulvestrant. Consistent with these findings, two independent datasets revealed that high SPEN protein and RNA expression in ERα-positive breast tumors predicted favorable outcome in patients treated with tamoxifen alone. Together, our data suggest that SPEN is a novel tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ERα-positive breast cancers.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Morte Celular , Linhagem Celular Tumoral , Estudos de Coortes , Hibridização Genômica Comparativa , Receptor alfa de Estrogênio/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Humanos , Mutação , Proteínas Nucleares/genética , Prognóstico , Receptores Estrogênicos/metabolismo , Transdução de Sinais , Transcrição Genética , Proteínas Supressoras de Tumor/genética
3.
Mol Cell Biol ; 32(10): 1855-66, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22431521

RESUMO

Mutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome.


Assuntos
Endossomos/metabolismo , Lipofuscinoses Ceroides Neuronais/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Complexo de Golgi , Células HeLa , Humanos , Lisossomos/metabolismo , Ligação Proteica , Transporte Proteico , Receptor IGF Tipo 2/metabolismo , Proteínas de Transporte Vesicular/metabolismo
4.
Blood ; 116(10): 1678-84, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20522713

RESUMO

It is believed that hemopoietic stem cells (HSC), which colonize the fetal liver (FL) rapidly, expand to establish a supply of HSCs adequate for maintenance of hemopoiesis throughout life. Accordingly, FL HSCs are actively cycling as opposed to their predominantly quiescent bone marrow counterparts, suggesting that the FL microenvironment provides unique signals that support HSC proliferation and self-renewal. We now report the generation and characterization of mice with a mutant allele of Baf250a lacking exons 2 and 3. Baf250a(E2E3/E2E3) mice are viable until E19.5, but do not survive beyond birth. Most interestingly, FL HSC numbers are markedly higher in these mice than in control littermates, thus raising the possibility that Baf250a determines the HSC pool size in vivo. Limit dilution experiments indicate that the activity of Baf250a(E2E3/E2E3) HSC is equivalent to that of the wild-type counterparts. The Baf250a(E2E3/E2E3) FL-derived stroma, in contrast, exhibits a hemopoiesis-supporting potential superior to the developmentally matched controls. To our knowledge, this demonstration is the first that a mechanism operating in a cell nonautonomous manner canexpand the pool size of the fetal HSC populations.


Assuntos
Proteínas de Ligação a DNA/genética , Células-Tronco Hematopoéticas/metabolismo , Fígado/metabolismo , Mutação , Proteínas Nucleares/genética , Alelos , Animais , Western Blotting , Contagem de Células , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Proteínas de Ligação a DNA/metabolismo , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Fígado/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo
5.
Curr Opin Biotechnol ; 19(1): 19-25, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18053705

RESUMO

With the widespread use of DNA microarrays, hundreds of biomarkers are in need of validation in cohorts of well-annotated clinical samples. Tissue microarrays are emerging as the tool par excellence to rapidly perform DNA, RNA, and especially protein expression analyses on large numbers of clinical samples. Although still somewhat limited by the subjectivity of scoring methods and tissue sample representativeness, TMAs represent an increasingly validated means of understanding the clinical impact of diagnostic-related, prognostic-related, and therapy-related markers. Automated methods are being developed for TMA analysis and cell microarrays and frozen tissue TMAs have been better optimized. More and more biomarker studies are availing themselves of the high-throughput nature of TMAs, recognizing that they are becoming indispensable for rapid translation of laboratory data to the clinic.


Assuntos
Análise em Microsséries/normas , Biomarcadores , Interpretação Estatística de Dados , Humanos , Análise em Microsséries/métodos , Análise em Microsséries/estatística & dados numéricos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência com Séries de Oligonucleotídeos/normas , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Prognóstico , Análise Serial de Proteínas/métodos , Análise Serial de Proteínas/normas , Análise Serial de Proteínas/estatística & dados numéricos
6.
Blood ; 108(2): 622-9, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16469876

RESUMO

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.


Assuntos
Transformação Celular Neoplásica , Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Leucemia/etiologia , Proteínas de Neoplasias/fisiologia , Ativação Transcricional/fisiologia , Animais , Células Cultivadas , Proteína Vmw65 do Vírus do Herpes Simples/fisiologia , Histona-Lisina N-Metiltransferase , Proteínas de Homeodomínio/química , Leucemia/patologia , Camundongos , Proteína Meis1 , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Estrutura Terciária de Proteína , Transdução Genética
7.
Blood ; 99(1): 121-9, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11756161

RESUMO

Cytogenetic, genetic, and functional studies have demonstrated a direct link between deregulated Hoxa9 expression and acute myeloid leukemia (AML). Hoxa9 overexpression in mouse bone marrow cells invariably leads to AML within 3 to 10 months, suggesting the requirement for additional genetic events prior to AML. To gain further insight into how Hoxa9 affects hematopoietic development at the preleukemic stage, we have engineered its overexpression (1) in hematopoietic stem cells using retrovirus-mediated gene transfer and generated bone marrow transplantation chimeras and (2) in lymphoid cells using transgenic mice. Compared with controls, recipients of Hoxa9-transduced cells had an about 15-fold increase in transplantable lymphomyeloid long-term repopulating cells, indicating the capacity for this oncogene to confer a growth advantage to hematopoietic stem cells. In addition, overexpression of Hoxa9 in more mature cells enhanced granulopoiesis and partially blocked B lymphopoiesis at the pre-B-cell stage but had no detectable effect on T lymphoid development. Interestingly, despite specifically directing high expression of Hoxa9 in T and B lymphoid lineages, none of the Hoxa9 transgenic mice developed lymphoid malignancies for the observation period of more than 18 months.


Assuntos
Células da Medula Óssea/metabolismo , Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Animais , Linfócitos B/patologia , Células da Medula Óssea/patologia , Contagem de Células , Divisão Celular , Regulação da Expressão Gênica , Granulócitos , Hematopoese , Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Retroviridae/genética , Linfócitos T/patologia , Transfecção , Quimeras de Transplante
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